ANNUAL REVIEWS
Annu. Rev. Med. 1991.42:189-197. Downloaded from www.annualreviews.org Access provided by University of California - San Francisco UCSF on 01/24/15. For personal use only.
Annu. Rev. Med. 1991. 42:189-197 Copyright © 1991 by Annual Reviews Inc. All rights reserved
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GRAFT-VERSUS-HOST DISEASE Robertson Parkman, M.D. Division of Research Immunology/Bone Marrow Transplantation, Childrens Hospital of Los Angeles, Los Angeles, California 90054; and Departments of Pediatrics and Microbiology, University of Southern California School of Medicine, Los Angeles, California 90033 KEY WORDS:
autoimmunity, bone marrow transplantation, leukemia
ABSTRACT
Graft-versus-host disease, both acute and chronic, continues to be the major complication of human bone marrow transplantation. Improved posttransplant chemoprophylaxis has reduced the incidence of acute graft versus-host disease, but the incidence of the chronic form of the disease remains unchanged. The use of donors that are not genotypically identical at the major histocompatibility complex increases the incidence of acute and chronic graft-versus-host disease. The clinical consequences of acute and chronic graft-versus-host disease are discussed.
INTRODUCTION
Bone marrow transplantation has an established role in the treatment of hematological, immunological, genetic, and neoplastic diseases (1). Although a variety of clinical problems is associated with bone marrow transplantation (opportunistic infections, veno-occlusive disease, relapsed neoplastic disease), the major clinical problem encountered following allogeneic bone marrow transplantation is graft-versus-host disease. Billingham, Brent, and Medawar established three prerequisites for the development of graft-versus-host disease: (a) a source of donor immuno competent cells, (b) a histocompatibility antigenic difference between the donor and recipient, and (c) an inability of the recipient to reject the 189 0066-4219/91/0401-0189$02.00
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immunocompetent donor cells (2). Following allogeneic bone marrow transplantation, these three prerequisites are fulfilled.
Annu. Rev. Med. 1991.42:189-197. Downloaded from www.annualreviews.org Access provided by University of California - San Francisco UCSF on 01/24/15. For personal use only.
Clinical Presentation Graft-versus-host disease can present as one of two clinical syndromes. Acute graft-versus-host disease has its onset between 7 and 21 days after bone marrow transplantation and is characterized by an erythematous dermatitis, elevation in hepatocellular enzymes, and diarrhea. In addition to the classic triad, a capillary leak syndrome also occurs. Chronic graft versus-host disease has its onset 30-100 days after transplantation and is usually preceded by acute graft-versus-host disease. Chronic graft-versus host disease is clinically characterized by increased collagen deposition, auto-antibody production, and immunodeficiency. The increased collagen deposition results in sclerodermatous skin changes, pulmonary fibrosis, gastrointestinal malabsorption, decreased esophageal motility, and other clinical symptoms similar to those seen in patients with autoimmune diseases. An increased incidence of auto-antibody production has been noted with antibodies to thyroid, muscle, erythrocytes, and granulocytes. In contrast to the increased incidence of auto-antibodies, the patients are unable to make protective antibodies to environmental pathogens, especially encapsulated respiratory bacteria.
Histocompatibility Initially, most bone marrow transplants were performed between geno typically identical siblings, who were identical at both class I (HLA-A, -B, and -C) and class II (DR, DP, DQ) histocompatibility antigens. As the success of transplantation increased, transplants were performed between family members who differed at one or more major histocompatibility antigens (3). The introduction of computerized transplantation registries has allowed transplant centers to identify unrelated individuals who share histocompatibility antigens with recipients for whom no family donors exist (4). The use of matched unrelated donor transplants has increased markedly during the last several years, particularly for diseases such as chronic myelogenous leukemia that allow the physician adequate time to identify the matched unrelated donors. Using standard prophylaxis regimens, an age-dependent incidence of graft-versus-host disease has been observed, with children showing lower incidences of both acute and chronic disease than adults (5). Analysis of the Seattle experience revealed a relationship between the degree of histocompatibility identity and the incidence of significant (grade II-IV) acute graft-versus-host disease. The use of phenotypically identical donors had an incidence of acute graft-versus-host disease identical to that seen
Annu. Rev. Med. 1991.42:189-197. Downloaded from www.annualreviews.org Access provided by University of California - San Francisco UCSF on 01/24/15. For personal use only.
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with genotypically identical histocompatible donors. If, however, the donor and recipient differed at one or more major histocompatibility antigens, the incidence markedly increased. Although there was an associ ation between the incidence of acute graft-versus-host disease and the number of histocompatibility antigens that differed, the greatest incremen tal increase was seen with a single major histocompatibility antigen differ ence. Thus, in adult patients, 40% had acute graft-versus-host disease when no major histocompatibility antigen difference existed, whereas 70% of the patients developed acute graft-versus-host disease with a single major histocompatibility antigen difference. The presence of three major histocompatibility antigen differences resulted in an 85% incidence of acute graft-versus-host disease.
Environmental Factors Besides the degree of histocompatibility, environmental factors may influ ence the severity of acute graft-versus-host disease. Bone marrow trans plants between germ-free histocompatible mice result in no clinically detectable graft-versus-host disease while animals remained pathogen free (6). When either bacteria or endotoxin was given to recipients, they developed clinical acute graft-versus-host disease. The clinical analogue to the pathogen-free animal experiments is the transplantation of patients in protective environments where they receive nonabsorbable gastrointestinal antibiotics and topical antibacterial care resulting in a markedly reduced bacterial load. Patients with severe aplastic anemia transplanted in laminar air flow isolation with antimicrobial decontamination have a reduced incidence of acute graft-versus-host disease during the first 30 days fol lowing transplantation (7). The laminar flow patients were removed from isolation on day 30, which resulted in bacterial colonization thereaftcr. The subsequent increase in the incidence of graft-versus-host disease was the same in the conventional patients and those isolated in laminar flow. European investigators note an association between pretransplant infec tions with herpesviruses (varicella-zoster, herpes simplex, cytomegalo virus) and posttransplant graft-versus-host disease (8). Acute graft-versus host disease may reactivate latent herpesviruses, which can be the target of a donor antirecipient reaction and thus increase the severity of acute graft-versus-host disease.
T-Lymphocyte Depletion Murine experiments demonstrate that the removal of T lymphocytes prior to transplantation prevents acute graft-versus-host disease (9). Therefore, clinical investigators have attempted to eliminate T lymphocytes from the transplant inoculum in order to reduce the incidence and severity of acute
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and chronic graft-versus-host disease. The first patients to be successfully transplanted with T-Iymphocyte-depleted, histoincompatible bone mar row were children with severe combined immune deficiency. T lymphocytes were eliminated from the haploidentical parental bone marrow in vitro either (a) by lysis with monoclonal antibodies to T-Iymphocyte differ entiation antigens and complement or (b) by physical removal by aggluti nation with soybean agglutinin (SBA) and E-roseUe formation (10, 11). Both of these techniques resulted in successful transplantation without either acute or chronic graft-versus-host disease and engraftment with hematopoietic and lymphoid stem cells of donor origin. T-lymphocyte depleted, haploidentical transplants in patients with severe combined immune deficiency using the SBA E-roseUe formation technique have resulted in a clinical survival (67%) similar to that seen with patients who received unmodified histocompatible bone marrow (75%) (12). Transplant centers have used T-lymphocyte-depleted bone marrow in adult patients to reduce the incidence of acute and chronic graft-versus host disease. In randomized trials of adult histocompatible bone marrow transplant recipients with leukemia, T-Iymphocyte depletion markedly reduced the incidence of acute and chronic graft-versus-host disease (13). However, the T-Iymphocyte-depleted recipients had an increased incidence of hematopoietic nonengraftment and leukemic relapse that decreased the overall survival rate of the treated patients. Thus, most transplant centers no longer use T-lymphocyte depletion for histocompatible adult bone marrow transplants. If, however, histoincompatible or matched unrelated donor bone marrow is used, T-lymphocyte depletion may decrease the incidence of acute graft-versus-host disease, with acceptable incidences of hematopoietic nonengraftment and leukemic relapse (14).
Graft-versus-Host Disease Prophylaxis Preclinical studies in a canine bone marrow transplantation model dem onstrated that the prophylactic administration of methotrexate following transplantation reduced the incidence of acute graft-versus-host disease (15). Based upon these studies, histocompatible transplant recipients were prophylactically treated with methotrexate for the first 100 days following transplantation (1). No clinical trials were initially undertaken to dem onstrate the necessity for posttransplant prophylaxis. A small number of patients have been transplanted without any posttransplant graft-versus host disease prophylaxis. Two studies, primarily in children, demonstrated that about 35% of patients without graft-versus-host disease prophy laxis did not develop acute disease (16, 17). A randomized study in adults, however, demonstrated that alliS patients, who received no methotrexate prophylaxis, died from acute graft-versus-host disease (18). The major
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difference between the Seattle and the other studies was the age of the transplant recipients. The incidence of acute graft-versus-host disease is significantly less in pediatric as compared to adult patients. Thus, prophy laxis for acute graft-versus-host disease is necessary for adult patients and the majority of pediatric patients. In spite of prophylaxis with metho trexate, 40% of adult patients developed clinically significant acute graft versus-host disease. Additional agents have been evaluated for graft versus-host disease prophylaxis (antithymocyte globulin, steroids, cyclo phosphamide). None of the drugs, individually or in combination, sig nificantly reduced the incidence or severity of acute graft-versus-host disease. Cyclosporine, used as an immunosuppressant agent for solid organ transplantation, and methotrexate were compared as single agents to prevent acute graft-versus-host disease and were found to be equally efficacious (19). However, cyclosporine, in combination with either metho trexate or steroids, can reduce the incidence of acute graft-versus-host disease in adult patients from 40% to 20% (20). The combination of cyclosporine and steroids results in more rapid hematopoietic recovery than is seen with eyclosporine and methotrexate since methotrexate is an antimetabolite.
Graft-versus-Leukemia Effect The classic model of graft-versus-host disease states that the target antigens are histocompatibility antigens uniquely expressed on recipient cells. Residual leukemic cells express recipient histocompatibility antigens. Analysis of patients transplanted for leukemia, especially patients with acute lymphoblastic leukemia, shows a decreased incidence of leukemic relapse in recipients of allogeneic, as opposed to syngeneic or autologous, bone marrow (21). When allogeneic transplant recipients were analyzed for the presence or absence of acute graft-versus-host disease, a decreased incidence of leukemic relapse was observed in individuals with the disease. Individuals without acute graft-versus-host disease had a leukemic relapse rate similar to that seen in recipients of syngeneic or autologous bone marrow. Presumably, the effector mechanisms of acute graft-versus-host disease are capable of destroying residual leukemic cells. Although such a graft-versus-Ieukemia effect is clear cut in patients with acute lym phoblastic leukemia, controversy exists as to its role (if any) in patients with acute myelogenous leukemia, lymphoma, and chronic myelogenous leukemia (22). The decreased incidence of leukemic relapse in allogeneic transplant recipients with acute graft-versus-host disease has not improved overall survival, since acute graft-versus-host disease results in an increased inci dence of transplant-related deaths. Most studies, therefore, show no net
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improvement in overall survival. The recent introduction of more effective graft-versus-host disease prophylaxis (cyclosporine plus steroids or cyclo sporine plus methotrexate) may result in an increased incidence of leukemic relapse. The presence of a graft-versus-Ieukemia effect only highlights the need for better preparative regimens for patients with neoplastic diseases. The initial analyses of the graft-versus-Ieukemia effect showed an associ ation with acute graft-versus-host disease. More recent analysis has shown that the graft-versus-Ieukemia effect is associated with the presence of chronic graft-versus-host disease as well (23). Since steroids are a major therapeutic modality for chronic graft-versus-host disease, one of the com pounding variables is whether the steroids exert an antileukemic effect or whether the disease itself has a direct antileukemia effect.
Chronic Graft-versus-Host Disease As early transplant-related deaths due to infections, acute graft-versus host disease, and therapeutic toxicities are reduced, more patients survive with chronic graft-versus-host disease. Chronic graft-versus-host disease is an age-dependent phenomenon, with the presence of the acute form being the major predictor for the development of the chronic form of the
disease (24). In patients in whom no acute graft-versus-host disease occurs, recipient age and transplantation from a multiparous female into a male recipient are associated with an increased risk of chronic graft-versus-host disease. The principal pathologic feature of graft-versus-host disease is increased collagen deposition, which leads to the clinical manifestations of sclerodermatous skin changes, hypo- and hyperpigmentation, pulmonary fibrosis, decreased gastrointestinal motility, and malabsorption (25). The clinical similarity between patients with chronic graft-versus-host disease and patients with other immune diseases, particularly scleroderma, is striking. Initially, chronic graft-versus-host disease patients had an increased incidence of latc bacterial and varicella-zoster infections (26). The routine administration of both intravenous immunoglobulin to compensate for the patients' inability to make protective antipolysaccharide antibodies and trimethoprim/sulfamethoxazole prophylaxis markedly reduced the incidence of infections with encapsulated respiratory bacteria. The emer gcnce of antiviral agents (acyclovir) has reduced the morbidity and mortality associated with varicella-zoster infections. Initially, therapy for chronic graft-versus-host disease consisted first of steroids and later of steroids plus azathioprine (27). Comparative trials, however, revealed that the use of azathioprine, particularly in patients with thrombocytopenia, increased mortality. The introduction of combined
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modality therapy, with cyclosporine and steroids on an alternate-day basis, has improved both survival rates and performance scores (28).
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Immunocompetence Although selective experiments have been able to show the transfer of donor-specific immunity to recipients, particularly if donors are immu nized in the pretransplant period, the long-term transfer of clinically sig nificant immunity from donor to recipient does not routinely occur (29,30). The pretransplant cytoablation that transplant recipients receive eradicates their antigen-specific immunological memory. Thus, since there is no sig nificant transfer of antigen-specific donor T and B lymphocytes and since the recipient immunity is ablated, patients in the immediate posttransplant period have no antigen-specific immune function. Patients need to be reimmunized with standard vaccines in order to develop protective immun ity to the common viral pathogens. The presence of acute graft-versus host disease and its concomitant therapy can further delay immunological competence. A recapitulation of immunological ontogeny occurs in transplant recipi ents paralleling that seen in normal fetuses and infants. Of particular importance is the fact that delays occur in the ability of transplant recipi ents to make anticarbohydrate antibodies, just as normal children are unable to make antibodies to encapsulated respiratory pathogens. In vitro analysis of the immunological function of transplant recipients has shown defects in both T- and B-lymphocyte function (31,32). In vitro experiments, in which normal donor T and B lymphocytes are co-cultured with recipient T and B lymphocytes, show functional abnormalities in both recipient T and B lymphocytes. Thus, the immunodeficiency of the posttransplant patient is complex and can be made worse by chronic graft versus-host disease with its concomitant immunosuppressive therapy.
Conclusion Graft-versus-host disease is a complex biological event that occurs fol lowing allogeneic bone marrow transplantation. Graft-versus-host disease and its clinical consequences contribute to much of the morbidity and mortality associated with bone marrow transplantation. Improved therapy to prevent and treat acute and chronic graft-versus-host disease will improve the results of bone marrow transplantation. ACKNOWLEDGMENTS
This work was supported in part by the American Cancer Society Grant IM-602.
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Annu. Rev. Med. 1991.42:189-197. Downloaded from www.annualreviews.org Access provided by University of California - San Francisco UCSF on 01/24/15. For personal use only.
Literature Cited 12. O'Reilly, R. J., Keever, C. A., Small, T. N., Brochstein, J. 1989. The use ofHLA non-identical T-cell-depleted marrow transplants for correction of severe com bined immunodeficiency disease. Immu node! Rev. I: 273-309 13. Mitsuyasu, R., Champlin, R. E., Gale, R. P., et al. 1986. Depletion of T lym phocytes from donor bone marrow for the prevention of graft-versus-host dis ease following bone marrow trans plantation. Ann. Intern. Med. 105: 2026 14. Ash, R. C., Casper, J. T., Chitambar, C. R., et al. 1990. Successful allogeneic transplantation of T-celi-depleted bone marrow from closely HLA-matched unrelated donors. N. Engl. J. Med. 322:
1. Thomas, E. D., Storb, R., Clift, R. A., et al. 1975. Bone marrow trans plantation. N. Engl. J. Med. 292: 83240, 895-902 2. Billingham, R. E. 1966-1967. The biology of graft-versus-host reactions. Harvey Leet. 62: 21-73 3. Beatty, P. G., Clift, R. A., Mickelson, E. M., et al. 1985. Marrow transplantation from related donors other than HLA identical siblings. N. Engl. J. Med. 313: 765-71 4. Beatty, P. G., Ash, R., Hows, J. M., et al. 1989. The use of unrelated bone marrow donors in the treatment of pati ents with chronic myelogenous leu kemia: Experience of four marrow trans plant centers. Bone Marrow Transplant. 4: 287-90 5. Gale, R. P., Bortin, M. M., van Bekkum, D. W., Biggs, J. c., Dicke, K. A., et al. 1987. Risk factors for acute graft-versus host disease. Br. J. Haematol. 67: 397406 6. Pollard, M., Chang, C. F., Srivastava, K. K. 1976. The role of microflora
regimens for control of graft-versus-host disease in dogs with allogeneic marrow grafts. Transplantation 9: 240-46 16. Lazarus, H. M., Coccia, P. F., Herzig, R. H., et al. 1984. Incidence of acute graft-versus-host disease with and with
disease. Transplant. Proc. 8: 533-36 7. Storb, R., Prentice, R. L., Buckner, C. D., et al. 1983. Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow grafts from HLA-identical siblings. Beneficial effect of the protective environment. N. Engl. J.Med. 308: 302-7 8. Bostrom, L., Ringden, 0., Sundberg, B., Linde, A., Tollemar,J., Nilsson, B. 1988. Pretransplant herpes virus serology and acute graft-versus-host disease. Trans plantation 46: 548-52 9. Hamilton, B. L., Brevan, M. J., Parkman, R. 1981. Anti-recipient cyto toxic T lymphocyte precursors are pre sent in the spleen of mice with acute graft versus host disease due to minor histocompatibility antigens. J. Immunol. 126: 621-25 10. Reinherz, E., Geha, R., Rappeport, J. M., et al. 1982. Recunstitutiun after transplantation with T-Iymphocyte depleted HLA haplotype-mismatched bone marrow for severe combined immunodeficiency. Proc. Natl. Acad. Sci. USA 79: 6047-51 II. Reisner, Y., Kapoor, N., Kirkpatrick, D., et al. 1983. Transplantation for severe combined immunodeficiency with HLA-A,B,D,Dr incompatible parental marrow fractionated by soybean agglu tinin and sheep red blood cells. Blood 61: 341-48
bone marrow transplant patients. Blood 64: 215-20 17. Elfenbein, G., Graham-Pole, J., Weiner, R., Goedert, T., Gross, S. 1987. Conse quences of no prophylaxis for acute graft-versus-host disease after HLA identical bone marrow transplantation. Blood 70: 305a 18. Sullivan, K. M., Deeg, H. J., Sanders, J., et al. 1986. Hyperacute graft-versus-host disease in patients not given immu nosuppression after allogeneic marrow transplant. Blood 67: 1172 -75 19. Storb, R., Deeg, H. J., Thomas, E. D., ct al. 1985. Marrow transplantation for chronic myelocytic leukemia: A con trolled trial of cyclosporine-versus metllOtrexate for prophylaxis of graft versus-host disease. Blood 66: 698-702 20. Storb, R., Deeg, H. J., Whitehead, J., et al. 1986. Methotrexate and cylosporine versus cyc1osporine alone for prophy laxis of acute graft-versus-host disease after marrow transplantation for leu kemia. N. Engl. J. Med. 314: 729-35 21. Weiden, P. L., Flournoy, N., Thomas, E. D. 1982. Anti-leukemic effects of graft versus-host disease in human recipients of allogeneic marrow grafts. N. Engl. J. Aled. 300: 1068-73 22. ApperJey,J. F., Mauro, F. R., Goldman, J. M., et al. 1988. Bone marrow trans plantation for chronic myeloid leukemia in first chronic phase: Importance of a
in
development
of graft-versus-host
485-94 15. Storb, R., Epstein, R. B., Graham, T. c., Thomas, E. D. 1970. Methotrexate
out methotrexate and prophylaxis in
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23.
graft-versus-leukaemia effect. Br. J. Haematul. 69: 239-45 Sullivan, K. M., Weiden, P. L., Storb, R., et al. 1989. Influence of acute and ch ronic gra ft ve rsus -hos t disease on relapse and survival after bone marrow transplantation from HLA-identical sib lings as treatment of acute and chronic leukemia. Blood 73: 1720-28 Atkinson, K., Horowitz, M. M., Gale, R. P., ct al. 1990. Risk factors for chronic graft-versus-host disease after HLA identical sibling bone marrow trans plantation. Blood 75: 2459-64 Hood, A. F., Soter, N. A., Rappeport, J., Gigli, I. 1977. Graft-versus-host reac tion: Cutaneous manifestations fol lowing bone marrow transplantation. Arch. Dermatol. 1 13: 1087-91 Atkinson, K., Storb, R., Prentice, R. L., et al. 1979. Analysis of late infections in S9 longterm survivors of bone marrow transplantation. Blood 53: 720-31 Sullivan, K. M., Withers poo n, R. P., Storb R., et al. 1988. Prednisone and azathioprine compared with prednisone and placebo for treatment of chronic graft versus host disease: Prognostic -
Annu. Rev. Med. 1991.42:189-197. Downloaded from www.annualreviews.org Access provided by University of California - San Francisco UCSF on 01/24/15. For personal use only.
24.
25.
26.
27.
,
influence cytopenia
of prolonged thrombo after allogeneic marrow transplantation. Bluod 72: 546-54
28. S ulliv an, K. M., Witherspoon, R., Storb, R., et al. 1988. Altern atin g day cyclosporine and prednisone for treat ment of high risk chronic gr aft vers us host disease. Blood 72: 555-61 29. Saxon, A., Mitsuyasu, R., Stevens, R., et a l 1986. Designed transfer of specific immune responses with bone marrow transplantation. J. Clin. Invest. 7S: 95967 30. Wimperis, J. Z., Brenner, M. K., Prentice, H. G., et al. 1987. B cell devel opment and regulation after T cell depleted marrow transplantation. J. Immunol. 138: 2445-50 3 1. Lum, L. G., Seigneuret, M. C., Orcutt Thordarson, N., et al. 1985. The regu lation of immunoglobulin synthesis after HLA-identical bone marrow trans plantation. VI. Differential rates of maturation of distinct functional groups within lymphoid subpopulations in pati ents after human marrow grafting. Blood -
.
65: 1422-33
32. Wi the rspoo n R. P., Goehle, S., Kret schmer, M., et al. 1986. Regulation of immunoglobulin production after human marrow grafting: The role of he lp er and suppre ss or T cells in acute graft-versus-host disease. Transplan tation 4 1: 328-35 ,
Annu. Rev. Med. 1991.42:189-197. Downloaded from www.annualreviews.org Access provided by University of California - San Francisco UCSF on 01/24/15. For personal use only.
Annu. Rev. Med. 1991. 42:189-197 Copyright © 1991 by Annual Reviews Inc. All rights reserved
Further
Quick links to online content
GRAFT-VERSUS-HOST DISEASE Robertson Parkman, M.D. Division of Research Immunology/Bone Marrow Transplantation, Childrens Hospital of Los Angeles, Los Angeles, California 90054; and Departments of Pediatrics and Microbiology, University of Southern California School of Medicine, Los Angeles, California 90033 KEY WORDS:
autoimmunity, bone marrow transplantation, leukemia
ABSTRACT
Graft-versus-host disease, both acute and chronic, continues to be the major complication of human bone marrow transplantation. Improved posttransplant chemoprophylaxis has reduced the incidence of acute graft versus-host disease, but the incidence of the chronic form of the disease remains unchanged. The use of donors that are not genotypically identical at the major histocompatibility complex increases the incidence of acute and chronic graft-versus-host disease. The clinical consequences of acute and chronic graft-versus-host disease are discussed.
INTRODUCTION
Bone marrow transplantation has an established role in the treatment of hematological, immunological, genetic, and neoplastic diseases (1). Although a variety of clinical problems is associated with bone marrow transplantation (opportunistic infections, veno-occlusive disease, relapsed neoplastic disease), the major clinical problem encountered following allogeneic bone marrow transplantation is graft-versus-host disease. Billingham, Brent, and Medawar established three prerequisites for the development of graft-versus-host disease: (a) a source of donor immuno competent cells, (b) a histocompatibility antigenic difference between the donor and recipient, and (c) an inability of the recipient to reject the 189 0066-4219/91/0401-0189$02.00
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immunocompetent donor cells (2). Following allogeneic bone marrow transplantation, these three prerequisites are fulfilled.
Annu. Rev. Med. 1991.42:189-197. Downloaded from www.annualreviews.org Access provided by University of California - San Francisco UCSF on 01/24/15. For personal use only.
Clinical Presentation Graft-versus-host disease can present as one of two clinical syndromes. Acute graft-versus-host disease has its onset between 7 and 21 days after bone marrow transplantation and is characterized by an erythematous dermatitis, elevation in hepatocellular enzymes, and diarrhea. In addition to the classic triad, a capillary leak syndrome also occurs. Chronic graft versus-host disease has its onset 30-100 days after transplantation and is usually preceded by acute graft-versus-host disease. Chronic graft-versus host disease is clinically characterized by increased collagen deposition, auto-antibody production, and immunodeficiency. The increased collagen deposition results in sclerodermatous skin changes, pulmonary fibrosis, gastrointestinal malabsorption, decreased esophageal motility, and other clinical symptoms similar to those seen in patients with autoimmune diseases. An increased incidence of auto-antibody production has been noted with antibodies to thyroid, muscle, erythrocytes, and granulocytes. In contrast to the increased incidence of auto-antibodies, the patients are unable to make protective antibodies to environmental pathogens, especially encapsulated respiratory bacteria.
Histocompatibility Initially, most bone marrow transplants were performed between geno typically identical siblings, who were identical at both class I (HLA-A, -B, and -C) and class II (DR, DP, DQ) histocompatibility antigens. As the success of transplantation increased, transplants were performed between family members who differed at one or more major histocompatibility antigens (3). The introduction of computerized transplantation registries has allowed transplant centers to identify unrelated individuals who share histocompatibility antigens with recipients for whom no family donors exist (4). The use of matched unrelated donor transplants has increased markedly during the last several years, particularly for diseases such as chronic myelogenous leukemia that allow the physician adequate time to identify the matched unrelated donors. Using standard prophylaxis regimens, an age-dependent incidence of graft-versus-host disease has been observed, with children showing lower incidences of both acute and chronic disease than adults (5). Analysis of the Seattle experience revealed a relationship between the degree of histocompatibility identity and the incidence of significant (grade II-IV) acute graft-versus-host disease. The use of phenotypically identical donors had an incidence of acute graft-versus-host disease identical to that seen
Annu. Rev. Med. 1991.42:189-197. Downloaded from www.annualreviews.org Access provided by University of California - San Francisco UCSF on 01/24/15. For personal use only.
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with genotypically identical histocompatible donors. If, however, the donor and recipient differed at one or more major histocompatibility antigens, the incidence markedly increased. Although there was an associ ation between the incidence of acute graft-versus-host disease and the number of histocompatibility antigens that differed, the greatest incremen tal increase was seen with a single major histocompatibility antigen differ ence. Thus, in adult patients, 40% had acute graft-versus-host disease when no major histocompatibility antigen difference existed, whereas 70% of the patients developed acute graft-versus-host disease with a single major histocompatibility antigen difference. The presence of three major histocompatibility antigen differences resulted in an 85% incidence of acute graft-versus-host disease.
Environmental Factors Besides the degree of histocompatibility, environmental factors may influ ence the severity of acute graft-versus-host disease. Bone marrow trans plants between germ-free histocompatible mice result in no clinically detectable graft-versus-host disease while animals remained pathogen free (6). When either bacteria or endotoxin was given to recipients, they developed clinical acute graft-versus-host disease. The clinical analogue to the pathogen-free animal experiments is the transplantation of patients in protective environments where they receive nonabsorbable gastrointestinal antibiotics and topical antibacterial care resulting in a markedly reduced bacterial load. Patients with severe aplastic anemia transplanted in laminar air flow isolation with antimicrobial decontamination have a reduced incidence of acute graft-versus-host disease during the first 30 days fol lowing transplantation (7). The laminar flow patients were removed from isolation on day 30, which resulted in bacterial colonization thereaftcr. The subsequent increase in the incidence of graft-versus-host disease was the same in the conventional patients and those isolated in laminar flow. European investigators note an association between pretransplant infec tions with herpesviruses (varicella-zoster, herpes simplex, cytomegalo virus) and posttransplant graft-versus-host disease (8). Acute graft-versus host disease may reactivate latent herpesviruses, which can be the target of a donor antirecipient reaction and thus increase the severity of acute graft-versus-host disease.
T-Lymphocyte Depletion Murine experiments demonstrate that the removal of T lymphocytes prior to transplantation prevents acute graft-versus-host disease (9). Therefore, clinical investigators have attempted to eliminate T lymphocytes from the transplant inoculum in order to reduce the incidence and severity of acute
Annu. Rev. Med. 1991.42:189-197. Downloaded from www.annualreviews.org Access provided by University of California - San Francisco UCSF on 01/24/15. For personal use only.
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and chronic graft-versus-host disease. The first patients to be successfully transplanted with T-Iymphocyte-depleted, histoincompatible bone mar row were children with severe combined immune deficiency. T lymphocytes were eliminated from the haploidentical parental bone marrow in vitro either (a) by lysis with monoclonal antibodies to T-Iymphocyte differ entiation antigens and complement or (b) by physical removal by aggluti nation with soybean agglutinin (SBA) and E-roseUe formation (10, 11). Both of these techniques resulted in successful transplantation without either acute or chronic graft-versus-host disease and engraftment with hematopoietic and lymphoid stem cells of donor origin. T-lymphocyte depleted, haploidentical transplants in patients with severe combined immune deficiency using the SBA E-roseUe formation technique have resulted in a clinical survival (67%) similar to that seen with patients who received unmodified histocompatible bone marrow (75%) (12). Transplant centers have used T-lymphocyte-depleted bone marrow in adult patients to reduce the incidence of acute and chronic graft-versus host disease. In randomized trials of adult histocompatible bone marrow transplant recipients with leukemia, T-Iymphocyte depletion markedly reduced the incidence of acute and chronic graft-versus-host disease (13). However, the T-Iymphocyte-depleted recipients had an increased incidence of hematopoietic nonengraftment and leukemic relapse that decreased the overall survival rate of the treated patients. Thus, most transplant centers no longer use T-lymphocyte depletion for histocompatible adult bone marrow transplants. If, however, histoincompatible or matched unrelated donor bone marrow is used, T-lymphocyte depletion may decrease the incidence of acute graft-versus-host disease, with acceptable incidences of hematopoietic nonengraftment and leukemic relapse (14).
Graft-versus-Host Disease Prophylaxis Preclinical studies in a canine bone marrow transplantation model dem onstrated that the prophylactic administration of methotrexate following transplantation reduced the incidence of acute graft-versus-host disease (15). Based upon these studies, histocompatible transplant recipients were prophylactically treated with methotrexate for the first 100 days following transplantation (1). No clinical trials were initially undertaken to dem onstrate the necessity for posttransplant prophylaxis. A small number of patients have been transplanted without any posttransplant graft-versus host disease prophylaxis. Two studies, primarily in children, demonstrated that about 35% of patients without graft-versus-host disease prophy laxis did not develop acute disease (16, 17). A randomized study in adults, however, demonstrated that alliS patients, who received no methotrexate prophylaxis, died from acute graft-versus-host disease (18). The major
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difference between the Seattle and the other studies was the age of the transplant recipients. The incidence of acute graft-versus-host disease is significantly less in pediatric as compared to adult patients. Thus, prophy laxis for acute graft-versus-host disease is necessary for adult patients and the majority of pediatric patients. In spite of prophylaxis with metho trexate, 40% of adult patients developed clinically significant acute graft versus-host disease. Additional agents have been evaluated for graft versus-host disease prophylaxis (antithymocyte globulin, steroids, cyclo phosphamide). None of the drugs, individually or in combination, sig nificantly reduced the incidence or severity of acute graft-versus-host disease. Cyclosporine, used as an immunosuppressant agent for solid organ transplantation, and methotrexate were compared as single agents to prevent acute graft-versus-host disease and were found to be equally efficacious (19). However, cyclosporine, in combination with either metho trexate or steroids, can reduce the incidence of acute graft-versus-host disease in adult patients from 40% to 20% (20). The combination of cyclosporine and steroids results in more rapid hematopoietic recovery than is seen with eyclosporine and methotrexate since methotrexate is an antimetabolite.
Graft-versus-Leukemia Effect The classic model of graft-versus-host disease states that the target antigens are histocompatibility antigens uniquely expressed on recipient cells. Residual leukemic cells express recipient histocompatibility antigens. Analysis of patients transplanted for leukemia, especially patients with acute lymphoblastic leukemia, shows a decreased incidence of leukemic relapse in recipients of allogeneic, as opposed to syngeneic or autologous, bone marrow (21). When allogeneic transplant recipients were analyzed for the presence or absence of acute graft-versus-host disease, a decreased incidence of leukemic relapse was observed in individuals with the disease. Individuals without acute graft-versus-host disease had a leukemic relapse rate similar to that seen in recipients of syngeneic or autologous bone marrow. Presumably, the effector mechanisms of acute graft-versus-host disease are capable of destroying residual leukemic cells. Although such a graft-versus-Ieukemia effect is clear cut in patients with acute lym phoblastic leukemia, controversy exists as to its role (if any) in patients with acute myelogenous leukemia, lymphoma, and chronic myelogenous leukemia (22). The decreased incidence of leukemic relapse in allogeneic transplant recipients with acute graft-versus-host disease has not improved overall survival, since acute graft-versus-host disease results in an increased inci dence of transplant-related deaths. Most studies, therefore, show no net
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improvement in overall survival. The recent introduction of more effective graft-versus-host disease prophylaxis (cyclosporine plus steroids or cyclo sporine plus methotrexate) may result in an increased incidence of leukemic relapse. The presence of a graft-versus-Ieukemia effect only highlights the need for better preparative regimens for patients with neoplastic diseases. The initial analyses of the graft-versus-Ieukemia effect showed an associ ation with acute graft-versus-host disease. More recent analysis has shown that the graft-versus-Ieukemia effect is associated with the presence of chronic graft-versus-host disease as well (23). Since steroids are a major therapeutic modality for chronic graft-versus-host disease, one of the com pounding variables is whether the steroids exert an antileukemic effect or whether the disease itself has a direct antileukemia effect.
Chronic Graft-versus-Host Disease As early transplant-related deaths due to infections, acute graft-versus host disease, and therapeutic toxicities are reduced, more patients survive with chronic graft-versus-host disease. Chronic graft-versus-host disease is an age-dependent phenomenon, with the presence of the acute form being the major predictor for the development of the chronic form of the
disease (24). In patients in whom no acute graft-versus-host disease occurs, recipient age and transplantation from a multiparous female into a male recipient are associated with an increased risk of chronic graft-versus-host disease. The principal pathologic feature of graft-versus-host disease is increased collagen deposition, which leads to the clinical manifestations of sclerodermatous skin changes, hypo- and hyperpigmentation, pulmonary fibrosis, decreased gastrointestinal motility, and malabsorption (25). The clinical similarity between patients with chronic graft-versus-host disease and patients with other immune diseases, particularly scleroderma, is striking. Initially, chronic graft-versus-host disease patients had an increased incidence of latc bacterial and varicella-zoster infections (26). The routine administration of both intravenous immunoglobulin to compensate for the patients' inability to make protective antipolysaccharide antibodies and trimethoprim/sulfamethoxazole prophylaxis markedly reduced the incidence of infections with encapsulated respiratory bacteria. The emer gcnce of antiviral agents (acyclovir) has reduced the morbidity and mortality associated with varicella-zoster infections. Initially, therapy for chronic graft-versus-host disease consisted first of steroids and later of steroids plus azathioprine (27). Comparative trials, however, revealed that the use of azathioprine, particularly in patients with thrombocytopenia, increased mortality. The introduction of combined
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modality therapy, with cyclosporine and steroids on an alternate-day basis, has improved both survival rates and performance scores (28).
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Immunocompetence Although selective experiments have been able to show the transfer of donor-specific immunity to recipients, particularly if donors are immu nized in the pretransplant period, the long-term transfer of clinically sig nificant immunity from donor to recipient does not routinely occur (29,30). The pretransplant cytoablation that transplant recipients receive eradicates their antigen-specific immunological memory. Thus, since there is no sig nificant transfer of antigen-specific donor T and B lymphocytes and since the recipient immunity is ablated, patients in the immediate posttransplant period have no antigen-specific immune function. Patients need to be reimmunized with standard vaccines in order to develop protective immun ity to the common viral pathogens. The presence of acute graft-versus host disease and its concomitant therapy can further delay immunological competence. A recapitulation of immunological ontogeny occurs in transplant recipi ents paralleling that seen in normal fetuses and infants. Of particular importance is the fact that delays occur in the ability of transplant recipi ents to make anticarbohydrate antibodies, just as normal children are unable to make antibodies to encapsulated respiratory pathogens. In vitro analysis of the immunological function of transplant recipients has shown defects in both T- and B-lymphocyte function (31,32). In vitro experiments, in which normal donor T and B lymphocytes are co-cultured with recipient T and B lymphocytes, show functional abnormalities in both recipient T and B lymphocytes. Thus, the immunodeficiency of the posttransplant patient is complex and can be made worse by chronic graft versus-host disease with its concomitant immunosuppressive therapy.
Conclusion Graft-versus-host disease is a complex biological event that occurs fol lowing allogeneic bone marrow transplantation. Graft-versus-host disease and its clinical consequences contribute to much of the morbidity and mortality associated with bone marrow transplantation. Improved therapy to prevent and treat acute and chronic graft-versus-host disease will improve the results of bone marrow transplantation. ACKNOWLEDGMENTS
This work was supported in part by the American Cancer Society Grant IM-602.
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Literature Cited 12. O'Reilly, R. J., Keever, C. A., Small, T. N., Brochstein, J. 1989. The use ofHLA non-identical T-cell-depleted marrow transplants for correction of severe com bined immunodeficiency disease. Immu node! Rev. I: 273-309 13. Mitsuyasu, R., Champlin, R. E., Gale, R. P., et al. 1986. Depletion of T lym phocytes from donor bone marrow for the prevention of graft-versus-host dis ease following bone marrow trans plantation. Ann. Intern. Med. 105: 2026 14. Ash, R. C., Casper, J. T., Chitambar, C. R., et al. 1990. Successful allogeneic transplantation of T-celi-depleted bone marrow from closely HLA-matched unrelated donors. N. Engl. J. Med. 322:
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32. Wi the rspoo n R. P., Goehle, S., Kret schmer, M., et al. 1986. Regulation of immunoglobulin production after human marrow grafting: The role of he lp er and suppre ss or T cells in acute graft-versus-host disease. Transplan tation 4 1: 328-35 ,
