Fig. 15.54 Graft-versus-host disease is due to donor T cells in the graft that attack the recipient’s tissues. After bone marrow transplantation, any mature donor CD4 and CD8 T cells present in the graft that are specific for the recipient’s HLA allotypes become activated in secondary lymphoid tissues. Effector CD4 and CD8 T cells move into the circulation and preferentially enter and attack tissues of the graft recipient, particularly epithelial cells of the skin, intestines, and liver that have been damaged by the conditioning regimen of chemotherapy and irradiation prior to transplantation.
Fig. 15.55 The mixed lymphocyte reaction (MLR) can be used to detect histoincompatibility. Peripheral blood mononuclear cells, which include lymphocytes and monocytes, are isolated from the two individuals to be tested. The cells from the person who serves as the stimulator (yellow) are first irradiated to prevent their proliferation. Then they are mixed with the cells from the other person, who serves as the responder (blue), and cultured for 5 days (top panel). In the culture, responder lymphocytes are stimulated by allogeneic HLA class I and II molecules expressed by the stimulator’s monocytes and the dendritic cells that differentiate from the monocytes. The stimulated lymphocytes proliferate and differentiate into effector cells. Five days after mixing, the culture is assessed for T‑cell proliferation (bottom left panel), which is due to CD4 T cells recognizing HLA class II differences, and for cytotoxic T cells (bottom right panel) produced in response to HLA class I differences. The mixed lymphocyte reaction is instrumental in distinguishing MHC class II from MHC class I.
Although GVHD is harmful to the recipient of an HSC transplant, it can have beneficial effects that are crucial to the success of the therapy. Much of the therapeutic effect of HSC transplantation for leukemia can be due to a graft-versus-leukemia effect, in which the donor T cells in the allogeneic preparations of HSCs recognize minor histocompatibility antigens expressed by the leukemic cells and kill the leukemic cells. One of the treatment options for suppressing the development of GVHD is the elimination of mature T cells from the preparations of donor HSCs in vitro before transplantation, thereby removing alloreactive T cells. Those T cells that subsequently mature from the donor marrow in vivo in the recipient are tolerant to the recipient’s antigens. Although the elimination of GVHD has benefits for the patient, there is an increased risk of leukemic relapse, which provides strong evidence in support of the graft-versus-leukemia effect.
Immunodeficiency is another complication of donor T-cell depletion. Because most of the recipient’s T cells are destroyed by the combination of chemotherapy and irradiation used to treat the recipient before transplant, donor T cells are the major source for reconstituting a mature T-cell repertoire early after transplant. This is particularly true in adults, who have poor residual thymic function and therefore a limited ability to repopulate their T-cell repertoire from T-cell precursors. Thus, if too many T cells are depleted from the graft, transplant recipients experience, and can die from, opportunistic infections. The need to balance the beneficial effects of the graft-versus-leukemia effect and immunocompetence with the adverse effects of GVHD caused by donor T cells has spawned much research. One particularly promising approach is to prevent donor T cells from reacting with recipient antigens that they could meet shortly after the transplant. This is accomplished by depleting the recipient’s antigen-presenting cells. Here, the donor T cells are not activated during the initial inflammation that accompanies the transplant, and thereafter they do not promote GVHD. However, it is unclear whether there would be a graft-versus-leukemia effect in this context.