Graft VersusHost Disease

Graft-versus-host disease (GVHD) is caused by the reaction of grafted mature T cells in the marrow inoculum with alloantigens of the host. It occurs when the host is immunocompromised and therefore unable to reject the allogeneic cells in the graft. In most cases, the reaction is directed against minor histocompatibility antigens of the host because bone marrow transplantation is not performed when the donor and recipient have differences in MHC molecules. GVHD may also develop when solid organs that contain significant numbers of T cells are transplanted, such as the small bowel, lung, or liver.

GVHD is the principal limitation to the success of bone marrow transplantation. As in solid organ transplantation, GVHD may be classified on the basis of histologic patterns into acute and chronic forms.

Acute GVHD is characterized by epithelial cell death in the skin, liver (mainly the biliary epithelium), and gastrointestinal tract (Fig. 16-14). It is manifested clinically by rash, jaundice, diarrhea, and gastrointestinal hemorrhage. When the epithelial cell death is extensive, the skin or lining of the gut may slough off. In this circumstance, acute GVHD may be fatal.

Chronic GVHD is characterized by fibrosis and atrophy of one or more of the same organs, without evidence of acute cell death. Chronic GVHD may also involve the lungs and produce obliteration of small airways. When it is severe, chronic GVHD leads to complete dysfunction of the affected organ.

Apoptotic cells

Apoptotic cells

FIGURE 16-14 Histopathology of acute GVHD in the skin. A sparse lymphocytic infiltrate can be seen at the dermal-epidermal junction, and damage to the epithelial layer is indicated by spaces at the dermal-epidermal junction (vacuolization), cells with abnormal keratin staining (dyskeratosis), apoptotic keratinocytes, and disorganization of maturation of keratinocytes from the basal layer to the surface. (Courtesy of Dr. Scott Grantor, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.)

FIGURE 16-14 Histopathology of acute GVHD in the skin. A sparse lymphocytic infiltrate can be seen at the dermal-epidermal junction, and damage to the epithelial layer is indicated by spaces at the dermal-epidermal junction (vacuolization), cells with abnormal keratin staining (dyskeratosis), apoptotic keratinocytes, and disorganization of maturation of keratinocytes from the basal layer to the surface. (Courtesy of Dr. Scott Grantor, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.)

In animal models, acute GVHD is initiated by mature T cells present in the bone marrow inoculum, and elimination of mature donor T cells from the graft can prevent the development of GVHD. In clinical hematopoietic stem cell transplantation, efforts to eliminate T cells from the marrow inoculum have reduced the incidence of GVHD but also decrease the graft-versus-leukemia effect that is often critical in treating leukemias by this type of transplantation. T cell-depleted marrow also tends to engraft poorly, perhaps because mature T cells produce colony-stimulating factors that aid in stem cell repopulation. One approach that has been tried is to combine removal of T cells with supplemental colony-stimulating factor treatment to promote engraftment.

Although GVHD is initiated by grafted T cells recognizing host alloantigens, the effector cells that cause epithelial cell injury are less well defined. On histologic examination, NK cells are often attached to the dying epithelial cells, suggesting that NK cells are important effector cells of acute GVHD. CD8+ CTLs and cytokines also appear to be involved in tissue injury in acute GVHD.

The relationship of chronic GVHD to acute GVHD is not known and raises issues similar to those of relating chronic allograft rejection to acute allograft rejection. For example, chronic GVHD may represent the fibrosis of wound healing secondary to loss of epithelial cells. However, chronic GVHD can arise without evidence of prior acute GVHD. An alternative explanation is that chronic GVHD represents a response to ischemia caused by vascular injury.

Both acute and chronic GVHD are commonly treated with intense immunosuppression. It is not clear that either condition responds very well. A possible explanation for this therapeutic failure is that conventional immunosuppression is targeted against T lymphocytes, which may be only one of several mediators of GVHD. Cyclosporine and the metabolic toxin methotrexate are also used for prophylaxis against GVHD. Various new therapies are being studied in clinical trials, including rapamycin, anti-TNF antibodies, and regulatory T cell transfer.

Was this article helpful?

0 0
How To Win Your War Against Allergies

How To Win Your War Against Allergies

Not Able To Lead A Happy Life Because Of Excessive Allergies? Want To Badly Get Rid Of Your Allergy Problems, But Are Super Confused And Not Sure Where To Even Start? Don't Worry, Help Is Just Around The Corner Revealed The All-In-One Power Packed Manual Containing Ample Strategies And Little-Known Tips To Get Rid Of Any Allergy Problems That Are Ruining Your Life Learn How You Can Eliminate Allergies Completely Reclaim Your Life Once Again

Get My Free Ebook


Post a comment