Graft-versus-Host Disease — From the Bench to the Bedside?
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《新英格兰医药杂志》
Myeloablative conditioning with high doses of chemotherapy before transplantation of allogeneic hematopoietic stem cells is a procedure that can cure hematologic malignant diseases, but its wide applicability is limited by a substantial death rate. Acute graft-versus-host disease (GVHD), which occurs in more than half the patients who undergo this treatment, is the main contributor to transplant-related mortality.
Recent experimental data indicate that acute GVHD develops in three phases1,2: epithelial-cell injury caused by the conditioning regimen; activation of donor T-cell lymphocytes by antigens presented by the recipient's dendritic cells; and cell death induced by activated T cells, cytokines (such as tumor necrosis factor ), and cells of the innate immune system. HLA disparity between donor and recipient is the major predisposing factor. Other factors include the ages of the donor and the recipient, sex mismatch (female donor and male recipient), mismatched minor histocompatibility antigens in HLA-matched transplants, the source and dose of the transplanted hematopoietic stem cells, the intensity of the preparative regimen, and prophylaxis against GVHD or T-cell depletion of the graft.3,4
In the past few years, the development of nonmyeloablative conditioning regimens has been spurred by two concepts.5,6 The first is that the curative potential of hematopoietic-cell transplantation is due mainly to the killing of the recipient's malignant cells by T lymphocytes in the graft (graft-versus-leukemia effect), rather than by the dose-intensity of the regimen. The second is that highly immunosuppressive, nonmyeloablative conditioning regimens can allow the engraftment of allogeneic cells and lessen epithelial-cell injury, thereby reducing the risk of GVHD. Nonmyeloablative conditioning regimens are being used increasingly; today, they are used in at least 40 percent of all hematopoietic stem-cell–transplantation procedures. These regimens allow transplantation in older patients and in patients with coexisting conditions who would otherwise be precluded from receiving an allogeneic transplant.5
Reduced-intensity preparation for transplantation not only limits damage to the recipient's tissues but also can establish a transient or long-lasting donor–host chimerism. Such a state of hematopoietic-cell chimerism — an indication of mutual immunologic tolerance of the graft for the host, and vice versa — may reduce GVHD activity.7 Indeed, two retrospective analyses of cohorts of patients who had undergone either nonablative or myeloablative conditioning found that the cumulative incidence of severe acute GVHD was significantly lower among those who had undergone nonablative conditioning.8,9 In both studies, the nonablative conditioning regimens were associated with delayed onset of GVHD. This delay is important, because in the past, any manifestation of GVHD at 100 days after transplantation or thereafter was arbitrarily defined as chronic GVHD, even if the clinical manifestations were indistinguishable from those of the acute disease. It appears from these two studies and other studies that nonablative conditioning has altered the presentation and natural history of both acute and chronic GVHD, bringing previous definitions of these complications into question. Currently, the consensus is that clinical manifestations, and not time to onset after transplantation, determine whether GVHD is considered to be acute or chronic.
Although nonablative conditioning reduces the risk of GVHD, this complication of hematopoietic stem-cell transplantation remains a clinically significant problem. A new approach to its prevention takes advantage of the immune system's regulatory T cells. In mice, two types of regulatory T cells, natural killer T cells and CD4+CD25+ T cells, can inhibit acute GVHD. CD4 + CD25+ T cells not only have a vital role in the maintenance of tolerance to self-antigens but also, when present in the stem-cell graft, prevent GVHD without loss of the graft-versus-leukemia effect.10,11
Experimental studies have shown that regulatory natural killer T cells can also prevent acute GVHD.12 Natural killer T cells constitute only a minority of all T cells in the spleen of a normal mouse, but after repeated treatments with low-dose irradiation targeted to lymphoid organs, these cells increase in number and ultimately become the majority of T cells in the spleen and marrow because they are radioresistant, as compared with CD4+ T cells. The potential clinical usefulness of these observations was shown in murine recipients of allogeneic bone marrow that were conditioned with anti–T cell antibodies and repeated low doses of total lymphoid irradiation. These mice were fully protected from GVHD.
In this issue of the Journal, Lowsky and coworkers report on bringing these experiments in mice to the clinic.13 They report data on 37 patients with lymphoid malignant diseases or acute leukemia who underwent conditioning with total lymphoid irradiation and polyclonal antithymocyte globulin as preparation for hematopoietic stem-cell transplantation. Of these 37 patients, only 2 had acute GVHD. In patients with lymphoid malignant diseases, antitumor effects were shown by the change from partial to complete remission.
The low incidence of GVHD in this study is impressive. The incidence is within the range that has been reported with use of T-cell–depleted grafts, but such grafts increase the risk of relapse because they lack graft-versus-tumor T cells. There are, however, some caveats with regard to the study by Lowsky and coworkers. First, the small number of patients precludes a definitive conclusion. Second, a calculation of the cumulative incidence rate of acute GVHD that takes competing risks into account was not used, making it difficult to compare the 5.4 percent crude incidence reported with cumulative incidences reported by others. Third, the authors defined acute GVHD with the use of the day 100 benchmark, but this may underestimate the true incidence because of the delayed onset of GVHD after nonablative conditioning. Fourth, it is unclear whether the low incidence of GVHD can be attributed to the presence of natural killer T cells, as in the murine model; the small numbers of circulating host T cells do not provide a clear answer for an increase in natural killer T cells. Finally, antithymocyte globulin could account for T-cell depletion of the graft even if antithymocyte globulin was not detected a week after transplantation.
Nonablative conditioning regimens have opened a new era in the field of allogeneic stem-cell transplantation. Forthcoming studies will compare, in randomized trials, different types of nonablative or reduced-intensity conditioning in well-defined cohorts of patients with single diseases. These trials will be the ideal platform to test the role of regulatory T cells and to learn more about GVHD from the bedside to the bench.
Source Information
From the Service d'Hématologie–Greffe de Moelle, H?pital Saint Louis, Université Paris VII, and INSERM Unité 728 — all in Paris.
References
Ferrara JLM, Deeg HJ. Graft-versus-host disease. N Engl J Med 1991;324:667-674.
Antin JH, Ferrara JL. Cytokine dysregulation and acute graft-versus-host disease. Blood 1992;80:2964-2968.
Socie G, Cahn JY. Acute graft-versus-host disease. In: Barrett AJ, Treleaven J, eds. The clinical practice of stem-cell transplantation. Oxford, England: Isis Medical Media, 1998:595-618.
Couriel D, Caldera H, Champlin RE, Komanduri K. Acute graft-versus-host disease: pathophysiology, clinical manifestations, and management. Cancer 2004;101:1936-1946.
Storb RF, Champlin R, Riddell SR, Murata M, Bryant S, Warren EH. Non-myeloablative transplants for malignant disease. Hematology (Am Soc Hematol Educ Program) 2001:375-91.
Little MT, Storb R. The future of allogeneic hematopoietic stem cell transplantation: minimizing pain, maximizing gain. J Clin Invest 2000;105:1679-1681.
Satwani P, Harrison L, Morris E, Del Toro G, Cairo MS. Reduced-intensity allogeneic stem cell transplantation in adults and children with malignant and nonmalignant diseases: end of the beginning and future challenges. Biol Blood Marrow Transplant 2005;11:403-422.
Couriel DR, Saliba RM, Giralt S, et al. Acute and chronic graft-versus-host disease after ablative and nonmyeloablative conditioning for allogeneic hematopoietic transplantation. Biol Blood Marrow Transplant 2004;10:178-185.
Mielcarek M, Martin PJ, Leisenring W, et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 2003;102:756-762.
Edinger M, Hoffmann P, Ermann J, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 2003;9:1144-1150.
Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med 2002;196:389-399.
Zeng D, Lewis D, Dejbakhsh-Jones S, et al. Bone marrow NK1.1(-) and NK1.1(+) T cells reciprocally regulate acute graft versus host disease. J Exp Med 1999;189:1073-1081.
Lowsky R, Takahashi T, Liu YP, et al. Protective conditioning for acute graft-versus-host disease. N Engl J Med 2005;353:1321-1331.(Gérard Socié, M.D., Ph.D.)
Recent experimental data indicate that acute GVHD develops in three phases1,2: epithelial-cell injury caused by the conditioning regimen; activation of donor T-cell lymphocytes by antigens presented by the recipient's dendritic cells; and cell death induced by activated T cells, cytokines (such as tumor necrosis factor ), and cells of the innate immune system. HLA disparity between donor and recipient is the major predisposing factor. Other factors include the ages of the donor and the recipient, sex mismatch (female donor and male recipient), mismatched minor histocompatibility antigens in HLA-matched transplants, the source and dose of the transplanted hematopoietic stem cells, the intensity of the preparative regimen, and prophylaxis against GVHD or T-cell depletion of the graft.3,4
In the past few years, the development of nonmyeloablative conditioning regimens has been spurred by two concepts.5,6 The first is that the curative potential of hematopoietic-cell transplantation is due mainly to the killing of the recipient's malignant cells by T lymphocytes in the graft (graft-versus-leukemia effect), rather than by the dose-intensity of the regimen. The second is that highly immunosuppressive, nonmyeloablative conditioning regimens can allow the engraftment of allogeneic cells and lessen epithelial-cell injury, thereby reducing the risk of GVHD. Nonmyeloablative conditioning regimens are being used increasingly; today, they are used in at least 40 percent of all hematopoietic stem-cell–transplantation procedures. These regimens allow transplantation in older patients and in patients with coexisting conditions who would otherwise be precluded from receiving an allogeneic transplant.5
Reduced-intensity preparation for transplantation not only limits damage to the recipient's tissues but also can establish a transient or long-lasting donor–host chimerism. Such a state of hematopoietic-cell chimerism — an indication of mutual immunologic tolerance of the graft for the host, and vice versa — may reduce GVHD activity.7 Indeed, two retrospective analyses of cohorts of patients who had undergone either nonablative or myeloablative conditioning found that the cumulative incidence of severe acute GVHD was significantly lower among those who had undergone nonablative conditioning.8,9 In both studies, the nonablative conditioning regimens were associated with delayed onset of GVHD. This delay is important, because in the past, any manifestation of GVHD at 100 days after transplantation or thereafter was arbitrarily defined as chronic GVHD, even if the clinical manifestations were indistinguishable from those of the acute disease. It appears from these two studies and other studies that nonablative conditioning has altered the presentation and natural history of both acute and chronic GVHD, bringing previous definitions of these complications into question. Currently, the consensus is that clinical manifestations, and not time to onset after transplantation, determine whether GVHD is considered to be acute or chronic.
Although nonablative conditioning reduces the risk of GVHD, this complication of hematopoietic stem-cell transplantation remains a clinically significant problem. A new approach to its prevention takes advantage of the immune system's regulatory T cells. In mice, two types of regulatory T cells, natural killer T cells and CD4+CD25+ T cells, can inhibit acute GVHD. CD4 + CD25+ T cells not only have a vital role in the maintenance of tolerance to self-antigens but also, when present in the stem-cell graft, prevent GVHD without loss of the graft-versus-leukemia effect.10,11
Experimental studies have shown that regulatory natural killer T cells can also prevent acute GVHD.12 Natural killer T cells constitute only a minority of all T cells in the spleen of a normal mouse, but after repeated treatments with low-dose irradiation targeted to lymphoid organs, these cells increase in number and ultimately become the majority of T cells in the spleen and marrow because they are radioresistant, as compared with CD4+ T cells. The potential clinical usefulness of these observations was shown in murine recipients of allogeneic bone marrow that were conditioned with anti–T cell antibodies and repeated low doses of total lymphoid irradiation. These mice were fully protected from GVHD.
In this issue of the Journal, Lowsky and coworkers report on bringing these experiments in mice to the clinic.13 They report data on 37 patients with lymphoid malignant diseases or acute leukemia who underwent conditioning with total lymphoid irradiation and polyclonal antithymocyte globulin as preparation for hematopoietic stem-cell transplantation. Of these 37 patients, only 2 had acute GVHD. In patients with lymphoid malignant diseases, antitumor effects were shown by the change from partial to complete remission.
The low incidence of GVHD in this study is impressive. The incidence is within the range that has been reported with use of T-cell–depleted grafts, but such grafts increase the risk of relapse because they lack graft-versus-tumor T cells. There are, however, some caveats with regard to the study by Lowsky and coworkers. First, the small number of patients precludes a definitive conclusion. Second, a calculation of the cumulative incidence rate of acute GVHD that takes competing risks into account was not used, making it difficult to compare the 5.4 percent crude incidence reported with cumulative incidences reported by others. Third, the authors defined acute GVHD with the use of the day 100 benchmark, but this may underestimate the true incidence because of the delayed onset of GVHD after nonablative conditioning. Fourth, it is unclear whether the low incidence of GVHD can be attributed to the presence of natural killer T cells, as in the murine model; the small numbers of circulating host T cells do not provide a clear answer for an increase in natural killer T cells. Finally, antithymocyte globulin could account for T-cell depletion of the graft even if antithymocyte globulin was not detected a week after transplantation.
Nonablative conditioning regimens have opened a new era in the field of allogeneic stem-cell transplantation. Forthcoming studies will compare, in randomized trials, different types of nonablative or reduced-intensity conditioning in well-defined cohorts of patients with single diseases. These trials will be the ideal platform to test the role of regulatory T cells and to learn more about GVHD from the bedside to the bench.
Source Information
From the Service d'Hématologie–Greffe de Moelle, H?pital Saint Louis, Université Paris VII, and INSERM Unité 728 — all in Paris.
References
Ferrara JLM, Deeg HJ. Graft-versus-host disease. N Engl J Med 1991;324:667-674.
Antin JH, Ferrara JL. Cytokine dysregulation and acute graft-versus-host disease. Blood 1992;80:2964-2968.
Socie G, Cahn JY. Acute graft-versus-host disease. In: Barrett AJ, Treleaven J, eds. The clinical practice of stem-cell transplantation. Oxford, England: Isis Medical Media, 1998:595-618.
Couriel D, Caldera H, Champlin RE, Komanduri K. Acute graft-versus-host disease: pathophysiology, clinical manifestations, and management. Cancer 2004;101:1936-1946.
Storb RF, Champlin R, Riddell SR, Murata M, Bryant S, Warren EH. Non-myeloablative transplants for malignant disease. Hematology (Am Soc Hematol Educ Program) 2001:375-91.
Little MT, Storb R. The future of allogeneic hematopoietic stem cell transplantation: minimizing pain, maximizing gain. J Clin Invest 2000;105:1679-1681.
Satwani P, Harrison L, Morris E, Del Toro G, Cairo MS. Reduced-intensity allogeneic stem cell transplantation in adults and children with malignant and nonmalignant diseases: end of the beginning and future challenges. Biol Blood Marrow Transplant 2005;11:403-422.
Couriel DR, Saliba RM, Giralt S, et al. Acute and chronic graft-versus-host disease after ablative and nonmyeloablative conditioning for allogeneic hematopoietic transplantation. Biol Blood Marrow Transplant 2004;10:178-185.
Mielcarek M, Martin PJ, Leisenring W, et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 2003;102:756-762.
Edinger M, Hoffmann P, Ermann J, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 2003;9:1144-1150.
Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med 2002;196:389-399.
Zeng D, Lewis D, Dejbakhsh-Jones S, et al. Bone marrow NK1.1(-) and NK1.1(+) T cells reciprocally regulate acute graft versus host disease. J Exp Med 1999;189:1073-1081.
Lowsky R, Takahashi T, Liu YP, et al. Protective conditioning for acute graft-versus-host disease. N Engl J Med 2005;353:1321-1331.(Gérard Socié, M.D., Ph.D.)