Key Points
-
Recent developments in allogeneic haematopoietic stem-cell transplantation (HSCT) for cancer patients are changing the focus of HSCT from a rescue strategy for high-dose chemotherapy and/or radiation therapy to a platform for new immunotherapeutic strategies.
-
Donor T cells are crucial in graft-versus-host disease (GVHD), graft-versus-tumour (GVT) activity and engraftment after allogeneic HSCT.
-
Donor T cells mediate GVHD and GVT activity through several pathways, including direct cytotoxicity by means of Fas ligand and cytotoxic granules that contain perforin and granzymes, and cytokines, such as tumour-necrosis factor and interferon-γ.
-
Donor T cells make selective use of their effector pathways to mediate target-organ GVHD. For example, Fas ligand is essential for liver GVHD, whereas TNF is important for intestinal GVHD.
-
Most studies indicate a dominant role for perforin in GVT activity.
-
Studies in mouse models have shown that GVHD and GVT activity can be separated by the specific inhibition of the Fas ligand or perforin pathways. This indicates that therapeutic strategies that target the cytolytic pathways could provide new opportunities to enhance GVT effects and/or decrease GVHD that is mediated by donor T cells.
Abstract
The remarkable activity of donor T cells against malignant cells in the context of an allogeneic haematopoietic stem-cell transplantation (HSCT) is arguably, at present, the most potent clinical immunotherapy for cancer. However, alloreactive donor T cells are also important effector cells in the development of graft-versus-host disease (GVHD), which is a potentially lethal complication for recipients of an allogeneic HSCT. Therefore, the separation of the GVHD and graft-versus-tumour (GVT) activity of donor T cells has become a topic of great interest for many investigators. Recent studies have shown that donor T cells make differential use of their cytolytic pathways in mediating GVHD and GVT effects. Therefore, the selective blockade or enhancement of cytolytic pathways provides an intriguing therapeutic opportunity to separate the desired GVT effect from the potentially devastating GVHD.
Similar content being viewed by others
References
Appelbaum, F. R. Haematopoietic cell transplantation as immunotherapy. Nature 411, 385–389 (2001).Describes the 'paradigm shift' in haematopoietic stem-cell transplantation from a platform for high-dose chemotherapy/radiation therapy to immunotherapy.
Ferrara, J. L., Levy, R. & Chao, N. J. Pathophysiologic mechanisms of acute graft-vs.-host disease. Biol. Blood Marrow Transplant. 5, 347–356 (1999).Provides a comprehensive, well-written analysis of our current understanding of the complex pathophysiology of graft-versus-host disease.
Vogelsang, G. B. Acute and chronic graft-versus-host disease. Curr. Opin. Oncol. 5, 276–281 (1993).
Truitt, R. L. & Johnson, B. D. Principles of graft-vs.-leukemia reactivity. Biol. Blood Marrow Transplant. 1, 61–68 (1995).
Goulmy, E. Human minor histocompatibility antigens: new concepts for marrow transplantation and adoptive immunotherapy. Immunol. Rev. 157, 125–140 (1997).
McSweeney, P. A. et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 97, 3390–3400 (2001).
Kolb, H. J. et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood 86, 2041–2050 (1995).
Kernan, N. A. in Hematopoietic Cell Transplantation (eds Forman, S. J., Blume, K. G. & Thomas, E. D.) 186–196 (Blackwell Science, Malden, Massachusetts, 1999).
Weiden, P. L. et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N. Engl. J. Med. 300, 1068–1073 (1979).
Kagi, D. et al. Fas and perforin pathways as major mechanisms of T-cell-mediated cytotoxicity. Science 265, 528–530 (1994).
Lowin, B., Hahne, M., Mattmann, C. & Tschopp, J. Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature 370, 650–652 (1994).References 10 and 11 used mice that are deficient for perforin or FasL to show that the perforin and FasL cytolytic pathways are responsible for most of the cytolytic activity of T cells.
Nagata, S. Apoptosis by death factor. Cell 88, 355–365 (1997).
Suzuki, I. & Fink, P. J. Maximal proliferation of cytotoxic T lymphocytes requires reverse signaling through Fas ligand. J. Exp. Med. 187, 123–128 (1998).
Kishimoto, H., Surh, C. D. & Sprent, J. A role for Fas in negative selection of thymocytes in vivo. J. Exp. Med. 187, 1427–1438 (1998).
Kagi, D. et al. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 369, 31–37 (1994).
Matloubian, M. et al. A role for perforin in downregulating T-cell responses during chronic viral infection. J. Virol. 73, 2527–2536 (1999).
Smyth, M. J., Godfrey, D. I. & Trapani, J. A. A fresh look at tumor immunosurveillance and immunotherapy. Nature Immunol. 2, 293–299 (2001).
Van den Broek, M. E. et al. Decreased tumor surveillance in perforin-deficient mice. J. Exp. Med. 184, 1781–1790 (1996).
Topham, D. J., Tripp, R. A. & Doherty, P. C. CD8+ T cells clear influenza virus by perforin- or Fas-dependent processes. J. Immunol. 159, 5197–5200 (1997).
Straus, S. E. et al. The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood 98, 194–200 (2001).
Davidson, W. F., Giese, T. & Fredrickson, T. N. Spontaneous development of plasmacytoid tumors in mice with defective Fas–Fas-ligand interactions. J. Exp. Med. 187, 1825–1838 (1998).
Spaner, D., Raju, K., Rabinovich, B. & Miller, R. G. A role for perforin in activation-induced T-cell death in vivo: increased expansion of allogeneic perforin-deficient T cells in SCID mice. J. Immunol. 162, 1192–1199 (1999).
Sambhara, S. et al. Enhanced antibody and cytokine responses to influenza viral antigens in perforin-deficient mice. Cell. Immunol. 187, 13–18 (1998).
Peng, S. L., Moslehi, J., Robert, M. E. & Craft, J. Perforin protects against autoimmunity in lupus-prone mice. J. Immunol. 160, 652–660 (1998).
Lee, S. et al. Difference in the expression of Fas/Fas-ligand and the lymphocyte subset reconstitution according to the occurrence of acute GVHD. Bone Marrow Transplant. 20, 883–888 (1997).
Shustov, A., Nguyen, P., Finkelman, F., Elkon, K. B. & Via, C. S. Differential expression of Fas and Fas ligand in acute and chronic graft-versus-host disease: up-regulation of Fas and Fas ligand requires CD8+ T-cell activation and IFN-γ production. J. Immunol. 161, 2848–2855 (1998).
Wasem, C. et al. Accumulation and activation-induced release of preformed Fas (CD95) ligand during the pathogenesis of experimental graft-versus-host disease. J. Immunol. 167, 2936–2941 (2001).
Das, H. et al. Levels of soluble FasL and FasL gene expression during the development of graft-versus-host disease in DLT-treated patients. Br. J. Haematol. 104, 795–800 (1999).
Kanda, Y. et al. Increased soluble Fas-ligand in sera of bone-marrow transplant recipients with acute graft-versus-host disease. Bone Marrow Transplant. 22, 751–754 (1998).
Liem, L. M. et al. Soluble Fas levels in sera of bone marrow transplantation recipients are increased during acute graft-versus-host disease but not during infections. Blood 91, 1464–1468 (1998).
Braun, M. Y., Lowin, B., French, L., Acha-Orbea, H. & Tschopp, J. Cytotoxic T cells deficient in both functional Fas ligand and perforin show residual cytolytic activity yet lose their capacity to induce lethal acute graft-versus-host disease. J. Exp. Med. 183, 657–661 (1996).
Via, C. S., Nguyen, P., Shustov, A., Drappa, J. & Elkon, K. B. A major role for the Fas pathway in acute graft-versus-host disease. J. Immunol. 157, 5387–5393 (1996).
Baker, M. B., Altman, N. H., Podack, E. R. & Levy, R. B. The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice. J. Exp. Med. 183, 2645–2656 (1996).References 31–33 (and reference 37 ) used mouse models of HSCT and mice that were deficient for FasL, perforin or granzyme B; they were the first to show the importance of the FasL and perforin–granzyme cytolytic pathways in the development of GVHD.
Baker, M. B., Riley, R. L., Podack, E. R. & Levy, R. B. Graft-versus-host-disease-associated lymphoid hypoplasia and B-cell dysfunction is dependent upon donor T-cell-mediated Fas-ligand function, but not perforin function. Proc. Natl Acad. Sci. USA 94, 1366–1371 (1997).
Graubert, T. A., DiPersio, J. F., Russell, J. H. & Ley, T. J. Perforin/granzyme-dependent and independent mechanisms are both important for the development of graft-versus-host disease after murine bone marrow transplantation. J. Clin. Invest. 100, 904–911 (1997).
Teshima, T. et al. IL-11 separates graft-versus-leukemia effects from graft-versus-host disease after bone marrow transplantation. J. Clin. Invest. 104, 317–325 (1999).
Graubert, T. A., Russell, J. H. & Ley, T. J. The role of granzyme B in murine models of acute graft-versus-host disease and graft rejection. Blood 87, 1232–1237 (1996).
Schmaltz, C. et al. Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect. Blood 97, 2886–2895 (2001).
Tsukada, N., Kobata, T., Aizawa, Y., Yagita, H. & Okumura, K. Graft-versus-leukemia effect and graft-versus-host disease can be differentiated by cytotoxic mechanisms in a murine model of allogeneic bone marrow transplantation. Blood 93, 2738–2747 (1999).References 37–39 (and reference 52 ) showed, in mouse HSCT models, the differential use of the FasL and perforin cytolytic pathways by donor T cells in GVHD and GVT activity.
Blazar, B. R., Taylor, P. A. & Vallera, D. A. CD4+ and CD8+ T cells each can utilize a perforin-dependent pathway to mediate lethal graft-versus-host disease in major histocompatibility complex-disparate recipients. Transplantation 64, 571–576 (1997).
Shustov, A. et al. Role of perforin in controlling B-cell hyperactivity and humoral autoimmunity. J. Clin. Invest. 106, R39–R47 (2000).
Miwa, K. et al. Therapeutic effect of an anti-Fas ligand mAb on lethal graft-versus- host disease. Int. Immunol. 11, 925–931 (1999).
Mori, T. et al. Involvement of Fas-mediated apoptosis in the hematopoietic progenitor cells of graft-versus-host-reaction-associated myelosuppression. Blood 92, 101–107 (1998).
Hattori, K. et al. Differential effects of anti-Fas ligand and anti-tumor necrosis factor-α antibodies on acute graft-versus-host disease pathologies. Blood 91, 4051–4055 (1998).This study showed, by the administration of neutralizing antibodies in mouse HSCT models, the specific role of the FasL and TNF pathways in the development of target-organ GVHD.
Van den Brink, M. R. et al. Fas-deficient lpr mice are more susceptible to graft-versus-host disease. J. Immunol. 164, 469–480 (2000).
Kondo, T., Suda, T., Fukuyama, H., Adachi, M. & Nagata, S. Essential roles of the Fas ligand in the development of hepatitis. Nature Med. 3, 409–413 (1997).
Piguet, P. F., Grau, G. E., Allet, B. & Vassalli, P. Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease. J. Exp. Med. 166, 1280–1289 (1987).
Herve, P. et al. Phase I–II trial of a monoclonal anti-tumor necrosis factor-α antibody for the treatment of refractory severe acute graft-versus-host disease. Blood 79, 3362–3368 (1992).
Lin, T. et al. Fas-ligand-mediated killing by intestinal intraepithelial lymphocytes. Participation in intestinal graft-versus-host disease. J. Clin. Invest. 101, 570–577 (1998).
Stuber, E., Buschenfeld, A., von Freier, A., Arendt, T. & Folsch, U. R. Intestinal crypt cell apoptosis in murine acute graft-versus-host disease is mediated by tumour necrosis factor-α and not by the FasL–Fas interaction: effect of pentoxifylline on the development of mucosal atrophy. Gut 45, 229–235 (1999).
Pan, L. et al. Granulocyte colony-stimulating factor-mobilized allogeneic stem cell transplantation maintains graft-versus-leukemia effects through a perforin-dependent pathway while preventing graft-versus-host disease. Blood 93, 4071–4078 (1999).
Hsieh, M. H. & Korngold, R. Differential use of FasL- and perforin-mediated cytolytic mechanisms by T-cell subsets involved in graft-versus-myeloid leukemia responses. Blood 96, 1047–1055 (2000).
Hattori, K. et al. A metalloproteinase inhibitor prevents lethal acute graft-versus-host disease in mice. Blood 90, 542–548 (1997).
Ito, M. & Shizuru, J. A. Graft-vs.-lymphoma effect in an allogeneic hematopoietic stem cell transplantation model. Biol. Blood Marrow Transplant. 5, 357–368 (1999).
Martin, P. J., Akatsuka, Y., Hahne, M. & Sale, G. Involvement of donor T-cell cytotoxic effector mechanisms in preventing allogeneic marrow graft rejection. Blood 92, 2177–2181 (1998).This study showed in mouse HSCT models that the recipient CD8+ T-cell effectors that are responsible for causing bone-marrow graft rejection are sensitive to cytotoxicity that is mediated by both perforin- and FasL-dependent mechanisms, and also, that donor T cells must have at least one functional cytotoxic mechanism to prevent allogeneic marrow graft rejection.
Baker, M. B., Podack, E. R. & Levy, R. B. Perforin- and Fas-mediated cytotoxic pathways are not required for allogeneic resistance to bone marrow grafts in mice. Biol. Blood Marrow Transplant. 1, 69–73 (1995).
Iwasaki, T. et al. Effect of graft-versus-host disease (GVHD) on host hematopoietic progenitor cells is mediated by Fas–Fas-ligand interactions but this does not explain the effect of GVHD on donor cells. Cell. Immunol. 197, 30–38 (1999).
Blazar, B. R. et al. Host T cells resist graft-versus-host disease mediated by donor leukocyte infusions. J. Immunol. 165, 4901–4909 (2000).
Lan, F., Zeng, D., Huie, P., Higgins, J. P. & Strober, S. Allogeneic bone marrow cells that facilitate complete chimerism and eliminate tumor cells express both CD8 and T-cell antigen receptor-αβ. Blood 97, 3458–3465 (2001).
Reich-Zeliger, S., Zhao, Y., Krauthgamer, R., Bachar-Lustig, E. & Reisner, Y. Anti-third party CD8+ CTLs as potent veto cells: coexpression of CD8 and FasL is a prerequisite. Immunity 13, 507–515 (2000).
Van den Brink, M. R. et al. Fas-ligand-deficient gld mice are more susceptible to graft-versus-host disease. Transplantation 70, 184–191 (2000).
Jiang, Z., Jones, M. & Levy, R. B. FasL and perforin cytotoxically impaired donor T cells induce GVHD in TNF receptor 1 (p55)-knockout MHC I/II mismatched recipients. Biol. Blood Marrow Transplant. 7, 76 (2001).
Jiang, Z., Podack, E. & Levy, R. B. Major-histocompatibility-complex-mismatched allogeneic bone marrow transplantation using perforin and/or Fas ligand double-defective CD4(+) donor T cells: involvement of cytotoxic function by donor lymphocytes prior to graft-versus-host disease pathogenesis. Blood 98, 390–397 (2001).
Ware, C. F., VanArsdale, T. L., Crowe, P. D. & Browning, J. L. The ligands and receptors of the lymphotoxin system. Curr. Top. Microbiol. Immunol. 198, 175–218 (1995).
Kaplan, M. J., Ray, D., Mo, R. R., Yung, R. L. & Richardson, B. C. TRAIL (Apo2 ligand) and TWEAK (Apo3 ligand) mediate CD4+ T-cell killing of antigen-presenting macrophages. J. Immunol. 164, 2897–2904 (2000).
Thomas, W. D. & Hersey, P. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in Fas ligand-resistant melanoma cells and mediates CD4 T-cell killing of target cells. J. Immunol. 161, 2195–2200 (1998).
Kayagaki, N. et al. Involvement of TNF-related apoptosis-inducing ligand in human CD4+ T-cell-mediated cytotoxicity. J. Immunol. 162, 2639–2647 (1999).
Horowitz, M. M. et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75, 555–562 (1990).
Slavin, S. et al. Allogeneic cell therapy with donor peripheral blood cells and recombinant human interleukin-2 to treat leukemia relapse after allogeneic bone marrow transplantation. Blood 87, 2195–2204 (1996).
Johnson, B. D., Drobyski, W. R. & Truitt, R. L. Delayed infusion of normal donor cells after MHC-matched bone marrow transplantation provides an antileukemia reaction without graft-versus-host disease. Bone Marrow Transplant. 11, 329–336 (1993).
Mackinnon, S. et al. Adoptive immunotherapy using donor leukocytes following bone marrow transplantation for chronic myeloid leukemia: is T-cell dose important in determining biological response? Bone Marrow Transplant. 15, 591–594 (1995).
Giralt, S. et al. CD8-depleted donor lymphocyte infusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation. Blood 86, 4337–4343 (1995).
Alyea, E. P. et al. Toxicity and efficacy of defined doses of CD4(+) donor lymphocytes for treatment of relapse after allogeneic bone marrow transplant. Blood 91, 3671–3680 (1998).
Palathumpat, V., Dejbakhsh-Jones, S. & Strober, S. The role of purified CD8+ T cells in graft-versus-leukemia activity and engraftment after allogeneic bone marrow transplantation. Transplantation 60, 355–361 (1995).
Martin, P. J. et al. A phase I–II clinical trial to evaluate removal of CD4 cells and partial depletion of CD8 cells from donor marrow for HLA-mismatched unrelated recipients. Blood 94, 2192–2199 (1999).
Nagler, A. et al. Selective CD4+ T-cell depletion does not prevent graft-versus-host disease. Transplantation 66, 138–141 (1998).
Koh, M. B., Prentice, H. G. & Lowdell, M. W. Selective removal of alloreactive cells from haematopoietic stem cell grafts: graft engineering for GVHD prophylaxis. Bone Marrow Transplant. 23, 1071–1079 (1999).
Blazar, B. R., Taylor, P. A., Panoskaltsis-Mortari, A., Sharpe, A. H. & Vallera, D. A. Opposing roles of CD28–B7 and CTLA-4–B7 pathways in regulating in vivo alloresponses in murine recipients of MHC disparate T cells. J. Immunol. 162, 6368–6377 (1999).
Guinan, E. C. et al. Transplantation of anergic histoincompatible bone marrow allografts. N. Engl. J. Med. 340, 1704–1714 (1999).
Krenger, W., Snyder, K. M., Byon, J. C., Falzarano, G. & Ferrara, J. L. Polarized type 2 alloreactive CD4+ and CD8+ donor T cells fail to induce experimental acute graft-versus-host disease. J. Immunol. 155, 585–593 (1995).
Fowler, D. H., Kurasawa, K., Husebekk, A., Cohen, P. A. & Gress, R. E. Cells of Th2 cytokine phenotype prevent LPS-induced lethality during murine graft-versus-host reaction. Regulation of cytokines and CD8+ lymphoid engraftment. J. Immunol. 152, 1004–1013 (1994).
Molldrem, J. J. et al. Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Nature Med. 6, 1018–1023 (2000).
Bonini, C. et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 276, 1719–1724 (1997).
Cooke, K. R. et al. LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation. J. Clin. Invest. 107, 1581–1589 (2001).
Krammer, P. H. CD95's deadly mission in the immune system. Nature 407, 789–795 (2000).
Watanabe-Fukunaga, R. et al. The cDNA structure, expression and chromosomal assignment of the mouse Fas antigen. J. Immunol. 148, 1274–1279 (1992).
Tanaka, M. et al. Fas ligand in human serum. Nature Med. 2, 317–322 (1996).
Shresta, S., Pham, C. T., Thomas, D. A., Graubert, T. A. & Ley, T. J. How do cytotoxic lymphocytes kill their targets? Curr. Opin. Immunol. 10, 581–587 (1998).
Siegel, R. M. et al. Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations. Science 288, 2354–2357 (2000).
Chan, F. K. et al. A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science 288, 2351–2354 (2000).
Lowin, B., Beermann, F., Schmidt, A. & Tschopp, J. A null mutation in the perforin gene impairs cytolytic T-lymphocyte- and natural-killer-cell-mediated cytotoxicity. Proc. Natl Acad. Sci. USA 91, 11571–11575 (1994).
Liu, C. C., Persechini, P. M. & Young, J. D. Perforin and lymphocyte-mediated cytolysis. Immunol. Rev. 146, 145–175 (1995).
French, L. E. & Tschopp, J. Inhibition of death receptor signaling by FLICE-inhibitory protein as a mechanism for immune escape of tumors. J. Exp. Med. 190, 891–894 (1999).
Hsieh, M. H., Patterson, A. E. & Korngold, R. T-cell subsets mediate graft-versus-myeloid leukemia responses via different cytotoxic mechanisms. Biol. Blood Marrow Transplant. 6, 231–240 (2000).
Motyka, B. et al. Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T-cell-induced apoptosis. Cell 103, 491–500 (2000).
Jones, M., Komatsu, M. & Levy, R. B. Cytotoxically impaired transplant recipients can efficiently resist major histocompatibility complex-matched bone marrow allografts. Biol. Blood Marrow Transplant 6, 456–464 (2000).
Acknowledgements
We apologize to all researchers whose publications have not been cited owing to space constraints. This work was supported by a National Institutes of Health program project grant (S.J.B.) and an award of the Wendy Will Case Cancer Fund (M.R.M.B.). M.R.M.B is the recipient of Scholar awards of the Cancer Research Fund of the Damon Runyan-Walter Foundation, and the V Foundation.
Author information
Authors and Affiliations
Corresponding author
Related links
Related links
DATABASES
LocusLink
Medscape DrugInfo
Mouse Genome Informatics
OMIM
FURTHER INFORMATION
Glossary
- CONDITIONING REGIMEN
-
The preparative treatment given to a patient before an allogeneic HSCT. This regimen can include chemotherapy, irradiation or specific immunosuppressive therapy and must accomplish two goals: tumour or disease cytoreduction/eradication and immunosuppression to overcome host rejection of the donor graft.
- SCLERODERMA
-
The clinical features of this syndrome are due to autoreactive antibodies and T cells and can vary greatly, including dermal fibrosis of the skin, liver-function abnormalities, keratoconjunctivitis sicca (dry eyes), dry mouth (due to salivary-gland involvement) and obstructive lung disease.
- DONOR LEUKOCYTE INFUSION
-
(DLI). The infusion of donor leukocytes into patients that have a recurrence of their malignancy after an allogeneic haematopoietic stem-cell transplanation. This adoptive cellular immunotherapy has been particularly successful in patients with chronic myeloid leukaemia, and results in durable, complete responses in most patients.
- NON-MYELOABLATIVE ALLOGENEIC HSCT
-
An allogeneic haematopoietic stem-cell transplantation (HSCT) in a recipient who has received a conditioning regimen to achieve immunosuppression and prevent graft rejection without the complete ablation of host haematopoiesis. The recipient might develop (transient) mixed chimerism owing to haematopoietic recovery of the host and engraftment of donor haematopoietic stem cells.
- IMMUNE-PRIVILEGED SITES
-
These are areas in the body with a decreased immune response to foreign antigens, including tissue grafts. The sites include the brain, eye, testis and uterus.
Rights and permissions
About this article
Cite this article
van den Brink, M., Burakoff, S. Cytolytic pathways in haematopoietic stem-cell transplantation. Nat Rev Immunol 2, 273–281 (2002). https://doi.org/10.1038/nri775
Issue Date:
DOI: https://doi.org/10.1038/nri775
- Springer Nature Limited
This article is cited by
-
hUC-EVs-ATO reduce the severity of acute GVHD by resetting inflammatory macrophages toward the M2 phenotype
Journal of Hematology & Oncology (2022)
-
Rational identification of a Cdc42 inhibitor presents a new regimen for long-term hematopoietic stem cell mobilization
Leukemia (2019)
-
Improving hematopoietic recovery through modeling and modulation of the mesenchymal stromal cell secretome
Stem Cell Research & Therapy (2018)
-
Late recurrence of autologous GvHD in a myeloma patient: a myth or diagnostic challenge?
Bone Marrow Transplantation (2017)
-
IL-35 mitigates murine acute graft-versus-host disease with retention of graft-versus-leukemia effects
Leukemia (2015)