The Role of Dendritic Cells in Graft-versus-host Disease

US Hematology, 2007;1(1):49-51

Allogeneic hematopoietic cell transplantation (alloHCT) represents a definitive therapy for a number of otherwise fatal conditions. Graft-versus-host disease (GVHD) is the major cause of morbidity after transplant and limits the extended use of this critical therapeutic modality. Dendritic cells (DCs), a population of professional antigen-presenting cells (APCs), are thought to play a critical role in the initiation of this devastating disease. In this article, we will discuss studies that have established the role of DCs in GVH reactions, as well as the therapeutic implications of these studies.
Dendritic Cell Subsets in Lymphoid and Non-lymphoid Tissue
DCs belong to a population of hematopoietic cells called APCs that also include B cells and macrophages. The two main DC subsets include conventional DCs and plasmacytoid DCs (PDCs). DCs take up antigens through a wide range of mechanisms 1 and are very well equipped to form peptide-major histocompatibility complex (MHC) class II and peptide-MHC class I complexes, migrate to the draining lymph nodes (LNs), and present tissue-derived MHC-peptide complexes to T lymphocytes.1 Presentation of peptide-MHC class II complexes to CD4 T cells is called direct presentation and can be mediated by all APCs, including DCs, macrophages, and B cells.1 The generation of peptide-MHC class I from soluble antigens2 is called cross-presentation and appears to be specific to DCs.3 Similarly to DCs, PDCs express MHC class II molecules constitutively. Freshly isolated human and mouse PDCs are very poor inducers of T-cell proliferation. However, upon activation PDCs can differentiate into mature DCs with a high level of MHC class II and co-stimulatory molecules and T-cell stimulatory activity.4
Dendritic Cell Homeostasis After Allogeneic Hematopoietic Cell Transplantation
AlloHCT has been an experimental tool in mice and a therapeutic modality in humans for almost half a century.6,7 Engraftment of allogeneic stem cells is facilitated by myelosuppressive and immunosuppressive conditioning given just prior to the infusion of stem cells. Mice, after a single dose of total body irradiation (TBI), are able to accommodate completely mismatched transplants without post-transplant immunosuppression. In humans, successful transplantation usually requires five to seven days of conditioning, an MHC geno-identical donor, and post-transplant immunosuppression.8 Even with these measures, GVHD, manifest as inflammation of the skin, bowel, and liver, occurs in 10–50% of human transplants and leads to death in 10–20%.9,10
References:
  1. Banchereau J, et al., Immunobiology of dendritic cells, Annu Rev Immunol, 2000;18:767–811.
  2. Lechler R, et al., Dendritic cells in transplantation—friend or foe?, Immunity, 2001;14:357–68.
  3. Guermonprez P, et al., Pathways for antigen cross presentation, Springer Semin Immunopathol, 2005;26:257–71.
  4. Colonna M, et al., Plasmacytoid dendritic cells in immunity, Nat Immunol, 2004;5:1219–26.
  5. Ochando JC, et al., Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts, Nat Immunol, 2006;7:652–62.
  6. Thomas ED, et al., Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy, N Engl J Med, 1957;257:491–6.
  7. Mathe G, et al., Transfusions and grafts of homologous bone marrow in humans after accidental high dosage irradiation, Rev Fr Etud Clin Biol, 1959;4:226–38.
  8. Storb R, et al., Marrow transplantation for severe aplastic anemia: methotrexate alone compared with a combination of methotrexate and cyclosporine for prevention of acute graftversus- host disease, Blood, 1986;68:119–25.
  9. Baron F, et al., Hematopoietic cell transplantation: Five decades of progress, Arch Med Res, 2003;34:528–44.
  10. Vogelsang GB, et al., Pathogenesis and treatment of graft-versushost disease after bone marrow transplant, Annu Rev Med, 2003;54:29–52.
  11. Ferrara JL, et al., Pathophysiologic mechanisms of acute graft-vs.- host disease, Biol Blood Marrow Transplant, 1999;5:347–56.
  12. Baron F, et al., Allogeneic hematopoietic cell transplantation as treatment for hematological malignancies: A review, Springer Semin Immunopathol, 2004;26:71–94.
  13. Burroughs L, et al., Low-intensity allogeneic hematopoietic stem cell transplantation for myeloid malignancies: Separating graftversus- leukemia effects from graft-versus-host disease, Curr Opin Hematol, 2005;12:45–54.
  14. Klangsinsirikul P, et al., Campath-1G causes rapid depletion of circulating host dendritic cells (DCs) before allogeneic transplantation but does not delay donor DC reconstitution, Blood, 2002;99:2586–91.
  15. Auffermann-Gretzinger S, et al., Rapid establishment of dendritic cell chimerism in allogeneic hematopoietic cell transplant recipients, Blood, 2002;99:1442–8.
  16. Merad M, et al., In vivo manipulation of dendritic cells to induce therapeutic immunity, Blood, 2002;99:1676–82.
  17. Merad M, et al., Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graftversus- host disease, Nat Med, 2004;10:510–17.
  18. Bogunovic M, et al., Identification of a radio-resistant and cycling dermal dendritic cell population in mice and men, J Exp Med, 2006;203:2627–38.
  19. Mohty M, et al., Recovery of lymphocyte and dendritic cell subsets following reduced intensity allogeneic bone marrow transplantation, Hematology, 2002;7:157–64.
  20. Arpinati M, et al., Acute graft-versus-host disease and steroid treatment impair CD11c+ and CD123+ dendritic cell reconstitution after allogeneic peripheral blood stem cell transplantation, Biol Blood Marrow Transplant, 2004;10:106–15.
  21. Weiden PL, et al., Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts, N Engl J Med, 1979;300:1068–73.
  22. Weiden PL, et al., Antileukemic effect of chronic graft-versus-host disease: Contribution to improved survival after allogeneic marrow transplantation, N Engl J Med, 1981;304:1529–33.
  23. Horowitz MM, et al., Graft-versus-leukemia reactions after bone marrow transplantation, Blood, 1990;75:555–62.
  24. Ho VT, et al., The history and future of T-cell depletion as graftversus- host disease prophylaxis for allogeneic hematopoietic stem cell transplantation, Blood, 2001;98:3192–3204.
  25. Kolb HJ, et al., Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients, Blood, 1990;76:2462–5.
  26. Kolb HJ, et al., Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients, Blood, 1995;86:2041–50.
  27. Kolb HJ, et al., Graft-versus-leukemia reactions in allogeneic chimeras, Blood, 2004;103:767–76.
  28. den Haan JM, et al., The minor histocompatibility antigen HA-1: A diallelic gene with a single amino acid polymorphism, Science, 1998;279:1054–7.
  29. Dickinson AM, et al., In situ dissection of the graft-versus-host activities of cytotoxic T cells specific for minor histocompatibility antigens, Nat Med, 2002;8:410–14.
  30. Shlomchik WD. Antigen presentation in graft-vs-host disease, Exp Hematol, 2003;31:1187–97.
  31. Shlomchik WD, et al., Prevention of graft versus host disease by inactivation of host antigen-presenting cells, Science, 1999;285: 412–15.
  32. Zhang Y, et al., Preterminal host dendritic cells in irradiated mice prime CD8+ T cell-mediated acute graft-versus-host disease, J Clin Invest, 2002;109:1335–44.
  33. Teshima T,, et al. Acute graft-versus-host disease does not require alloantigen expression on host epithelium, Nat Med, 2002;6: 575–81.
  34. Matte CC, et al., Donor APCs are required for maximal GVHD but not for GVL, Nat Med, 2004;10:987–92.
  35. Duffner UA, et al., Host dendritic cells alone are sufficient to initiate acute graft-versus-host disease, J Immunol, 2004;172: 7393–8.
  36. Xia G, et al., Graft-versus-leukemia and graft-versus-host reactions after donor lymphocyte infusion are initiated by host-type antigenpresenting cells and regulated by regulatory T cells in early and long-term chimeras, Biol Blood Marrow Transplant, 2006;12: 397–407.
  37. Kaplan G, et al., Distribution and turnover of Langerhans cells during delayed immune responses in human skin, J Exp Med, 1987;165:763–76.
  38. Bennett CL, et al., Inducible ablation of mouse Langerhans cells diminishes but fails to abrogate contact hypersensitivity, J Cell Biol, 2005;169:569–76.
  39. Kaplan DH, et al., Epidermal langerhans cell-deficient mice develop enhanced contact hypersensitivity, Immunity, 2005;23:611–20.
  40. Collin MP, et al., The fate of human Langerhans cells in hematopoietic stem cell transplantation, J Exp Med, 2006;203:27–33.
  41. Fagnoni FF, et al., Reconstitution dynamics of plasmacytoid and myeloid dendritic cell precursors after allogeneic myeloablative hematopoietic stem cell transplantation, Blood, 2004;104:281–9.
  42. Perreault C, et al., Persistence of host Langerhans cells following allogeneic bone marrow transplantation: Possible relationship with acute graft-versus-host disease, Br J Haematol, 1985;60:253–60.
  43. Merad M, et al., Langerhans cells renew in the skin throughout life under steady-state conditions, Nat Immunol, 2002;3:1135–41.
  44. Blazar BR, et al., Flt3 ligand (FL) treatment of murine donors does not modify graft-versus-host disease (GVHD) but FL treatment of recipients post-bone marrow transplantation accelerates GVHD lethality, Biol Blood Marrow Transplant, 2001;7:197–207.
  45. Waller EK, et al., Larger numbers of CD4(bright) dendritic cells in donor bone marrow are associated with increased relapse after allogeneic bone marrow transplantation, Blood, 2001; 97: 2948–56.
  46. Fugier-Vivier IJ, et al., Plasmacytoid precursor dendritic cells facilitate allogeneic hematopoietic stem cell engraftment, J Exp Med, 2005;201:373–83.
  47. Morison WL, Effects of ultraviolet radiation on the immune system in humans, Photochem Photobiol, 1989;50:515–24.
  48. Yuksel M, et al., Peritransplant use of ultraviolet-B irradiation (UVB) therapy is detrimental to allogeneic stem cell transplantation outcome, Biol Blood Marrow Transplant, 2006;12:665–71.