Immunology and Cell Biology (2012) 90, 253–254 & 2012 Australasian Society for Immunology Inc. All rights reserved 0818-9641/12 www.nature.com/icb
NEWS AND COMMENTARY Graft-versus-host disease
Graft-versus-host disease: who’s responsible? Rhodri Ceredig Immunology and Cell Biology (2012) 90, 253–254; doi:10.1038/icb.2011.62; published online 12 July 2011
A
major obstacle to the successful outcome of bone marrow transplantation (BMT) is the development of so-called graft-versus-host disease (GVHD). As originally described by Korngold and Sprent,1 GVHD represents an immunological attack by donor (grafted) T lymphocytes on host tissues. Currently, there are B40 000 BMT procedures carried out annually, frequently between donors and hosts that differ genetically. Understanding the details of how GVHD is initiated and possibly controlled are important to circumvent this lifethreatening, iatrogenic disease. In this issue, Lee et al.,2 using allogeneic BM chimeras, provide an interesting perspective on this topic. Generally, it was assumed that in chimeras GVHD was mediated exclusively by donor T cells present in the BM inoculum mounting an immunological attack against host tissues (Figure 1). Consequently and to overcome GVHD, considerable effort was invested in depleting BM inocula of residual T cells and/ or purifying donor HSC (hematopoietic stem cell). However, neither strategy was successful. There are many different forms of GVHD. One particular form of chronic GVHD affects the skin, which becomes thickened and less flexible, called scleroderma. Now, Lee et al.2 demonstrate, using a battery of allogeneic host and donor mouse strain combinations, that it is host-derived T cells that are responsible for sclerodermatous chronic GVHD. Transplantation of donor BM suspensions containing rare HSCs results in reconstitution of the recipient’s hematopoietic and lymphoid system by mostly donor-derived cells. Thus, recipients are described as hematopoietic chimeras, where host BM and lymphoid organs contain hematopoietic cells from R Ceredig is at the Regenerative Medicine Institute, National Centre for Biomedical Engineering Science, National University of Ireland, Room 221, Orbsen Building, NUI Galway, Galway, Ireland. E-mail:
[email protected]
another source. However, in chimeras it is clear that some reconstitution, particularly of liver Kupffer cells, skin Langerhans cells and dendritic cells (DCs), can occur from hostderived cells.3–5 To allow engraftment of donor HSC, the hosts’ endogenous HSC niches are depleted by either irradiation or chemotherapy or a combination of both. As a result, recipients are lymphopenic for a considerable period. During lymphopenia, GVHD can frequently manifest, due either to a primarily T cell-mediated attack on host tissues or to an autoimmune disease manifesting as GVHD, that involves B cells, that is the result of an imbalance between naive and regulatory T cells (Tregs).6 The normal process of hematopoiesis, and the reconstitution following BMT, is crucially dependent upon non-hematopoietic or ‘stromal’ elements of the BM and thymus, which are assumed to be unaffected by irradiation. After reconstitution of the host thymus by donor progenitor T cells, the newly generated donor T cells display the functional activity, particularly the major histocompatibility complex-restricted characteristics, of recipients rather than of their former hosts. This phenomenon, called positive selection, was first described by Bevan.7 However, the thymus in chimeras is initially reconstituted by host-derived cells, and the cells responsible for this were recently shown to be an immature thymocyte sub-population, called a DN2 cell.4 DN2 thymocytes, both freshly isolated and after irradiation, also retain non-T lineage, particularly natural killer and myeloid (DC), potential.4 Whether the myeloid potential of DN2 is exploited in vivo and whether these cells can contribute to the thymic DC population, however, is hotly debated.8 It is known that thymic DCs, because of their strategic location, have a role in purging the developing T-cell repertoire of potentially self-reactive cells, a process called negative selection. It would seem that the efficiency with which the post-irradiation
thymus mediates negative selection has a key role in controlling GVHD after BMT. Lee et al.2 demonstrate that it is the origin of thymic DC in chimeras that is of crucial importance to this process. Using novel transplantation approaches, Lee et al.2 show that residual thymic DC in their chimeras were not derived from radioresistant thymic progenitors but rather from donor cells. This is relevant, because hostderived T cells recovered from chimeras displayed residual autoreactivity in that they proliferated in vitro when stimulated by host genotype antigen-presenting (dendritic) cells. To explain this, they suggest that during thymic reconstitution by radioresistant DN2 cells the absence of host DC resulted in the escape from negative selection of potentially autoreactive T cells. Persistence of host DCs and Langerhans cells in the skin of chimeras would then activate these thymus-derived autoreactive T cells to initiate an autoimmune reaction. The work of Lee et al.2 therefore provides some novel insights into the role of host thymic DCs and T cells in the pathology of GVHD. However, there are few important points to be borne in mind in relation to GVHD and BMT. First, in BM chimeras, the thymus is not the only source of host-derived T cells. In thymectomized BM recipients, B30% of host-derived T cells found in lymphoid organs are derived from a peripheral T cell source,4 most likely the intestine.9 However, their T-cell receptor (TCR) repertoire is oligoclonal and they have a memory-like phenotype, presumably the result of homeostatic expansion in a lymphopenic environment. The major thymus-derived cohort of host-derived T cells has a polyclonal TCR repertoire and contains, as expected, naive phenotype T cells. The failure of Lee et al.2 to detect many non-thymic-derived host T cells may be because, in this case, they used anti-H-2 antibodies to distinguish hostand donor-derived cells rather than CD45
News and Commentary 254
Lymphocyte number and origin
Original notion
GvHD
Protective Immune response against pathogens
Host Mature T cell
Thymus
T cell
Bone marrow HSC
Conditioning
Donor
Treg
Time
BMT
of thymus and extrathymic sources to the host-derived Treg cell pool is uncertain. Interestingly, B50% of BM CD4T cells are Tregs. Where, anatomically, such BM Tregs reside, whether they are functional and what their role is in BM homeostasis are being actively investigated.2 Their depletion from the BM inoculum might not necessarily be beneficial to the prevention of autoimmunity following BMT. Thus, although the paper of Lee et al.11 underscores the role of host-derived T cells in mediating GVHD after BMT, much research is still required to increase our understanding of and ability to control GVHD following BMT.
Current notion
Lymphocyte number and origin
Autoreactive T cell
Sclerodermatous chronic GvHD GvHD
Thymus DN2 Host
Treg? Peripheral T cell
Mature T cell Bone marrow HSC
Thymus
Protective Immune response against pathogens T cell
Treg
Treg? Donor Conditioning
Time
BMT
Figure 1 (a) Originally, it was thought that there was no contribution of host-derived T cells to the lethally irradiated host and that GVHD was due to donor-derived T cells contaminating the BM inoculum. (b) Now, we know that the host contributes to the T-cell pool after BMT. As shown by Lee et al.,2 by the abscence of complete negative selection, thymus-derived host cells can mediate GVHD. Host T cells also contain Treg, which may come from either thymic or extrathymic sources, and it is the balance between Treg and autoreactive T cells that determines whether GVHD is seen after BMT. Whether donor BM-derived Treg could also be functional in preventing GVHD is not known.
allele-specific antibodies. Second, the thymus constitutes a target organ for GVHD, which could result in DC depletion and a defect in negative selection.10 Thus, the mechanisms controlling loss of thymic host DCs need to be further investigated. Third, other factors, in addition to the role of host T cells, may explain the failure of T-cell depletion from BM before transplant to prevent GVHD. In normal, lymphopenic and post-BMT
Immunology and Cell Biology
mice, autoimmunity is crucially dependent upon the balance between Treg and conventional T cells. Such autoimmunity can manifest as GVHD. Thus, infusion of Treg with the T-cell-depleted BM inoculum can prevent autoimmunity in the immediate post-BMT period.6 In BM chimeras where recipients initially contained T cells, host-derived T cells are enriched for Treg3,6 and these can prevent GVHD. The relative contribution
1 Korngold R, Sprent J. Lethal graft-versus-host disease after bone marrow transplantation across minor histocompatibility barriers in mice. Prevention by removing mature T cells from marrow. J Exp Med 1978; 148: 1687–1698. 2 Lee YJ, Min HS, Kang EH, Park HJ, Jeon YK, Kim JH et al. Sclerodermatous chronic graft-versus-host disease induced by host T-cell-mediated autoimmunity. Immunol Cell Biol 2011; 90: 358–367. 3 Anderson BE, McNiff JM, Matte C, Athanasiadis I, Shlomchik WD, Shlomchik MJ. Recipient CD4+ T cells that survive irradiation regulate chronic graftversus-host disease. Blood 2004; 104: 1565–1573. 4 Bosco N, Swee LK, Benard A, Ceredig R, Rolink A. Auto-reconstitution of the T-cell compartment by radioresistant hematopoietic cells following lethal irradiation and bone marrow transplantation. Exp Hematol 2010; 38: 222–232, e2. 5 Greenberger JS, Epperly M. Bone marrow-derived stem cells and radiation response. Semin Radiat Oncol 2009; 19: 133–139. 6 Benard A, Ceredig R, Rolink AG. Regulatory T cells control autoimmunity following syngeneic bone marrow transplantation. Eur J Immunol 2006; 36: 2324–2335. 7 Bevan MJ. In a radiation chimaera, host H-2 antigens determine immune responsiveness of donor cytotoxic cells. Nature 1977; 269: 417–418. 8 Schlenner SM, Rodewald HR. Early T cell development and the pitfalls of potential. Trends Immunol 2010; 31: 303–310. 9 Burdelya LG, Krivokrysenko VI, Tallant TC, Strom E, Gleiberman AS, Gupta D et al. An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science 2008; 320: 226–230. 10 Krenger W, Hollander GA. The immunopathology of thymic GVHD. Semin Immunopathol 2008; 30: 439–456. 11 Fujisaki J, Wu J, Carlson AL, Silberstein L, Putheti P, Larocca R et al. In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche. Nature 2011; 474: 216–219.
