Hematopoietic Stem Cell Transplantation

The transplantation of allogeneic pluripotent hematopoi-etic stem cells is done commonly using an inoculum of bone marrow cells collected by aspiration, and the procedure is often called bone marrow transplantation. Hematopoietic stem cells can also be purified from the blood of donors after treatment with colony-stimulating factors, which mobilize stem cells from the bone marrow. The recipient is treated before transplantation to deplete bone marrow cells to free up niches for the transferred stem cells. After transplantation, stem cells repopulate the recipient's bone marrow and differentiate into all the hematopoietic lineages. We consider bone marrow transplantation separately because this type of grafting has several unique features that are not encountered with solid organ transplantation.

Bone marrow transplantation is most often used clinically in the treatment of leukemias. In some forms of leukemia, the grafted cells are effective in destroying residual leukemia cells. In addition, the chemotherapeu-tic agents needed to destroy cancer cells also destroy normal marrow elements, and bone marrow transplantation is used to "rescue" the patient from the side effects of chemotherapy. Hematopoietic stem cell transplantation is also used clinically to treat diseases caused by inherited mutations in genes affecting only cells derived from hematopoietic stem cells, such as lymphocytes or red blood cells. Examples of such diseases that can be cured by hematopoietic stem cell transfer are adenosine deaminase (ADA) deficiency, X-linked severe combined immunodeficiency disease, and hemoglobin mutations such as beta-thalassemia major and sickle cell disease.

Allogeneic hematopoietic stem cells are rejected by even a minimally immunocompetent host, and therefore the donor and recipient must be carefully matched at all MHC loci. The mechanisms of rejection of bone marrow cells are not completely known, but in addition to adaptive immune mechanisms, hematopoietic stem cells may be rejected by NK cells. The role of NK cells in bone marrow rejection has been studied in experimental animals. Irradiated Fi hybrid mice reject bone marrow donated by either inbred parent. This phenomenon, called hybrid resistance, appears to violate the classical laws of solid tissue transplantation (see Fig. 16-2). Hybrid resistance is seen in T cell-deficient mice, and depletion of recipient NK cells with anti-NK cell antibodies prevents the rejection of parental bone marrow. Hybrid resistance is probably due to host NK cells reacting against bone marrow precursors that lack class I MHC molecules expressed by the host. Recall that normally, recognition of self class I MHC inhibits the activation of NK cells, and if these self MHC molecules are missing, the NK cells are released from inhibition (see Chapter 4, Fig. 4-6). Donor-versus-recipient NK cell alloreactivity has been used to reduce leukemia relapses after HLA haplotype-mismatched hematopoietic stem cell transplantation.

Even after successful engraftment, two additional problems are frequently associated with bone marrow transplantation, namely, graft-versus-host disease and immunodeficiency.

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