Graft-Versus-Host Reaction - Transplantation Immunology

GRAFT-VERSUS-HOST REACTION

Whenever a patient with a profound immunodeficiency (primary, secondary, or iatrogenic) receives a graft of an organ rich in immunocompetent cells, there is a risk that a graft versus host GVH reaction may develop. GVH reactions are a significant problem in infants and children with primary immunodeficiencies in whom a bone marrow transplant is per-formed with the goal of reconstituting the immune system, as well as in adults receiving a bone marrow transplant as part of a therapeutic protocol for aplastic anemia or for a hematopoietic malignancy. Small bowel, heart-lung, and even liver transplantation rank second in risk of causing GVH reactions, since these organs have a substantial amount of lymphoid tissue. In contrast, transplantation of organs such as the heart and kidneys, poor in endogenous lymphoid tissue, very rarely results in GVH reaction. The probability of de-veloping graft-versus-host disease (GVHD) is greatest in the 2-month period immediately following transplantation.

A. Pathogenesis

Two elements are essential for the development of a GVH reaction: the immune system of the recipient needs to be severely compromised, and the transplanted organ or tissue needs to contain viable immunocompetent cells. The deficiency of the immune system may be congenital or acquired. For example, patients receiving bone marrow transplants receive cytotoxic and immunosuppressive therapy, and their immune system is completely or par-tially destroyed to avoid rejection of the transplanted bone marrow.

When a graft containing immunocompetent cells is placed into an immunoincompe-tent host, the transplanted cells can recognize as nonself the host antigens. In response to these antigenic differences, the donor T lymphocytes become activated, proliferate, and dif-ferentiate into helper and effector cells that attack the host cells and tissues, producing the signs and symptoms of GVH disease. The crucial role played by the donor T cells in GVHD is demonstrated by the fact that their elimination from a bone marrow graft avoids the reac-tions . However, as the GVH reaction evolves and reaches its highest intensity, the majority of the cells infiltrating the different tissues affected by the GVH reaction are of host origin and include T and B lymphocytes as well as monocytes and macrophages. The proliferation of host cells is probably a result of the release of high concentrations of non-specific mitogenic and differentiation factors by activated donor T lymphocytes.

However, it must be noted that several groups have reported findings suggesting that a low grade GVH reaction may actually accelerate bone marrow engraftment.

B. Pathology

The initial proliferation of donor T cells takes place in lymphoid tissues, particularly in the liver and spleen (leading to hepatomegaly and splenomegaly). Later, at the peak of the pro-liferative reaction, the skin, liver, and intestinal walls are heavily infiltrated leading to se-vere skin rashes or exfoliative dermatitis, hepatic insufficiency, and severe diarrhea or even intestinal perforation. The splenic involvement results in a loss of function not unlike that seen in splenectomized patients. The patients often develop Streptococcus pneumoniae bacteremia, and antibiotic prophylaxis may be necessary.

C. Treatment

All immunosuppressive drugs used in the prevention and treatment of rejection have been used for treatment of the GVH reaction. In addition, thalidomide, the tranquilizer drug that achieved notoriety due to its teratogenic effects, has been used successfully for the control of chronic GVH reaction unresponsive to traditional immunosuppressants, and it may be-come an extremely useful drug in the future.

D.  Prevention

Once a GVH reaction is initiated, its control may be extremely difficult. Thus, great em-phasis is placed on preventing GVH reactions. Besides the administration of immunosup-pressive drugs, other approaches have been tried with variable success.

T-cell depletion of the graft can be achieved by pretreatment of the bone marrow with antilymphocyte/thymocyte immunoglobulin or with monoclonal antibodies reacting with T cells (e.g., anti-CD3) and can reduce significantly the incidence of GVH reactions. The ma-jor problem with this approach is that the transplantation of T-cell–depleted bone marrow into immunosuppressed adults may result in a persistent state of severe immunodeficiency. These data suggest that the T cells facilitate the engraftment of the donor stem cells within the host bone marrow, although the mechanism for this is not understood. In addition, a low-grade, controllable GVHD is often associated with better outcomes in leukemic pa-tients, perhaps as a result of the elimination of leukemic cells by the grafted lymphocytes (graft-versus-leukemia effect).

Autologous stem cell transplantation using purified CD34+ cells and allogeneic um-bilical cord stem cell transplantation (stem cells obtained from cord blood after delivery) is also associated with a lower risk of GVH reactions. Umbilical cord stem cell transplanta-tion is also associated with reduced graft-versus-leukemia effect and a higher frequency of relapse.

Case 25.1 Revisited

The initial deterioration of kidney function seen 2 weeks after the graft would most likely correspond to a first-set acute rejection, but the possibility that cyclosporine toxicity was causing the symptoms could not be immediately ruled out. The findings on the biopsy, how-ever, were typical of acute rejection, and treatment with large doses of glucocorticoids, or “pulse” steroids was instituted

The clinical deterioration seen 8 weeks after the transplant was obviously systemic in nature. GVH reaction was not a very likely possibility because of its very infrequent association with kidney grafts. A systemic CMV infection was suspected and confirmed by bronchoscopic biopsy, which revealed cells with intranuclear inclusion bodies on interstitial cells, colonoscopy with colonic biopsies of superficial ulcers of the right colon, which also revealed cells with intranuclear inclusions, and blood cultures that were positive for CMV virus.

A systemic CMV infection in an immunosuppressed patient requires energetic antiviral therapy. The patient was started on intravenous ganciclovir and had a reduction in the dosage of his immunosuppressive drugs. Over the course of the next 2 weeks he gradually improved and resolved his lung and colon pathology.