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How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

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Immunity Crisis

Have you ever wondered WHY you get sick from different things, sometimes seemingly for no reason? Haven't you ever wished that you could find some way to stop yourself from getting sick and stay healthy all the time? Well, that might be more possible than you thought at first! Your immune system is an odd system, that many scientists are still struggling to understand. However, there have been some amazing breakthroughs! Once you get access to this detailed and helpful book, you will be able to find REAL and Applicable ways to improve your immune system and keep yourself from getting sick all of the time. This book teaches you everything that you never learned about your immune system Start learning what you can Really do to improve your immune system's health and keep your body healthier for longer! It's not hard at all Get started today!

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Properties and Overview of Immune Responses

INNATE AND ADAPTIVE IMMUNITY, 2 TYPES OF ADAPTIVE IMMUNE RESPONSES, 3 CARDINAL FEATURES OF ADAPTIVE IMMUNE RESPONSES, 6 CELLULAR COMPONENTS OF THE ADAPTIVE IMMUNE SYSTEM, 8 CYTOKINES, SOLUBLE MEDIATORS OF THE IMMUNE SYSTEM, 8 OVERVIEW OF IMMUNE RESPONSES TO MICROBES, 10 The Early Innate Immune Response to Microbes, 10 The Adaptive Immune Response, 10 The term immunity is derived from the Latin word immu-nitas, which referred to the protection from legal prosecution offered to Roman senators during their tenures in office. Historically, immunity meant protection from disease and, more specifically, infectious disease. The cells and molecules responsible for immunity constitute the immune system, and their collective and coordinated response to the introduction of foreign substances is called the immune response. The physiologic function of the immune system is defense against infectious microbes. However, even noninfectious foreign substances can elicit immune responses. Furthermore,...

Types Of Adaptive Immune Responses

There are two types of adaptive immune responses, called humoral immunity and cell-mediated immunity, that are FIGURE 1-2 Types of adaptive immunity. In humoral immunity, B lymphocytes secrete antibodies that prevent infections by and eliminate extracellular microbes. In cell-mediated immunity, helper T lymphocytes activate macrophages to kill phagocytosed microbes or cytotoxic T lymphocytes directly destroy infected cells.

Cellular Components Of The Adaptive Immune System

The principal cells of the immune system are lymphocytes, antigen-presenting cells, and effector cells. Lymphocytes are the cells that specifically recognize and respond to foreign antigens and are therefore the mediators of humoral and cellular immunity. There are distinct subpopulations of lymphocytes that differ in how they recognize antigens and in their functions (Fig. 1-5). B lymphocytes are the only cells capable of producing antibodies. They recognize extracellular (including cell surface) antigens and differentiate into antibody-secreting plasma cells, thus functioning as the mediators of humoral immunity. T lymphocytes, the cells of cell-mediated immunity, recognize the antigens of intracellular microbes and either help phagocytes to destroy these microbes or directly kill the infected cells. T cells do not produce antibody molecules. Their antigen receptors are membrane molecules distinct from but structurally related to antibodies (see Chapter 7). T lymphocytes have a...

Overview Of Immune Responses To Microbes

Now that we have introduced the major components of the immune system and their properties, it is useful to summarize the principles of immune responses to different types of microbes. Such a summary will be a foundation for the topics that are discussed throughout the book. The immune system has to combat many and diverse microbes. As we shall see shortly, immune responses to all infectious pathogens share some common features, and responses to different classes of these microbes may also have unique features. How these adaptive immune reactions are initiated, orchestrated, and controlled are the fundamental questions of immunology. We start with a discussion of the innate immune response.

The Early Innate Immune Response to Microbes

The innate immune system blocks the entry of microbes and eliminates or limits the growth of many microbes that are able to colonize tissues. The main sites of interaction between individuals and their environment the skin and gastrointestinal and respiratory tracts are lined by continuous epithelia, which serve as barriers to prevent the entry of microbes from the external environment. If microbes successfully breach the epithelial barriers, they encounter the cells of innate immunity. The cellular innate immune response to microbes consists of two main types of reactions inflammation and antiviral defense. Inflammation is the process of recruitment of leukocytes and plasma proteins from the blood, their accumulation in tissues, and their activation to destroy the microbes. Many of these reactions involve cytokines, which are produced by dendritic cells, macrophages, and other types of cells during innate immune reactions. The major leukocytes that are recruited in inflammation are...

The Adaptive Immune Response

The adaptive immune system uses three main strategies to combat most microbes. All adaptive immune responses develop in steps, each of which corresponds to particular reactions of lymphocytes (Fig. 1-6). We start this overview of adaptive immunity with the first step, which is the recognition of antigens. may also be small, special mechanisms are needed to capture microbes, to concentrate their antigens in the correct location, and to deliver the antigens to specific lymphocytes. Dendritic cells are the APCs that display microbial peptides to naive CD4+ and CD8+ T lymphocytes and initiate adaptive immune responses to protein antigens. Dendritic cells located in epithelia and connective tissues capture microbes, digest their proteins into peptides, and express on their surface peptides bound to MHC molecules, the specialized peptide display molecules of the adaptive immune system. Dendritic cells carry their antigenic cargo to draining lymph nodes and take up residence in the same...

Cells Of The Immune System

The cells that serve specialized roles in innate and adaptive immune responses are phagocytes, dendritic cells, antigen-specific lymphocytes, and various other leukocytes that function to eliminate antigens. The cells of the immune system were introduced briefly in Chapter 1. Here we describe the morphology and functional characteristics of phagocytes, other leukocytes, APCs, and lymphocytes and how these cells are organized in lymphoid tissues. The numbers of some of these cell types in the blood are listed in Table 2-1. Although most of these cells are found in the blood, their responses to microbes are usually localized to tissues and are generally not reflected in changes in the total numbers of circulating leukocytes.

Pharmacokinetics and immune response

Antibodies to gemtuzumab ozogamicin were measured in all of the clinical trials. In the phase I study, one patient developed antibody to the calicheam-icin-linker complex after the third dose and a second patient developed antibodies to the calicheamicin-linker during the second dose of a second course of gemtuzumab ozogamicin. In the phase II studies, no humoral immune response to gemtuzumab ozogamicin occurred in the 188 evaluable patients.

Subversion and Coercion The Art of Redirecting Tumor Immune Surveillance

Abstract Tumor immune surveillance and CD8+ T cells in particular appear capable of recognizing the antigenic properties of human tumor cells. However, those antigen specific T cells are often excluded from tumor tissue or are functionally limited in their cytotoxic capacity. Instead, the immune response provides proinflammatory cytokines and proteases promoting tumor growth and progression while subverting cytotoxic anti-tumor immunity. The cytokines and the inflammatory mechanisms driving tumor associated inflammation resemble tissue remodeling processes during wound healing and chronic inflammatory diseases. In this chapter, we summarize the current knowledge of how inflammatory cytokines may promote the deviation of anti-tumor immunity toward a tumor promoting, noncy-totoxic inflammation. G. Dranoff (ed.), Cancer Immunology and Immunotherapy, 25

Recognition Of Microbes And Damaged Self By The Innate Immune System

The specificities of innate immune recognition have evolved to combat microbes and are different from the specificities of the adaptive immune system in several respects (Table 4-1). The innate immune system recognizes molecular structures that are characteristic of microbial pathogens but not mammalian cells. The microbial substances that stimulate innate immunity are called pathogen-associated molecular patterns (PAMPs). Different classes of microbes (e.g., viruses, gram-negative bacteria, grampositive bacteria, fungi) express different PAMPs. These structures include nucleic acids that are unique to microbes, such as double-stranded RNA found in replicating viruses and unmethylated CpG DNA sequences found in bacteria features of proteins that are found in microbes, such as initiation by N-formylmethionine, which is typical of bacterial proteins and complex lipids and carbohydrates that are synthesized by microbes but not by mammalian cells, such as lipopolysaccharide (LPS) in...

Cellular Components Of The Innate Immune System

The cells of the innate immune system perform several functions that are essential for defense against microorganisms. Some cells form physical barriers that impede infections. Several cell types express the various pattern recognition receptors we have just discussed, and after recognizing PAMPs and DAMPs, they respond by producing inflammatory cytokines and antiviral proteins and by killing microbes or infected cells. In addition, some of the cells of innate immunity are critical for stimulating subsequent adaptive immune responses. We will now discuss the cell types that perform these functions.

Immune Response To

It is often said that the mechanism of action of BCG is unknown, but without an effective cellular immune response BCG does not inhibit tumor growth. In fact, a great deal is known about the immune response to BCG. As a complex living organism, the responses induced to BCG infection are broad and highly varied. BCG attaches to bladder tumor cells and urothelial cells by means of specific receptors, fibronectin and integrin 45,46 . Internalization of BCG is correlated with immune response and sensitivity to BCG. In vitro studies suggest that poorly differentiated cell lines, unlike well-differentiated lines, internalize BCG and are sensitive to BCG 47 . Clinical studies similarly suggest that low-grade tumors are relatively less sensitive to BCG 48 . BCG antigens are expressed on the surface of tumor cells, and MHC class II antigen expression is upregulated 49-51 . BCG is a nonspecific stimulant to the reticuloendothelial system and induces a local inflammatory response with the...

STAT3 A Target to Enhance Antitumor Immune Response

Dranoff (ed.), Cancer Immunology and Immunotherapy, 41 Abstract Signal transducer and activator of transcription 3 (Stat3) has emerged as a critical regulator for tumor-associated inflammation. Activation of Stat3 negatively regulates the Thl-type immune response and promotes expansion of myeloid-derived suppressor cells (MDSCs) and regulatory T-cell functions in the tumor microenvironment. Mounting evidence suggests that Stat3 and related pathways may serve as a target for changing the tumor immunologic microenvironment to benefit cancer immunotherapies. Many recent studies support the use of certain tyrosine kinase inhibitors, through inhibition of Stat3, in decreasing immunosuppression in the tumor microenvironment. Other potential therapeutic avenues include the use of targeted delivery of Stat3 siRNA into immune cells. Here, we describe the role of Stat3 in regulating the immunologic properties of tumors as a background for Stat3-based...

Metabolic Effects of Immune Response Mediators

When the organism is stressed by an injury, infection or illness, the daily swing of insulin- and glucagon-mediated metabolic shifts between fed and fasted states is disturbed. The organ system charged with recognising and responding to an injury is the immune system, which has the capacity to radically change body protein and energy metabolism and thus body composition 5 . The antigen-presenting cell (APC) of the immune system is typically a macrophage, tissue monocyte or skin dendritic cell. The APC contacts an antigen, phagocytoses it, processes an antigenic determinant, and brings it to its surface in an HLA-restricted manner in order to trigger an immune response. This immune response requires both the presence of a specific epitope from the antigen and the elaboration of one or more non-specific signals, chiefly via secretion of the cytokine IL-1. IL-1 secretion triggers activation of T cells and other portions of the immune response. The subsequent APC-initiated signals include...

Stat3Mediated Immune Suppression 21 Inhibition of the Thl Immune Response

The first study demonstrating Stat3 as a negative regulator of Thl-type immune responses reported that ablation of Stat3 in neutrophils and macrophages increased production of Thl cytokines, such as IFNg, TNFa, and IL-1, after LPS stimulation (Takeda et al. 1999). A role of Stat3 in inhibiting immunostimu-latory Thl cytokines and other mediators in tumors was subsequently shown (Nabarro et al. 2005 Sumimoto et al. 2006 Wang et al. 2004). Because of Stat3 is a critical oncogenic molecule, a direct link between oncogenesis and tumor immune evasion was thus substantiated. Further studies revealed that Stat3 activation in immune cells is in part mediated by tumor-derived factors, such as VEGF, IL-10, and IL-6 (Sumimoto et al. 2006 Wang et al. 2004). Conversely, Stat3 ablation in immune cells leads to induction of Thl mediators involved in both innate and T-cell-mediated adaptive immunity. In turn, this causes increased anti-tumor activity of immune cells that impedes tumor progression...

Tumor Necrosis Family Apoptosis and Immune Surveillance

Apoptotic tumor-infiltrating lymphocytes (TIL).199,201 The ability of tumor-expressed FasL to suppress the immune response has been extensively verified experimentally.202 In addition, increased FasL expression accompanies disease progression in colorectal carcinoma and has been significantly associated with the probability of breast and cervical carcinomas to form lymph node metastasis.197,203 In an analogous fashion, upregulation of TRAIL has been observed in hepatocellular carcinoma, and its expression in gastric carcinoma is correlated with metastasis and the presence of

Leptin and Immune Function

Initially described as an antiobesity hormone, lep-tin has subsequently been shown also to influence haematopoiesis, thermogenesis, reproduction, angiogenesis and immune response. Circulating levels of this adipocyte-derived hormone are proportional to fat mass, but may be lowered rapidly by fasting. Impaired cell-mediated immunity and reduced levels of leptin are both features of low body weight in humans. There is enough reported evidence to suggest a role for leptin in linking nutritional status to cognate cellular immune function, and to provide a molecular mechanism to account for the immune dysfunction observed in starvation 44 . The decrease in leptin plasma concentrations during food deprivation leads to impaired immune function, whereas the restoration of leptin to normal levels by feeding after starvation is sufficient to ameliorate the immune response and is followed by a significant increase in Th1 activity, supporting further the role of lep-tin as a nutritional sensor...

Other Cytokines Produced During Innate Immune Responses

In addition to TNF, IL-1, and IL-6, dendritic cells and macrophages activated by PAMPs and DAMPs produce other cytokines that have important roles in innate immune responses (see Table 4-4). Some of the main features of these cytokines and their roles in innate immunity are discussed in this section. These cytokines also have important effects in stimulating adaptive immunity, as we will discuss later in this chapter and in more detail in Chapters 9 and 10. The receptor for IL-12 (IL-12R) is a heterodimer composed of P1 and P2 subunits, both of which are members of the type I cytokine receptor family. Both chains are required for high-affinity binding of IL-12 and for signaling, which activates the transcription factor STAT4. Expression of the P2 chain of the IL-12 receptor is itself enhanced by IFN-y, whose production is stimulated by IL-12, and this is another example of a positive amplification loop in immune responses. Studies with gene knockout mice and the phenotype of rare...

Influence of Nutritional Status on Immune Response

A survey of the literature shows that most nutritional deficits lead to suppressed immune responses. This is not surprising, since anabolic and catabolic pathways in the immune system require the same sort of building blocks and energy sources as other physiological activities. Caloric restriction is another area of emerging interest, with important implications for human health. In general, moderate caloric restriction appears to have beneficial effects on longevity and disease resistance. However, these trends and generalisations must be approached with some caution 62 .

Selfantigens For Immunotherapy Of

Proteinase 3, a serine protease stored in azurophilic granules, is a differentiation antigen associated with myeloid granule formation and is overexpressed in a variety of myeloid leukemia types, including CML cells. Therefore, it has been considered a possible target antigen for specific active immunotherapy. CTLs specific for an HLA-A2.1-restricted nonpolymorphic peptide (PR1) derived from proteinase 3 have shown HLA-restricted cytotoxicity, and selectively inhibit CML progenitors over normal marrow cells.67 68 PR1-specific T cells have been identified by HLA-A2-PR1 peptide HLA tetramers in a majority of CML patients who responded to either IFN-a or allogeneic stem cell transplantation.69 PRl-specific CTLs isolated from these patients were capable of lysing fresh leukemia cells. Follow-up studies in patients with relapsed CML revealed a selective loss of the high-avidity PR1-CTL population by tetramer determination. A functional PRl-specific CTL immune response was also lost prior...

Principles of the Immune System

The immune system is the organ that fights infection by pathogenic organisms such as bacteria, viruses, protozoa, or even worms. It also protects against toxins, for instance those from bacteria. The defense system of invertebrates against pathogens is simple, relying mostly on macrophages and bactericidal substances. In vertebrates, however, highly specialized cells have evolved, capable of producing cells with receptors of high binding specifity against literally billions of molecules, be they peptides, lipids, sugars, metal salts, or other chemical classes. The vertebrate immune system is a unique organ in that it is composed of a multitude of cells, molecules, and organized tissue structures, found distributed over the entire body as its field of action (Table 1). Immune cells are mobile and capable of communicating directly with each other by cell surface structures, or over considerable distances via lymphokines and chemokines. Close cell-cell contact is often necessary to...

Chemotherapy Plus Active Immunotherapy

Some recent clinical studies provide yet another somewhat surprising perspective on how active immunotherapy might synergize with chemotherapy. With the caveat associated with retrospective analysis, 25 patients with glio-blastoma multiforme were vaccinated with DCs loaded with autologous tumor HLA-eluted peptides or tumor lysate (78). Thirteen of these patients went on to receive subsequent chemotherapy. An additional 13 nonvaccinated patients analyzed in this study also received chemotherapy. Of the vaccine plus chemotherapy-treated patients, 42 were two-year survivors while only 8 of patients treated with chemotherapy alone or vaccine alone survived this long. It is hypothesized that infiltrating CD8+ T cells may upregulate markers on the tumor (e.g., Fas), which render cells more susceptible to chemotherapeutic drugs that kill targets via induction of apoptosis.

Acquired Immune Deficiency Syndrome

Primary non-Hodgkin lymphoma (NHL) of the brain has occurred consistently as an acquired immune deficiency syndrome (AIDS)-defining illness in around 0.5 of AIDS patients 39 . A population-based study in Italy during the period 1985-1994 found that 22 out of 40 (55 ) cases of brain NHL at age 15-49 years occurred in people with AIDS, giving a standardized incidence ratio of over 2,000 40 . In an analysis of cancer incidence among nearly 48,000 human immunodeficiency virus (HIV)-seropositive people from North America, Europe, and Australia, the adjusted annual incidence of cerebral NHL fell significantly from 1.7 per 1,000 during the period 1992-1996, to 0.7 per 1,000 during the years 1997-1999, indicating a

Nonspecific Immune Modulation Plus Active Immunotherapy

Another trend emerging in the practice of active immunotherapy with personalized (and nonpersonalized) cancer vaccines is their use in combination with other nonspecific immunomodulatory agents. Again, these combination approaches are likely to be necessary in any setting more advanced than minimal residual disease (83). Moreover, if the nonspecific agents prove to be well tolerated with minimal toxicity, there may be incentive to employ them even in the setting of minimal disease burden to further decrease the likelihood of disease recurrence. The nonspecific agents include antibodies against CTLA-4 that are designed to prevent effector T cell downregulation and a large number of agents that address the problem of immune suppression in tumor-bearing hosts. With emphases on pre-clinical testing, these various agents are discussed in turn below. Cyclophosphamide has been a mainstay of cancer therapy and is typically used in combination with other chemotherapeutic drugs. In these...

Impairment of the Immune System

Immunodepression is a key feature of patients with CACS. The severity of immunodepression is related to stage of disease and severity of cachexia. Several of our studies demonstrated that the immune system of cancer patients shows an impaired blastic response to mitogens. The reduced proliferative response to mitogens (such as PHA, anti-CD3 antibody and recombinant IL-2) of peripheral blood mononuclear cells (PBMCs) isolated from cancer patients has to be considered as an index of more complex functional alterations. In normal circumstances (PBMCs isolated from healthy individuals) the above-cited mitogens induce cell cascade events similar to those occurring after antigen activation production and release of cytokines, synthesis and release of IL-2 from CD4+ cells and surface expression of IL-2 receptor by lymphocytes. Thus, the blastic response depends on the amount of cytokines, IL-2 receptor expression and interaction between IL-2 and its receptor 55 . Patients with advanced...

Suppressive Effects of CD4CD25 Regulatory T Cells on the Innate Immune Response

Importantly, the regulation of APC function by CD4+CD25+ Tregs might also occur in vivo. It was shown recently that transfer of antigen-pulsed mature DCs into mice that were depleted for CD4+CD25+ Tregs resulted in higher Th1 responses compared to nondepleted mice 88 . A different study by Maloy et al. using a T cell-independent mouse model for intestinal inflammation demonstrated that transfer of CD4+CD25+ Tregs resulted in reduced activation and recruitment of neutrophils, monocytes macrophages, DCs and NK cells, which was partly mediated by IL-10 and TGF-3 89 . Together these data indicate that both the adaptive and the innate immune system are subject to CD4+CD25+ Treg-mediated suppression. The ability of Tregs to inhibit the function of many different cell types helps to explain the observations that CD4+CD25+ Tregs are efficient in suppressing many immune-mediated diseases including autoimmunity 12, 90, 91 , transplant rejection 92 , tumor immunity 93-95 , allergy 96 and...

Modification of Treg Biology as Cancer Immunotherapy 61 The Cellular Microenvironment

Tregs remain one of the major obstacles to successful cancer immunotherapy. Other leukocytes, including myeloid derived suppressor cells (MDSC), tumor associated macrophages (TAMs), type I II NKT cells, mast cells, B cells, and subsets of DC have also been implicated in promoting tumor progression. In this section, we will first discuss how Tregs and other immunomodulatory cells are associated in tumormediated suppression before discussing clinical strategies to attenuate Treg function to improve current immunotherapeutic strategies. intratumoral and systemic Tregs are found, along with high intratumoral and systemic IL-10, and moderate levels of intratumoral TGF-p (Elpek et al. 2007). Additional studies reveal that A20 cells also express PD-L1 and secrete IL-10 and immunomodulatory IDO all of which contribute to the generation and function of iTregs (Baban et al. 2009). Importantly, this study also showed by depletion experiments that Tregs played a dominant role in early tumor...

Concepts and Ways to Amplify the Antitumor Immune Response

Abstract In this chapter, a detailed description of how the innate and adaptive immune responses interact with malignant cells is presented. In addition, we discuss how developing tumors establish themselves, and how they benefit on one hand and organize their defense against the immune system on the other hand. New data from three tumor model systems in mice are discussed in particular, the intricate interactions between the immune cells and the tumor cells are highlighted. With the present data and knowledge, we conclude that a first prerequisite for the G. Dranoff (ed.), Cancer Immunology and Immunotherapy, 97 combat against tumors is the activation of the innate immune system via external danger signals or damage signals and internal danger signals. The second prerequisite for efficient tumor cell eradication is combined therapeutic approaches of physical, chemical, pharmacological, and immunological origin. Finally, we propose new ways for further investigation of the...

Reactive Nitrogen Intermediateinduced Parp Activation In The Immune System

As this chapter focuses on the role of PARP in the reactive nitrogen intermediate (RNI)-induced cytotoxicity, a relatively detailed outline of the role of RNI in the immune system is given. The possible effect of PARP on the formation of T and B lymphocyte repertoire and some aspects of PARP as a transcriptional regulator of immune functions are also discussed. In summary, these results show that activation of the immune system is accompanied by iNOS expression and peroxynitrite formation due to cross-activation of T lymphocytes and monocytes macrophages. According to this scenario (a similar one to that is depicted in Figure 7.10), activation of T cells by anti-CD3 or superantigens such as SEB results in cytokine (INFy) production by activated T cells. INFy in turn activates monocytes macrophages dendritic cells to express iNOS and to switch on the oxidative burst, fueling peroxynitrite production from both sides (NO and superoxide). Peroxynitrite produced by activated monocytes...

Antibody Feedback Regulation Of Humoral Immune Responses By Fc Receptors

Receptors on antigen-specific B cells (Fig. 11-21). This is the explanation for a phenomenon called antibody feedback, which refers to the downregulation of antibody production by secreted IgG antibodies. IgG antibodies inhibit B cell activation by forming complexes with the antigen, and these complexes bind to a B cell receptor for the Fc portions of the IgG, called the Fcy receptor II (FcyRIIB, or CD32). (The biology of Fc receptors is discussed in Chapter 12.) As discussed in Chapter 7, the cytoplasmic tail of FcyRIIB contains a six-amino acid (isoleucine-x-tyrosine-x-x-leucine) motif shared by other receptors in the immune system that mediate negative signals, including inhibitory receptors on NK cells. By analogy to ITAMs, this inhibitory motif is called an immunoreceptor tyrosine-based inhibition motif (ITIM). When the Fcy receptor of B cells is engaged, the ITIM on the cytosolic tail of the receptor is phosphory-lated on tyrosine residues, and it forms a docking site for the...

AIDS is a Disease of the Immune System

The increased susceptibility to illness in these men resulted from a decline in their immune-system function. As is discussed in detail in Chapter 11, the role of the immune system is to maintain the integrity of the body. The cells of the immune system constantly patrol the tissues and organs of the body for anything that is not clearly produced by the body that is, anything that is non-self. Upon encountering non-self entities, the immune system acts to eliminate it this is known as an immune response. A non-self substance, object, or organism typically has a unique chemical signature that causes an immune response. This signature is called an antigen. Immune-system cells called lymphocytes respond to antigens. Lymphocytes carry proteins on their cell membranes, called receptors, which recognize and are attracted to particular antigens (Figure 9.1). The binding of an antigen to an antigen receptor on a lymphocyte starts the immune response. Our bodies can make 100 trillion to 1...

Adoptive Immunotherapy

Khatri et al. demonstrated the striking temporal relationship between the endogenous expansion of a TCR Vfi-restricted, CD3+CD8+ population of MHC class I-restricted CTL and the regression of a monoclonal PTLD in a HSCT recipient. Unfortunately, the delay in recovery of such immune surveillance against transformed EBV-positive B cells results in the development of potentially fatal PTLD. T-cell immunotherapy has been reported to be efficacious in the management of PTLD in this setting.39 O'Reilly et al. reported on 18 HSCT patients with EBV-PTLD who were treated with nonspecific donor lymphocyte infusions (DLI) 16 of 18 patients experienced eradication of PTLD. However, only 10 survived in sustained CR and 3 patients died of GVHD, a major side effect of DLI.50 Attempts have been made to improve the efficacy and reduce the risk of GVHD by administering EBV-spe-cific CTLs.51 Rooney et al. detailed the outcome of 39 recipients of matched unrelated donor partially mismatched related donor...

Adaptive Immunity in the Gastrointestinal Tract

The adaptive immune system in the gastrointestinal tract has features that are distinct from adaptive immune functions in other organ systems. The major form of adaptive immunity in the gut is humoral immunity directed at microbes in the lumen, which prevents commensals and pathogens from colonizing and invading through the mucosal epithelial barrier. This function is mediated by dimeric IgA antibodies that are secreted into the lumen of the gut or, in the case of breast-feeding infants, IgA that is secreted into colostrum and mother's milk and ingested by the infant. Significant quantities of IgG and IgM antibodies are also present in the gut lumen and contribute to humoral immunity in this location. The dominant protective cell-mediated immune response consists of TH17 effector cells. The adaptive immune system in the gut must continuously suppress potential immune responses to food antigens and commensal microbial antigens to prevent

The Cutaneous Immune System

The skin includes two main layers, the outer epidermis composed mainly of epithelial cells and, separated by a thin basement membrane, the underlying dermis composed of connective tissue and specialized adnexal structures such as hair follicles and sweat glands. Within both of these layers, a variety of different cell types and their products, composing the cutaneous immune system (Fig. 13-9), provide physical barrier and active immune defense functions against microbes. The skin of an adult is about 2 m2 in area and is the second largest barrier of the body against environmental microbes and other foreign materials. Nonetheless, given its outermost location, the skin is normally colonized by many microbes and is frequently breached by trauma and burns. Therefore, the skin is a common portal of entry of a wide variety of microbes and other foreign substances and is the site of many immune responses.

Impaired Immune Function Associated With Malignant Gliomas

It has been demonstrated that patients diagnosed with GBM present with significant impaired immune function (23,24). The induction of potent and sustained antitumor immune responses in the immunocompetent host is extremely challenging due to intrinsic tumor tolerance mechanisms (5a). Studies have described tumor cells' ability to evade immune attack by using various strategies. Gomez and Kruse describe the various mechanisms of malignant glioma immune resistance and sources of immunosuppression (5a). We discuss their findings below.

An Environmental Factor Can Preferentially Costimulate Autoimmune Response and Disease in Neonatal Mice

The neonatal but not adult response to self-Ags is also uniquely modified by the environmental pinworm infection (Agersborg et al. 2001). Without pin-worm infection, neonatal injection of pZP3 in water did not elicit an immune response. However, when infected with the rodent pinworm Syphacia obve-lata, neonatal mice injected with self-pZP3 in water developed strong ZP3-specific Th2 responses and severe eosinophilic AOD, followed by a strong pathogenic Th2 memory when challenged with pZP3 in CFA. In contrast, pinworm-infected adults mounted a pathogenic Th1 response when immunized with pZP3 in CFA. Therefore, pinworm infection dramatically promotes a strong autoimmune Th2 pathogenic response however, the effect only impacts neonatal mice.

Active Specific Immunotherapy Vaccines

As a general concept a therapeutic antitumor vaccine refers to the subcutaneous administration of a tumor-specific antigen with the intent to induce an active and possibly long-lasting humoral and or cellular immune response able to eliminate tumor cells harboring the putative antigen. Many years of disappointing clinical results with antitumor vaccines against different types of advanced solid tumors has taught tumor immunologists that the best setting for effective immunotherapy is the situation of MRD (10). In CML, like in other tumors, the ideal vaccine candidate would be an antigen expressed only in tumor cells, but common to all patients. It should be highly immunogenic and should be essential for tumor cell survival, and thus not susceptible to mutation or deletion. Several CML antigens have been identified as potential targets for an anti-CML vaccine strategy (Fig. 1), and different approaches at different stages of development are now under evaluation for CML patients (Table...

Immunotherapy Approaches

Cancer immunotherapy is part of a growing research trend in attempting to harness the cytolytic function of immune cells against cancer. Difficulties in tumor immunotherapy arise due to the evasiveness of the cancer. Tumors are able to hide from NK cell immune surveillance by downregulating or shedding ligands of activating NK receptors. In addition, activating NK receptors succumb to the control of tumor cells and their released factors. Therefore, multiple studies have focused on the biological processes of tumor evasion to create therapies to counteract the tumor's progression.

Dcbased Immunotherapy Results Of Phase I And Ii Clinical Trials

It is very difficult to therapeutically target every remaining individual tumor cell due to the disseminated nature of GBM. It is extremely important to eliminate all intracranial neoplastic foci left behind after surgical resection of the primary tumor (4). The use of the immune system to target residual tumor cells is one such strategy to enhance visibility of tumor cells to the immune system. In a phase I study by Kikuchi and colleagues (44), eight patients were treated with a series of three to seven intradermal vaccinations with DC-autologous glioma fusion cells. Glioma fusion cells were used as a strategy to improve DC-mediated TAA presentation by enhancing tumor cell-DC interaction. Although the ability to induce a tumor-specific immune response was demonstrated, only slight temporary responses to therapy were detected in two patients who had tumor progression on follow-up neuroimaging studies. A direct injection of DCs into tumor is a novel immunotherapeutic approach. DCs...

Innate and Adaptive Immunity to Fungi

Cell-mediated immunity is the major mechanism of adaptive immunity against fungal infections. Histoplasma capsulatum, a facultative intracellular parasite that lives in macrophages, is eliminated by the same cellular mechanisms that are effective against intracellular bacteria. CD4+ and CD8+ T cells cooperate to eliminate the yeast forms of C. neoformans, which tend to colonize the lungs and brain in immunodeficient hosts. Many extracellular fungi elicit strong TH17 responses, which are driven in part by the activation of dendritic cells by fungal glucans binding to dectin-1, a receptor for this fungal polysac-charide, and this results in the production of TH17-inducing cytokines (IL-6, IL-23) from the dendritic cells (see Chapter 9). The TH17 cells stimulate inflammation, and the recruited neutrophils and monocytes destroy the fungi. Candida infections often start at mucosal surfaces, and cell-mediated immunity is believed to prevent spread of the fungi into tissues. TH1 responses...

Adaptive Immunity to Viruses

Adaptive immunity against viral infections is mediated by antibodies, which block virus binding and entry into In latent infections, viral DNA persists in host cells but the virus does not replicate or kill infected cells. Latency is often a state of balance between infection and the immune response. CTLs are generated in response to the virus that can control the infection but not eradicate it. As a result, the virus persists in infected cells, sometimes for the life of the individual. Any deficiency in the host immune response can result in reactivation of the latent infection, with expression of viral genes that are responsible for cytopathic effects and for spread of the virus. These cytopathic effects may include lysis of infected cells or uncontrolled proliferation of the cells. Such latent infections are common with Epstein-Barr virus and several other DNA viruses of the herpesvirus family. In some viral infections, tissue injury may be caused by CTLs. An experimental model of...

Nonspecific Immunotherapy Interferon

IFN-a has been a standard therapy for CP CML for nearly two decades. The introduction of imatinib has replaced its role as first line agent, but IFN-a could play a key role in modulating a nonspecific immune-mediated effect toward MRD persisting during imatinib therapy. Several immunologic effects of IFN-a have been documented, including increased expression of adhesion molecules, and enhanced antigen presentation and generation of highly active monocyte-derived DCs (45). Nevertheless, it is still unclear as to which effect is precisely responsible for its antileukemic activity. Recently, the presence of PR3-specific CTLs has been documented in IFN-a-treated patients, but not in imatinib-treated patients. This suggests that IFN-a may enhance the induction of natural anti-PR3 CTLs, thus modulating a direct immune-mediated antitumor effect against CML cells (27). Indirect evidence of an underlying immune control of leukemic cells mediated by IFN-a is the fact that some patients maintain...

Future Directions for Idiotype Specific T Cell Immunotherapy

For 30 years, idiotype vaccination has been shown to generate a protective immune response against lymphoma and myeloma tumors, mainly in preclinical models. Future directions will focus on how to improve the effect of the T cell response The observation that over 50 cancer patients can respond to the adoptive T cell transfer has made the adoptive immunotherapy one of the most attractive strategies (Dudley et al. 2002). A previous study has demonstrated that it is feasible to transfer idiotype-specific T cells from healthy donors to recipients (Kwak et al. 1995). The transferred idiotype-specific T cells protected mice against established tumor in mouse model (Hornung et al. 1995). T cells can also be generated in large number in vitro for adoptive T cell transfer. It has been demonstrated that the success of T cell transfer will depend heavily on the quality of transferred T cells. T cells that belong to central memory (TCM) type but not terminal differentiated type (TEM) can...

Adaptive Immunity to Parasites

Different protozoa and helminths vary greatly in their structural and biochemical properties, life cycles, and pathogenic mechanisms. It is therefore not surprising that different parasites elicit distinct adaptive immune responses (Table 15-4). Some pathogenic protozoa have evolved to survive within host cells, so protective immunity against these organisms is mediated by mechanisms similar to those that eliminate intracellular bacteria and viruses. In contrast, metazoa such as helminths survive in extracellular tissues, and their elimination is often dependent on special types of antibody responses. TABLE 15-4 Immune Responses to Disease-Causing Parasites Selected examples of parasites and immune responses to them are listed. are resistant to infection with L. major, but inbred BALB c and some related strains of mice are highly susceptible and die if they are infected with large numbers of parasites. After infection, the resistant strains produce large amounts of IFN-y in response...

Modulation of CTLA4 and GITR for Cancer Immunotherapy

Ludwig Center for Cancer Immunotherapy, Immunology Program, Sloan-Kettering Institute, New Ludwig Center for Cancer Immunotherapy, Immunology Program, Sloan-Kettering Institute, New York, NY 10065, USA e-mail wolchokj mskcc.org G. Dranoff (ed.), Cancer Immunology and Immunotherapy, 211 Abstract The rational manipulation of antigen-specific T cells to reignite a tumor-specific immune response in cancer patients is a challenge for cancer immunotherapy. Targeting coinhibitory and costimulatory T cell receptors with specific antibodies in cancer patients is an emerging approach to T cell manipulation, namely immune modulation. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor family receptor (GITR) are potential targets for immune modulation through anti-CTLA-4 blocking antibodies and anti-GITR agonistic antibodies, respectively. In this review, we first discuss preclinical findings key to the understanding of the mechanisms of action of these...

There Is No Immune Response to Prions

People die from infectious diseases when their immune systems have not made enough B or T cells to fight off the infection. In some cases, infectious agents carry antigens for which no amount of DNA rearrangement can yield the proper receptor. In other cases, one group of people may be able to rearrange their DNA to produce the right receptors while others do not. This partly explains why some people do not become ill when exposed to an infectious disease, while others die from the same exposure. Substance amplifies immune response Substance amplifies immune response Figure 11.15 Cell-mediated immunity. T lymphocytes divide to produce different populations of cells (1) Memory cells carry the specific antigen receptor (2) cytotoxic T cells attack and kill cells and (3) helper T cells boost the immune response. Sometimes an infectious agent is effectively combated by the immune system, only to reemerge in a form that is newly pathogenic. Pathogens are under evolutionary pressure to...

Current Strategies For Cancer Immunotherapy

Active immunization and adoptive T cell transfer therapy are the main strategies used thus far for cancer immunotherapy. Both of these strategies are designed to overcome the deficiency in the priming of tumor antigen-specific T cells in the cancer-bearing hosts. Cancer vaccines rely on immunization of patients with antigenic peptides, proteins, or DNA expressed by the tumor directly or delivered by DC, virus, or another vehicle. Despite its relative simplicity and safety, vaccine treatments have shown very limited success 9 . Although the generation in vivo of antitumor T cells in vaccinated patients could be demonstrated by techniques such as tetramer or ELISPOT assays 10-12 , clinical responses observed from these trials were few 9 . This was consistent with the finding in murine models that the presence of even large numbers of antigen-specific T cells is insufficient to mediate tumor regression 8,13 . There are a multitude of explanations for this, including the relatively...

Effect of Intestinal Microbiota on the Immune System Preclinical Studies

There is accumulating evidence that the interaction between the intestinal micro-biota and the gut plays an important role for the postnatal development of the immune system. However, the interactions between the intestinal epithelial and immune cells and the different species of the intestinal microbiota are very complex and not fully understood. The complexity of these interactions is based on the fact that on the one hand the human defense system consists of several layers, for example, of mechanical and chemical barriers (first line of defence) as well as innate and adaptive immunity (67) all of which can be influenced by microbiota (68). In a mouse vaccination model adapted to study the effect of prebiotics, the animals were vaccinated twice with the Influvac (Orthomyxovirus influenza) vaccine (booster vaccination after 21 days). The response to the vaccination was measured at day 30 after the first vaccination. Parameters used to identify the response to vaccination were DTH...

Primeboost Strategies In Cancer Immunotherapy

Immunization has traditionally relied on repeated administration of antigen to augment the magnitude of the immune response. With the advancement in recombinant DNA technology, genetically engineered vaccines such as expression plasmids, recombinant proteins, viruses, and bacteria have become the latest modalities for vaccine development. The first such vaccine in its class, a hepatitis B virus vaccine in the form of recombinant protein produced in yeast, has been shown to be potent in providing protective efficacy in humans (43,44). While this homologous protein-based immunization is very effective for generating humoral immune responses, it is generally inefficient in inducing cell-mediated immunity important for protection against infections caused by intracellular pathogens and for cancer immunotherapy. DNA vaccines, on the other hand, have been tested in small and large animal models, and have demonstrated efficacy in inducing both humoral and cellular immunity for infectious...

Evasion Of Immune Responses By Tumors

Many cancers develop mechanisms that allow them to evade anti-tumor immune responses. These mechanisms can broadly be divided into those that are intrinsic to the tumor cells and those that are mediated by other cells (Fig. 17-5). A major focus of tumor immunology is to understand the immune evasion mechanisms of tumors, with the hope that interventions to prevent immune evasion will increase the immunogenicity of tumors and maximize the responses of the host. Experimental evidence in mouse models indicates that immune responses to tumor cells impart selective pressures that result in the survival and outgrowth of variant tumor cells with reduced immunogenicity, a process that has been called tumor editing. For example, when tumors are induced by carcinogen treatment in either immunodeficient or immunocompetent mice and the tumors are then transplanted into new immunocompetent mice, the tumors that were derived from the immunodeficient mice are more frequently rejected by the...

The Immune System and Cancer Prevention

Inulin and fructooligosaccharides modulate the response of the immune system to illness, through the stimulation of bifidobacteria and lactobacilli, and the improvement of the general microfloral balance in the colon (Watzl et al., 2005 Yasui et al., 1992). In this role, prebiotics have been shown to promote the production of macrophages, lymphocytes, and antibodies, in particular the local production of immunoglobulin A (IgA)-positive cells in the intestines and cecal mucosa (Bornet, 2001 Hosono et al., 2003 Kadooka et al., 1991 Roberfroid, 2005 Yasui et al., 1992). In addition, thriving bifidobacteria and lactobacilli populations help to strengthen the mucosa-blood barrier in the intestine lining. They do this by outcompeting pathogens for adhesion sites on the intestinal lining, producing short-chain fatty acids that nourish cells in the mucosal layer, lowering intestinal pH to levels unfavorable to pathogens, and releasing bacteriocins against pathogens (Anon., 2006 Wang and...

Immunotherapy For Tumors

The potential for treatment of cancer patients by immu-nologic approaches has held great promise for oncologists and immunologists for many years. The main reason for interest in an immunologic approach is that most current therapies for cancer rely on drugs that kill dividing cells or block cell division, and these treatments have severe effects on normal proliferating cells. As a result, the treatment of cancers causes significant morbidity and mortality. Immune responses to tumors may be specific for tumor antigens and will not injure most normal cells. Therefore, immunotherapy has the potential of being the most tumor-specific treatment that can be devised. Advances in our understanding of the immune system and in defining antigens on tumor cells have encouraged many new strategies. Immunotherapy for tumors aims to augment the weak host immune response to the tumors (active immunity) or to administer tumor-specific antibodies or T cells, a form of passive immunity. In this...

The Role Of The Immune System In Promoting Tumor Growth

Although much of the emphasis in tumor immunology has been on the role of the immune system in eradicating tumors, it is clear that the immune system may also contribute to the development of some solid tumors. In fact, chronic inflammation has long been recognized as a risk factor for development of tumors in many different tissues, especially those affected by chronic inflammatory diseases such as Barrett's esophagus, Crohn's disease, pancreatitis, and prostatitis, for example. Some cancers associated with infections are also considered to be an indirect result of the carcinogenic effects of the chronic inflammatory states that are induced by the infectious organisms. These include gastric cancer in the setting of chronic Helicobacter pylori infection and hepatocellular carcinomas associated with chronic hepatitis B and C virus infections. Although the mechanisms by which chronic inflammation can promote tumor development are not well understood, there are several possibilities,...

Current Status Of Tumor Immunotherapy

Current immunotherapy approaches include adoptive transfer of T cells, peptides, recombinant viruses, autologous or allogeneic tumor cells, and dendritic cell (DC)-based vaccines 7 . All of these strategies have shown therapeutic responses and evidence of systemic immunity in preclinical murine models and in selected patients enrolled on early-phase clinical trials 8-11 . There is emerging evidence that measurement of immune responses can be used to predict clinical responses with these agents. In studies using recombinant poxviruses expressing T cell costimula-tory molecules with or without tumor antigens, objective clinical response and disease stabilization have been associated with an increase in antigen-specific T cell precursors detected by ELISpot assay 8 . Adoptive T cell immunotherapy has shown great promise, especially after nonmyeloablative but lymphodepleting chemotherapy, with objective clinical responses in 50 of patients 12,13 . Adoptively transferred T cell clones...

LAG3 in Cancer Immunotherapy

Dranoff (ed.), Cancer Immunology and Immunotherapy, 269 cell function (Andreae et al. J Immunol 168 3874-3880, 2002). Recent preclinical studies have documented a role for LAG-3 in CD8 T cell exhaustion (Blackburn et al. Nat Immunol 10 29-37, 2009), and blockade of the LAG-3 Class II interaction using a LAG-3 Ig fusion protein is being evaluated in a number of clinical trials in cancer patients. In this review, we will first discuss the basic structural and functional biology of LAG-3, followed by a review of preclinical and clinical data pertinent to a role for LAG-3 in cancer immunotherapy.

Acquired Immune Deficiency Syndrome AIDS

Acquired immune deficiency syndrome (AIDS) refers to the final stages of infection by the human immunodeficiency virus (HIV). The earlier stages of the disease are often asymptomatic (Table 21.4). Figure 21.15. Cytomegalovirus retinitis in acquired immune deficiency syndrome (AIDS).EQ Figure 21.15. Cytomegalovirus retinitis in acquired immune deficiency syndrome (AIDS).EQ

Mathematical Models of the Immune System

The immune system has some unique features, which render it appealing for mathematical modelling Immune system models can generally be classified into continuous models, describing the immune process by sets of differential equations, and discrete models, describing the immune process as a series of interactions in discrete time steps, or utilising combinatorial methods to predict immune properties. Traditionally, the approach to modelling the immune system involved ODE (ordinary differential equations) or PDE (partial differential equation) 30 . However, in the last two decades discrete mathematical models, and most notably, the CA approach, have become increasingly popular in the theoretical immunology community. These new trends were largely due to the wide-range use of CA in modelling complex phenomena in physics, biology, finance, and, more recently, sociology 31 . Below we briefly overview models belonging to each modelling group. A more detailed review can be found in 30 . Most...

Immune Response Monitoring as Potential Tool for Therapy Guidance

MKC's cancer vaccine is an active immunotherapy aimed at inducing or augmenting tumor-specific T cells in vivo that leads to tumor regression and survival benefit. With the initiation of various vaccination trials, accurate and reliable assays for testing T-cell function is crucial for the evaluation, comparison, and further development of these approaches. The cellular immune responses have been evaluated using methods measuring cytotoxicity, proliferation, or release of cytokines in a bulk culture. However, these assays often require in vitro stimulation prior to performing them. A selection bias is automatically introduced with culturing of the effector cells, and the results subsequently obtained from these assays may not reflect in vivo T-cell function. The immune function varies among individuals, and the variation is amplified among cancer patients. It is common that patients respond to cancer immunotherapy heterogeneously. Therefore, it is important to monitor each...

The Challenge of Cancer Immunotherapy

Effective cancer immunotherapy induces the killing of tumor cells by cytotoxic T lymphocytes (CTLs), resulting in tumor regression and a survival benefit for patients. Malignant tumors are often characterized by an intense proliferative capacity, and local to systemic invasiveness (Mbeunkui and Johann 2009 Curiel and Curiel 2002), and these lethal characteristics have rendered surgical resection, radiation treatment, and chemotherapy ineffective for many cancer patients. Tumors are also replete with antigens, resulting in immune recognition and significant immune-cell infiltrates, but tumor cells create microenvironments (e.g., production of immunosuppressive cytokines) that suppress anticancer activity (Mbeunkui and Johann 2009 Curiel and Curiel 2002). The potential for the innate immune system to react specifically and systemically against local and metastatic lesions (Curiel and Curiel 2002), and to obtain memory that may prevent tumor recurrence (Klebanoff et al. 2006) has...

Healthy Subjects Primary and Secondary Immune Response to a Generic Antigen

There are several ways in which normal immune response to a generic antigen can be simulated using our model. For instance one can inhibit the production of IL-4 in the model, thus knocking-out IL-4 activity 60 . Another possibility is to force Th cells to be of class 1 only (i.e., 1 ). Here we mimic a healthy subject by using the first method, that is, we set things so that no IL-4 can be released by Th2 cells. The consequence is a bias towards the Th1 response, i.e., a normal immune response. Immune response in healthy subjects (or IL-4 knockout mice 60 ). Allergenic drug injections are scheduled to be at initiation and in day 40. No histamine is released, because mast cells are not sensitised (not shown) given that no IgEs are secreted (panel (b)). The immune response is of the Th1-type (panel (c)) since IL-4 is absent (panel (a)). Immune response in healthy subjects (or IL-4 knockout mice 60 ). Allergenic drug injections are scheduled to be at initiation and in day 40. No...

CD137CD137 Ligand in the Antiviral Immune Response and in Viral Vaccination

Immunotherapy has potential for chronic and latent viral infections. Therapeutic vaccination and adoptive T-cell transfer are the strategies that are being explored for HIV and chronic viral hepatitis. Mice lacking CD137 or CD137 ligand show defects in CD8 T cell responses against viruses (DeBenedette et al., 1999 Kwon et al, 2002 Tan et al, 1999), with no defects in antibody or CD4 T cell responses to vesicular stomatitis virus (VSV), LCMV, or influenza virus (Kwon et al., 2002 Tan et al., 1999). Studies in CD137 ligand- - mice suggest that the role of this molecule is mainly focused in the long term CTL response and in the induction and maintenance of memory in the CD8+ T cell compartment (Bukczynski et al., 2004). These features make the CD137 CD137 ligand pair a very interesting target for manipulation in antiviral immunotherapy. However, very few reports have explored this possibility.

Modification of the Immune Response

The documentation of the graft vs leukemia (GVL) effect in decreasing relapse after allogeneic transplantation and the success of donor lymphocyte infusion (DLI) in producing sustained remission after leukemic relapse are clear indicators of the power of the immune system to control leukemia. Malignant cells may evade immune surveillance through several mechanisms, including actively suppressing the immune response (171-174), alteration of the CD95 Fas system (175) and downregulation of major histocompatibility complex (MHC) class I or II expression (176). The concept of exploiting the immunologic response to provide therapy for leukemia is not new. Math in 1965 treated children with ALL in remission with vaccinations consisting of leukemic blasts and BCG, documenting prolonged DFS in 8 of 20 patients, while all 10 controls relapsed (177). Our current ability to transfer and express genes has led to myriad possibilities to manipulate the immune system as a means of therapy. Of these,...

Three Dimensional Niches That Regulate Immune Responses In Situ

As a promising alternative to cell-based approaches (e.g., DC-based vaccines and adoptive T cell transfer) for cancer immunotherapy, biomaterials may be fashioned into three-dimensional matrices that regulate immune cell trafficking and activation in situ (Huebsch and Mooney 2009). Immune mechanisms have evolved to recognize and defend against pathogenic infection, and now infection-mimicking microenvironments may be developed using synthetic ECMs and immune cell niches aimed at promoting effective immune responses to cancer antigens. Three-dimensional biomaterial constructs may be designed to support DC and T cell transplantation or recruitment for extended periods while providing a distinct activating niche, via the controlled presentation of antigens and adjuvants while DCs reside within the matrix. Vaccine nodes were developed by utilizing injectable alginate hydrogels that crosslinked in vivo into a supporting matrix containing activated DCs. These transplanted DCs produced...

Tumor Vaccines and Active Specific Immunotherapy ASI

All forms of vaccination rely on the immune system's active cooperation and support in order to provoke a targeted immune response. This is true also for tumor vaccination, which is therefore referred to as active specific immunotherapy (ASI). The thesis favored initially, namely, that the immune system distinguishes only between self and nonself, is no longer valid today (13). Obviously, the immune system recognizes tumors and develops immune responses, although these are often inefficient (48). The recognized antigens are often classic autoantigens, which therefore also occur on normal cells of the body.

Immune Responses to HIV

HIV-specific humoral and cell-mediated immune responses develop after infection but generally provide limited protection. The early response to HIV infection is, in fact, similar in many ways to the immune response to other viruses and serves to clear most of the virus present in the blood and in circulating T cells. Nonetheless, it is clear that these immune responses fail to eradicate all virus, and the infection eventually overwhelms the immune system in most individuals. Despite the poor effectiveness of immune responses to the virus, it is important to characterize them for three reasons. First, the immune responses may be detrimental to the host, for example, by stimulating the uptake of opsonized virus into uninfected cells by Fc receptor-mediated endocytosis or by eradication of CD4+ T cells expressing viral antigens by CD8+ CTLs. Second, antibodies against HIV are diagnostic markers of HIV infection that are widely used for screening purposes. Third, the design of effective...

Effect of Intestinal Microbiota on the Immune System Clinical Trials

There is increasing evidence that the interaction between the intestinal microbiota and the intestinal epithelial and immune cells plays a key role in the postnatal development of the immune system. First studies with probiotics (74) and synbio-tics (40) demonstrate effects during infancy, and studies regarding the vaccination response in the elderly (75) indicate that the prebiotics might also influence the immune system. In particular, the animal experiments with prebiotics described above allow the hypothesis that prebiotics that are able to influence the composition of the entire intestinal microbiota toward microbiota found in breastfed infants might support the development of the immune system during infancy. Clinical studies designed to prove this hypothesis should be focused on clinical outcome (incidence of infectious and allergic symptoms) and biomarkers representing the status of the immune system.

General Features Of Humoral Immune Responses

The earliest studies of adaptive immunity were devoted to analyses of serum antibodies produced in response to microbes, toxins, and model antigens. Much of our current understanding of adaptive immune responses and the cellular interactions that take place during such responses has evolved from studies of antibody production. We begin with a summary of some of the key features of B cell activation and antibody production.

Innate And Adaptive Immunity

Defense against microbes is mediated by the early reactions of innate immunity and the later responses of adaptive immunity (Fig. 1-1 and Table 1-2). Innate immunity (also called natural or native immunity) provides the early line of defense against microbes. It consists of cellular and biochemical defense mechanisms that are in place even before infection and are poised to respond rapidly to infections. These mechanisms react to microbes and to the products of injured cells, and they respond in essentially the same way to repeated infections. The principal components of innate immunity are (1) physical and chemical barriers, such as epithelia and antimicrobial chemicals produced at epithelial surfaces (2) phagocytic cells (neutrophils, macrophages), dendritic cells, and natural killer (NK) cells (3) blood proteins, including members of the complement system and other mediators of inflammation and (4) proteins called cyto-kines that regulate and coordinate many of the activities of...

Adaptive Immunity to Extracellular Bacteria

Cancer Immun System

Humoral immunity is a major protective immune response against extracellular bacteria, and it functions to block infection, to eliminate the microbes, and to neutralize their toxins (Fig. 15-1A). Antibody responses against extracellular bacteria are directed against cell wall antigens and secreted and cell-associated toxins, which may be polysaccharides or proteins. The polysaccharides are prototypic thymus-independent antigens, and humoral immunity is the principal mechanism of defense against polysaccharide-rich encapsulated bacteria. The effector mechanisms used by antibodies to combat these infections include neutralization, opsonization and phagocytosis, and activation of complement by the classical pathway (see Chapter 12). Neutralization is mediated by high-affinity IgG, IgM, and IgA isotypes, the latter mainly in the lumens of mucosal organs opsonization by some subclasses of IgG and complement activation by IgM and subclasses of IgG. FIGURE 15-1 Adaptive immune responses to...

Cancer Immune Surveillance

In the early twentieth century, Ehrlich first proposed the existence of immune surveillance for eradicating nascent transformed cells before they are clinically detected (Ehrlich, 1909). Almost 50 years later, Burnet and Thomas postulated that the control of nascent transformed cells may represent the actions of an ancient immune system, which played a critical role in preventing malignant transformation (Burnet, 1957). The idea was supported by experimental results showing strong immune-mediated rejection of transplanted tumors into mice. Although there was excellent evidence in support of the belief that immune surveillance mechanisms prevent the outgrowth of tumor cells induced by horizontally transmitted, ubiquitous, potential oncogenic viruses, there was much less evidence for immune surveillance acting against chemically induced tumors in syn-geneic mice (Klein, 1976). The use of genetically identical mice, however, generated tumor-specific protection from methylcho-lantrene...

Adaptive Immunity to Intracellular Bacteria

The major protective immune response against intracellular bacteria is T cell-mediated immunity. Individuals with deficient cell-mediated immunity, such as patients with acquired immunodeficiency syndrome (AIDS), are extremely susceptible to infections with intracellular bacteria (and viruses). The mechanisms of cell-mediated immunity were studied in the 1950s in mice, in examining protection against the intracellular bacterium L. monocytogenes. This form of immunity could be adoptively transferred to naive animals with lymphoid cells but not with serum from infected or immunized animals (see Chapter 10, Fig. 10-6). FIGURE 15-3 Innate and adaptive immunity to intracellular bacteria. The innate immune response to intracellular bacteria consists of phagocytes and NK cells, interactions among which are mediated by cytokines (IL-12 and IFN-y). The typical adaptive immune response to these microbes is cell-mediated immunity, in which T cells activate phagocytes to eliminate the microbes....

Stimulation Of Adaptive Immunity

The innate immune response provides signals that function in concert with antigen to stimulate the proliferation and differentiation of antigen-specific T and B lymphocytes. As the innate immune response is providing the initial defense against microbes, it also sets in motion the adaptive immune response. The activation of lymphocytes requires two distinct signals, the first being antigen and the second being molecules that are produced during innate immune responses to microbes or injured cells (Fig. 4-16). This idea is called the two-signal hypothesis for lymphocyte activation. The requirement for antigen (so-called signal 1) ensures that the ensuing immune response is specific. The requirement for additional stimuli triggered by innate immune reactions to microbes (signal 2) ensures that adaptive immune responses are induced when there is a dangerous infection and not when lymphocytes recognize harmless antigens, including self antigens. The molecules produced during innate immune...

Immune System

Alcoholics often have impaired immune response, placing them at risk for frequent and severe infections. Alcohol increases hepatitis C virus (HCV) replication and inhibits the anti-HCV effect of interferon-alpha therapy. Alcohol's effect is most pronounced during the early phase of the immune response and interferes with the antigen-presenting cells (not directly on T-cells). The result is a decreased response from immunoglobulins (Latif, Peterson, & Waltenbaugh, 2002). People who abuse alcohol are more likely to participate in behaviors that put them at risk to develop human immunodeficiency virus (HIV), and alcohol use disorders are associated with an increased incidence of HIV, as well as opportunistic infections.

Immune Response

Even though we have a single immune system, it is diversified into two subsystems so we can combat the multitude of infectious agents we encounter in our lifetimes. This diversification is a result of the differing approaches that B and T cells have to ridding the body of infectious agents once they are found. B cells provide a response called humoral immunity, while T cells provide a cell-mediated immunity. Figure 11.13 Clonal populations. When a lymphocyte binds an antigen, it proliferates to produce many copies of the lymphocyte and its antigen receptor. This strengthens the immune system's ability to rid the body of that infectious agent. Figure 11.13 Clonal populations. When a lymphocyte binds an antigen, it proliferates to produce many copies of the lymphocyte and its antigen receptor. This strengthens the immune system's ability to rid the body of that infectious agent. The entire clonal population has the same DNA arrangement, and all the cells in a clonal population carry the...

Cancer Immunoediting

Although strong evidence has been presented supporting the existence of a functional cancer immune surveillance process against cancer in mice and humans, cancer continues to develop in intact immune systems and is refractory to many treatment approaches. These findings might be caused by the failure of early host tumor immunity to eradicate nascent transformed cells. Even in the presence of continued immune pressure, the failure to eradicate tumor cells results in tumor progression with reduced immunogenicity. Cancer immunoediting has been proposed in terms of the dual functions of host immunity not only for eliminating tumor cells but also for shaping malignant disease during the period of equilibrium between the tumor and host. Elimination is the hallmark of the original concept in cancer immune surveillance for the successful eradication of developing tumor cells, working in concert with the intrinsic tumor suppressor mechanisms of the nonimmunogenic surveillance processes. The...

Innate Antitumor Responses

Normal cells are endowed with intricate machinery that affords protection against genotoxic stress induced by cell intrinsic and extrinsic insults, including DNA replication errors, oxidative damage, microbial infection, and inflammation. The failure of the DNA damage response to resolve single-stranded or double-stranded DNA breaks poses a significant risk for malignant transformation. In this context, the innate immune system functions as an extrinsic surveillance mechanism for genotoxic injury. NKG2D ligands, which include the major histocompatibility complex (MHC) class I-related molecules (MHC class I chain-related A MICA and MHC class I chain-related B MICB ) and four UL16 binding proteins (ULBP1-4) in humans as well as the retinoic acid-early (RAE) indu-cible gene products and H60 in rodents, are induced by DNA damage through a pathway involving ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 related (ATR), Chk-1, and Chk-2 (Gasser et al., 2005). The surface...

Innate Immune Cells

Y8-T cells are a small population of T lymphocytes that integrate features of innate and adaptive immunity. While these cells undergo VDJ recombination during thymic development, their TCR diversity is relatively limited compared to conventional aP-T cells, and they function more in pattern recognition (Hayday, 2000). y8-T cells constitute a significant proportion of intraepi-thelial lymphocytes (IELs) in the skin and gastrointestinal and genitourinary tract mucosa. Their importance for tumor surveillance has been revealed by the increased incidence of chemically induced fibrosarco-mas and spindle cell carcinomas in y8-T cell deficient mice (Girardi et al., 2003). For example, V81-T cells are a type of y8-T cell that is enriched in various tumors, and they

Adaptive Antitumor Responses

Adaptive Immunity in Immunosurveillance The importance of adaptive immunity for tumor immunosurveillance was first established through studies of mice harboring targeted mutations of the recombinase-activating gene 2 (RAG-2), which is required for immunoglobulin and T cell receptor gene rearrangement (Shankaran et al., 2001). Since the assembly of B and T lymphocyte antigen receptors requires RAG-mediated double-stranded DNA breaks to initiate V(D)J immunoglobulin gene recombination, RAG-2-deficient mice lack all B lymphocytes, ap- and yS-T cells, and NKT cells. These mice manifested an increased susceptibility to chemical carcinogen-induced tumors, and the fibrosarcomas arising in these animals were frequently rejected upon transplant to wild-type animals. Subsequent studies of mice deficient in ap- or yS-T cells alone revealed a similar enhanced susceptibility to chemical carcinogens, highlighting the key roles of T lymphocytes in tumor protection. Consistent with these findings,...

Cytokine Regulation Of Immune Tolerance To Tumors

In most cases, an effective immune response against tumors is dependent on the cellular arm of the immune system, the major players of which include CD8 + cytotoxic T lymphocytes (CTLs), CD4 + Th1 cells, y8-T cells, and NK cells. The effector functions of these cells are responsible for direct target cell killing as well as production of cytokines and other modulators that regulate the function of various cell types, including tumor cells. The cellular immune response is responsible for the host defense of intracellular pathogens however, when the cellular immune response is dysregu-lated, it can also trigger autoimmune diseases (e.g., type I diabetes). As a self-tolerance mechanism, several cytokines are involved in the suppression of cellular immune responses either under steady state or during the resolution phase of infection or trauma, which impedes the development of tumor immunity. In addition, cytokines that skew immune responses to T helper 2 (Th2) cells or to the newly...

The Course of HIV Infection

The early symptoms of HIV infection resemble the flu in about 70 of infected individuals (there are no noticeable symptoms in the remaining 30 ). These symptoms occur because the HIV present in the bloodstream is destroying large numbers of T4 cells, thus interfering with normal immune responses. Most people infected with HIV begin to control the virus within six to 12 weeks, and therefore recover from these flu-like symptoms. This seeming recovery from the infection is due to the actions of the immune system. Among the pool of immune-system cells, particular lymphocytes recognize antigens that are present on HIV particles. T lymphocytes that have an HIV-anti-gen receptor are stimulated to reproduce so that a large number of cells are available to patrol the bloodstream for signs of the virus. (Note that the CD4+ receptor, which HIV binds to in order to enter T4 cells, is not an antigen receptor.) B lymphocytes that have an HIV-antigen receptor are also stimulated to divide and will...

The Natural Selection of HIV

During the asymptomatic period of HIV infection, the numbers of HIV virus particles in an infected person's bloodstream is relatively low. However, the immune response to HIV does not completely eliminate the virus. HIV persists inside immune-system structures called lymph nodes where it continues to infect and kill T4 cells. The dying T4 cells release the virus into the bloodstream, where anti-HIV antibodies quickly eliminate them. At the same time, the infected individual is maintaining a high rate of T4 cell production to replace those lost to HIV. In a sense, the virus and the immune system maintain a balance of power during this period. The population of HIV is not stable during the asymptomatic period, however. HIV particles are constantly being reproduced because they continue to infect cells in the lymph nodes any time there is reproduction, mutation can occur. As a result, during the asymptomatic period new variants of HIV arise. Some of these HIV variants have mutated...

The Ly49 Receptor Family

Dependent on the interaction of the positively charged arginine residue of the transmembrane domain of the Ly49 receptor and the negatively charged aspartic acid residue of DAP12. Interestingly, the specific Ly49 repertoire and the amount of each Ly49 receptor directly depend on the H-2 expression of the host (Yokoyama and Plougastel, 2003). IL-12 and IL-18 treatment enables NK cells to mediate cytotoxicity and produce IFN-y despite expression of inhibitory receptors (Ortaldo and Young, 2003). These NK cells need two activating signals (activating Ly49 receptor and IL-12 IL-18) to overcome inhibition. These observations support the notion that temporary autore-activity could occur during acute inflammation from IL12 IL18 production by dendritic cells (DCs) that can induce IFN-y expression in NK cells, ultimately leading to expansion of the immune response. Another possible explanation for this phenomenon is that the main activating ligand for the Ly49 receptors is not H-2 but some...

Shuang Wei Alfred Chang And Weiping

The tumor microenvironment is a battlefield between the tumor and host immune system. The myriad of cellular interactions in the tumor microenvironment determines immune response versus tolerance to tumor cells. Recent advances in molecular and cellular tumor immunology have demonstrated that the tumor actively recruits and alters immune cell phenotypes and functions, promoting either immune suppression or tolerance of tumor-associated antigens. In this chapter, we provide a framework for understanding how the immune response is altered in favor of forming a suppressive network in the tumor microenvironment, integrating different immune cell types and molecules.

Imbalance Between Stimulatory And Inhibitory B7 Family Molecules

In summary, epithelial tumor cells and associated myeloid DCs highly express B7-H1 and mediate T cell apoptosis or attenuate T cell activation. The significant influence of tumor environmental B7-H1 and PD-1 on the interaction between T cells, tumor cells, and APCs constitutes a novel target for tumor immunotherapy. ing their potential role in tumor pathogenesis (Bingle et al, 2002 Ohno et al, 2003 Zavadova et al, 1999). Thus, immune functional data are essential for understanding the roles and potential suppressive mechanisms of macrophages in human tumor microenvironment. In recent work, B7-H4 and TAM-mediated immune suppression have been linked in ovarian cancer.

Imbalance Between Regulatory T Cells And Conventional T Cells

Regulatory T cells or Tregs are functionally defined as T cells that inhibit an immune response by influencing the activity of another cell type (Shevach, 2004). The most well-defined Treg cells are CD4+CD25+ T cells (Sakaguchi et al, 2001 Shevach, 2002 Von Herrath and Harrison, 2003). The antigen specificity, phenotype, mechanisms of action, and function of Treg cells have been discussed in the literature (Chen et al., 2005 Green et al., 2003 Peng et al., 2004 Wang et al, 2004 Wang and Wang, 2005) and are discussed in Chapter 15 of this book. The immunosuppressive cell surface molecule CTLA-4 is conceptually related to Treg cell function. The role of CTLA-4 and the effects of CTLA-4 blockade in mouse and human cells have been discussed (Chapters 10 and 12). In this chapter, the focus will be the distribution and trafficking of Treg cells in human tumors and the imbalance between Treg cells and conventional T cells in the tumor environment.

Concluding Remarks

Owing to the abundant experimental and clinical evidence, there should no longer be any doubt for the existence of cancer immunoediting from immune surveillance to escape. Cancer cells are gradually able to gain several mechanisms of immune evasion during tumor progression even though they are pursued by the initial and continuing phases of immune surveillance. Immuno-logical sculpting contributes to immune selection pressure, which produces tumor cell variants that are resistant to immune effector cells due to their low immunogenic-ity. In advanced cancers, the marked shifting to immunosuppressive conditions due to the constitution of the immunosuppres-sive network in tumors makes it more difficult to provoke an immune activation to eliminate cancer cells. Given that adoptive immunotherapy using the peptide vaccine and DC transfer is not sufficient to reduce tumor volume and tumor elimination by direct priming for T cells in such conditions, indirect cross-priming for T cells, which...

Overview

Limited scientific collaborations have been conducted historically between immu-nologists, geneticists, and cell biologists who study cancer. This situation is beginning to change with an emerging consensus among all cancer researchers that inflammation and immune escape play key causal roles in the development and progression of malignancies. This finding is particularly true for adult solid tumors, the causes of which are complex and multifac-toral, posing a major clinical challenge. This book aims at cross-fertilizing ideas and concepts among investigators who are striving to develop combinatorial immunologi-cal or pharmacological agents as cancer therapeutics. The specific goals are (1) to highlight emerging principles of immune suppression in cancer patients and (2) to discuss how to combine immunotherapeu-tic and chemotherapeutic agents to defeat mechanisms of immune or inflammatory suppression and improve cancer treatment. Many immune-based therapies have focused on activating...

Parts Of The Book

Part I of the book introduces principles of cancer immunobiology. In Chapter 2, the central concept of immunoediting is introduced. This fundamental process has three parts, termed immunosurveillance, immune equilibrium, and immune escape, which lead to control, stasis, or outgrowth of a malignancy. Immunoediting starts with the immune recognition and destruction of cells that have acquired genetic and epigenetic alterations characteristic of tumor cells, but at the same time, the selective pressure produced by immunoediting drives tumor evolution and progression. In this process, the cell-intrinsic traits of cancer (immortalization, growth deregulation, apoptotic resistance, and tumor suppressor inactivation) lead to the development of subclinical or occult lesions that are not clinically important until cell-extrinsic traits (invasion, angiogenesis, metastasis, and immune escape) have been achieved. The complex roles for inflammatory cells and altered immunity in the development of...

Introduction

Since Ehrlich first proposed the idea in 1909 that nascent transformed cells arise continuously in human bodies and that the immune system scans for and eradicates these transformed cells before they are manifested clinically, immune surveillance has been a controversial topic in tumor immunology (Ehrlich, 1909). In the mid-twentieth century, experimental evidence that tumors could be repressed by the immune system came from the use of tumor transplantation models. The findings from these models strongly suggested the existence of tumor-associated antigens (TAAs) that formed the basis of immune surveillance, as postulated by Burnet and Thomas (Burnet, 1957). The functional role of antigen-presenting cells (APCs) in cross-priming for T cell activation was subsequently demonstrated, and the cancer immune surveillance model was developed. However, the idea of cancer immune surveillance resisted widespread acceptance until the 1990s when experimental animal models using knockout mice...

Conclusion

Investigations of endogenous antitumor responses have unveiled a previously unappreciated complexity of interaction among tumor cells, stroma, and immune elements. Innate immune activation by stress-inducible signals on tumor cells triggers a response aimed at controlling disease development effective responses may transition to adaptive immunity that manifests further specificity and memory. However, persistent immune activation may also result in an interplay of innate and adaptive elements that supports tumor cell proliferation, survival, invasion, angiogenesis, and metastasis. A central player that has emerged in coordinating these tumor-promoting inflammatory responses is the NF-kB transcription factor (Karin, 2006). A more detailed understanding of the mechanisms regulating the development of tumor-protective or tumor-promoting host responses is critical to the crafting of immunotherapeutic strategies. Chan, C. W., Crafton, E., Fan, H. N., Flook, J., Yoshimura, K., Skarica, M.,...

Mica Micb

Lesions, resulting in cells that display NKG2D ligands that tag themselves for NK recognition. Genotoxic stress, microbial infection, and cell transformation all constitute types of cellular alterations in which induction of NKG2D ligands acts as an indicator of cell stress. Therefore, elevating the expression of NKG2D ligands is a common natural means to alert the immune system to the presence of disease. It is also important to note that NKG2D can trigger NK cytotoxicity despite MHC class I expression on the target cell, suggesting that this receptor, when activated, can override the protective signal of self MHC class I as long as the danger signal provided by the NKG2D ligand is available (Diefenbach et al, 2001). In the mouse system, NKG2D is able to bind three subfamilies of RAET1 genes, Rael, histocompatibility 60 (H60), and mouse UL-16 binding protein 1 (Multl) (Dienfenbach et al, 2001). Although these genes are structurally related and localized on chromosome 10, they share...

Media Activities

Media Activity 11.1 The Immune System and Infectious Agents The infectious agent responsible for chickenpox, the varicella-zoster virus, sometimes causes shingles in older people, because the virus initially evades the immune system and then hides in the nerves in a latent form. You will explore information on what shingles is, how it occurs, and what can be done to treat the affected patient. Media Activity 11.6 Gene Therapy Trials for Immune Deficiency One strategy to help patients with immune system deficiencies is to use gene therapy. Retroviruses are used to deliver good genes into the host cells of a patient to correct their bad or missing genes. There are risks associated with these types of therapy, as we will explore in this activity.

Preface to Second Edition

The format of the book has not changed but some of the chapters have been expanded. For example, there is now a section dealing with the eye complications of acquired immune deficiency syndrome (AIDS). This problem barely existed at the time of the first edition. Cataract surgery has changed a great deal in this short time and is becoming one of the commonest major surgical procedures to be performed in a hospital. The management of glaucoma has also changed with the introduction of a range of new medications. Our aim has been to keep the original problem-oriented layout and to keep it as a book to read rather than a book to look at. There are a number of good atlases on eye disease and some of these are mentioned in the section at the end on further reading. Although the title of the book is Common Eye Diseases, some less common conditions are mentioned and it is hoped that the reader will gain some overall impression of the incidence of different eye diseases.

How Does MS Affect the Nervous System

In contrast to many diseases that affect a single part of the human body, MS affects two different body systems the immune system and the nervous system. The immune system is not a distinct organ like the brain or liver. Instead, it is composed of many different types of molecules and cells (known as white blood cells) that travel through the bloodstream. The immune cells use chemical messages to protect the body from attack by bacteria, viruses, and cancers. MS is believed to be an autoimmune condition in which the immune system is excessively active and actually attacks the nervous system. The central nervous system (CNS) is the part of the nervous system involved in MS. The CNS includes the brain and spinal cord. The nerves in the CNS communicate with each other through long, wire-like processes that have a central fiber (axon) surrounded by an insulating material (myelin). In MS, the immune system cells produce inflammation that injures the myelin. In addition, damage occurs to...

The History Of Aids Psychiatry

In a more detailed article, published on December 10, 1981, in the New England Journal of Medicine, Gottlieb and colleagues (1981) linked an immune deficiency with this new cluster of infections. They presented evidence for an association ofthe illnesses PCP, candidiasis, and multiple viral infections and a new acquired cellular immunodeficiency'' with a decrease in CD4 T cells as a hallmark. Another article (Masur et al., 1981) described this outbreak of community-acquired Pneumocystis carinii pneumonia'' as a manifestation of an immune deficiency. Over the next year, several other articles described the opportunistic infections and cancers that characterized this new syndrome of immune deficiency, including not only Pneumocystis carinii (now named Pneumocystis jeroveci) pneumonia but also cytomegalovirus retinitis, central nervous system toxoplasmosis, progressive multifocal leukoencephalopathy, disseminated Kaposi's sarcoma, and central nervous system lymphoma. Initially, the...

Natural killer NK cell

B lymphocytes recognize soluble antigens and develop into antibody-secreting cells. Helper T lymphocytes recognize antigens on the surfaces of antigen-presenting cells and secrete cytokines, which stimulate different mechanisms of immunity and inflammation. Cytotoxic T lymphocytes recognize antigens on infected cells and kill these cells. Regulatory T cells suppress and prevent immune response (e.g., to self antigens). NK cells use receptors with more limited diversity than T or B cell antigen receptors to recognize and kill their targets, such as infected cells. Some cytokines are mediators and regulators of innate immunity. They are produced by innate immune cells such as dendritic cells, macrophages, and mast cells, and they drive the process of inflammation or contribute to defense against viral infections. Other cytokines, especially those produced by helper T cell subsets, contribute to host defense mediated by the adaptive immune system and...

Scientific Foundations

Anti-rejection drugs work by blocking the immune response from attacking the new organ. Some anti-rejection drugs limit the number of T-lymphocyte cells, so there are fewer of them to attack the organ. Others slow the production of substances in the body that are used to make T-lymphocyte cells. Steroid drugs such as predni-sone reduce the swelling that occurs with an immune response. Prednisone This drug is a steroid. The body naturally makes steroids. Steroids reduce the swelling that occurs with an immune response. This drug is often used with cyclosporine. Mycophenolate mofetil (brand name CellCept) This drug also holds back the immune system so that it does not reject the new organ. Its side effects include loose stools (diarrhea), lower numbers of white blood cells, blood infection, and other kinds of infections.

Diagnosing Infection By Serologic Means

In addition, because the immune system of the fetus is relatively immature, particularly early in gestation, the ability to make specific antibody in utero may be impaired. In congenital rubella infection prior to 10 weeks of gestation, no antibody production may occur (25). Fewer than 50 of fetuses with congenital parvovirus infection have measurable IgM (26), and less than 50 of fetal blood from toxoplasma-infected fetuses was IgM positive (27). Even if antibody production occurs, competition from the presence of high titers of maternal IgG antibodies in the serum or plasma may obscure the antigen and prevent binding of the child's IgG or IgM (28). In addition, if there is rheumatoid factor (e.g., IgM anti-IgG) present in the pediatric serum, the detection of non-IgG antibodies binding to the pathogen antigen in the infant serum may represent antimaternal IgG (perhaps specific for the pathogen of interest) rather than actual antibody directed at the micro-organism itself. The...

Cancer Screening Diagnosis and Prevention

Molecular biomarkers may be used to identify early responses to DNA damage and to assess cancer risk.45-47 Unscheduled DNA synthesis, chromosome aberrations, sister chromatid exchanges, and the micronucleus tests are some examples of these tumor markers. These markers are also referred to as genetic markers and can be scored in advance of preneoplastic lesions that are usually detected by histological methods.45-47 Genetic markers can also be used to show that the vast majority of cancers originate from a single stem cell. In addition to the clonogenic nature of cancer, there are numerous epigenetic events that create an environment for abnormal cell division, such as chronic inflammation or persistent stimulation of the immune system.

Clinical studies cervical and other cancers

Effect of therapy on the immune system of cervical cancer patients undergoing external irradiation and intracavity brachytherapy with or without concurrent cisplatin and found that administration of concurrent cisplatinum with radiation therapy may have synergis-tically increased cytotoxic effects of radiation on tumor cells but did not alter the magnitude or characteristics of the radiation-induced immunosuppression. The role of concurrent radiation therapy and chemotherapy consisting of 5-fluorouracil and cisplatin was explored in the treatment of local-regionally advanced vulvar cancer and results appeared positive (143). The combination of cisplatin or carboplatin and radiation therapy has been discussed for locally advanced prostate cancer (144). Kaufman et al. (145) conducted a study of 34 patients to assess the safety, tolerance, and efficacy of transurethral surgery plus concomitant cisplatin, 5-fluorouracil, and radiation therapy in conjunction with selective bladder...