Transplant Tolerance by Treg Therapy (2013)

Transfer of T regulatory cells prevents islet allograft rejection. See article by Lee et al on page 27. Transfer of T regulatory cells prevents islet allograft rejection. See article by Lee et al on page 27. The idea of harnessing the natural power of immune regulation to overcome the problems of graft rejection and the need for nonspecific immunosuppressive drugs is extremely attractive. A number of different lymphoid cell types display an immune regulatory function of which the most important and best studied are a subset of CD4 T cells (regulatory T cells [Tregs]) characterized phenotypically by their expression of the of the high-affinity IL-2 receptor α-chain, CD25 and the transcription factor Foxp3 (1Wood KJ Bushell A Hester J Regulatory immune cells in transplantation.Nat Rev Immunol. 2012; 12: 417-430Crossref PubMed Scopus (323) Google Scholar). CD4 Tregs are present in healthy individuals at sufficiently high levels to maintain self-tolerance and prevent autoimmunity while at the same time permitting effective immune surveillance and transplant rejection. Attempts to augment the activity of naturally occurring or induced Tregs in transplant recipients by administering pharmacological or biological agents that target immune cell activity has proven problematic. The requirements for activating Tregs are very similar to those for conventional T cells, so the outcome of such interventions may be ineffective, unpredictable or counterproductive. An alternative and arguably more attractive approach that has gained considerable recent publicity is that of adoptive Treg therapy (2McMurchy AN Bushell A Levings MK Wood KJ Moving to tolerance: Clinical application of T regulatory cells.Semin Immunol. 2011; 23: 304-313Crossref PubMed Scopus (82) Google Scholar,3Riley JL June CH Blazar BR Human T regulatory cell therapy: Take a billion or so and call me in the morning.Immunity. 2009; 30: 656-665Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar). The clinical concept here is simple, although the practicalities of clinical application pose a considerable challenge: Foxp3 expressing Tregs, which typically comprise only a small percentage of CD4+ CD25+ T cells in peripheral blood, are purified and expanded ex vivo. Alternatively Tregs are generated ex vivo from CD4+ CD25− Treg precursors in peripheral blood. Large numbers of purified autologous Tregs are then injected back into the patient around the time of transplantation with the aim of subverting graft rejection. The article by Lee et al (4Lee K Nguyen V Lee K-M Kang S-M Tang Q Attenuation of donor-reactive T cells allows effective control of allograft rejection using regulatory T cell therapy.Am J Transplant. 2014; 14: 27-38Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar) in this issue adds to an increasing body of preclinical evidence demonstrating the effectiveness of adoptive Treg therapy in preventing allograft rejection. The findings from this study also provide a convenient backdrop for briefly considering the main hurdles of translating adoptive Treg therapy to the clinic. Lee et al (4Lee K Nguyen V Lee K-M Kang S-M Tang Q Attenuation of donor-reactive T cells allows effective control of allograft rejection using regulatory T cell therapy.Am J Transplant. 2014; 14: 27-38Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar) show that a single injection of donor-specific Tregs given the day before transplantation of fully MHC mismatched pancreatic islets promotes long-term graft survival. Importantly, however, and in keeping with other studies (2McMurchy AN Bushell A Levings MK Wood KJ Moving to tolerance: Clinical application of T regulatory cells.Semin Immunol. 2011; 23: 304-313Crossref PubMed Scopus (82) Google Scholar), Treg therapy in this model was not effective in immune competent recipients. Instead success requires recipients to be preconditioned, in this case by prior injection of donor spleen cells plus cyclophosphamide to deplete 70–80% of donor-reactive T cells. It seems clear that for Treg therapy to be effective in patients, lymphodepletion or an equally effective alternative, will also be required and could, for example, be achieved using thymoglobulin or alemtuzumab (2McMurchy AN Bushell A Levings MK Wood KJ Moving to tolerance: Clinical application of T regulatory cells.Semin Immunol. 2011; 23: 304-313Crossref PubMed Scopus (82) Google Scholar). An additional hurdle in humans is that the preconditioning regimen used must also be effective in neutralizing heterologous memory T cells that have arisen in response to environmental pathogens but cross-react with alloantigens (5Adams AB Williams MA Jones TR et al.Heterologous immunity provides a potent barrier to transplantation tolerance.J Clin Invest. 2003; 111: 1887-1895Crossref PubMed Scopus (535) Google Scholar). Unfortunately memory T cell responses are not easily subverted, and Lee et al (4Lee K Nguyen V Lee K-M Kang S-M Tang Q Attenuation of donor-reactive T cells allows effective control of allograft rejection using regulatory T cell therapy.Am J Transplant. 2014; 14: 27-38Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar) found that polyclonal Tregs were not able to protect allogeneic islets in autoimmune diabetic NOD mice. Interestingly, however, the memory/effector T cell response causing islet destruction in the autoimmune setting was attenuated when, in addition to polyclonal Tregs, islet autoantigen-specific Tregs were injected. The second major challenge for clinical translation of Treg therapy is that of obtaining therapeutic Tregs in sufficient number and of sufficient purity and stability (2McMurchy AN Bushell A Levings MK Wood KJ Moving to tolerance: Clinical application of T regulatory cells.Semin Immunol. 2011; 23: 304-313Crossref PubMed Scopus (82) Google Scholar,3Riley JL June CH Blazar BR Human T regulatory cell therapy: Take a billion or so and call me in the morning.Immunity. 2009; 30: 656-665Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar). Lee et al (4Lee K Nguyen V Lee K-M Kang S-M Tang Q Attenuation of donor-reactive T cells allows effective control of allograft rejection using regulatory T cell therapy.Am J Transplant. 2014; 14: 27-38Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar) found, like others, that donor-specific Tregs were considerably more effective in promoting graft survival than polyclonal Tregs—five times more polyclonal Tregs were required to achieve long-term allograft survival. The relative paucity of naturally occurring Tregs in peripheral human blood makes isolation and expansion of large numbers of polyclonal Tregs technically demanding. A better solution may instead be to generate adaptive Tregs in vitro from conventional CD4+ CD25− precursor T cells since these are much more abundant than naturally occurring Tregs. Various protocols involving, for example, culture with donor antigen presenting cells and cytokines have been shown to be effective for generation and expansion of allospecific Tregs from CD4 T cells (2McMurchy AN Bushell A Levings MK Wood KJ Moving to tolerance: Clinical application of T regulatory cells.Semin Immunol. 2011; 23: 304-313Crossref PubMed Scopus (82) Google Scholar,3Riley JL June CH Blazar BR Human T regulatory cell therapy: Take a billion or so and call me in the morning.Immunity. 2009; 30: 656-665Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar,6Safinia N Leech J Hernandez-Fuentes M Lechler R Lombardi G Promoting transplantation tolerance; adoptive regulatory T cell therapy.Clin Exp Immunol. 2013; 172: 158-168Crossref PubMed Scopus (51) Google Scholar). Irrespective of their source, preparing clinical grade Tregs and ensuring their purity, stability and functional effectiveness is likely to prove technically challenging (3Riley JL June CH Blazar BR Human T regulatory cell therapy: Take a billion or so and call me in the morning.Immunity. 2009; 30: 656-665Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar). In addition, any immune regulation achieved in humans may be less durable over time than that seen in pathogen-free experimental animals, and repeat administration of Tregs may be required, necessitating either long-term storage of functional Tregs or preparation of fresh cells as required. Another major issue regarding Treg therapy is its clinical safety, and in particular the concern that it may lead to generalized suppression of the adoptive immune system making recipients prone to infection and malignancy. On this count, the study of Lee et al (4Lee K Nguyen V Lee K-M Kang S-M Tang Q Attenuation of donor-reactive T cells allows effective control of allograft rejection using regulatory T cell therapy.Am J Transplant. 2014; 14: 27-38Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar) provides some reassurance. Perhaps surprisingly, they found no evidence from their experiments that adoptive Treg therapy induced systemic tolerance. The protective effect of Tregs was instead localized anatomically to the islet grafts. Transferred Tregs migrated initially to the site of the islet allografts, in keeping with previous trafficking studies that have shown migration of transferred Tregs to the allograft site is essential for graft protection (7Zhang N Schröppel B Lal G et al.Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response.Immunity. 2009; 30: 458-469Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar). Earlier studies have reported that migration of activated Tregs from the graft to the draining lymph nodes is also required for optimal graft protection (7Zhang N Schröppel B Lal G et al.Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response.Immunity. 2009; 30: 458-469Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar) but Lee et al (4Lee K Nguyen V Lee K-M Kang S-M Tang Q Attenuation of donor-reactive T cells allows effective control of allograft rejection using regulatory T cell therapy.Am J Transplant. 2014; 14: 27-38Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar) found that transferred Tregs were barely detectable in either the periphery or the allograft site itself beyond the first few days. Tregs appear, at least in this particular model, to protect islets from rejection by preventing CD8 T effector cells from accumulating within the allograft. Perhaps they do so by competing with CD8 cells for access to antigen presenting cells and cytokines such as IL-2 that are required for T cell growth and survival: if so delivering Treg directly into the environment of the allograft rather than injecting them intravenously might prove more efficacious. Interestingly, Lee et al (4Lee K Nguyen V Lee K-M Kang S-M Tang Q Attenuation of donor-reactive T cells allows effective control of allograft rejection using regulatory T cell therapy.Am J Transplant. 2014; 14: 27-38Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar) observed that transferred Tregs also promoted the recruitment of significant numbers of endogenous Tregs into the graft environment, presumably to the grafts benefit. These observations, suggesting that Tregs have a local but not systemic immunosuppressive effect, goes some way to allaying fears about the safety of Treg therapy. Whether the success of Treg therapy in preclinical animal models can be translated successfully into an effective clinical cell therapy for patients undergoing organ transplants remains uncertain. However, enthusiasm for Treg therapy is not confined to transplantation—there is also great deal of interest in adoptive Tregs as a potential treatment for autoimmune disease, particularly patients with newly diagnosed type 1 diabetes (8Leslie M Immunology, regulatory T cells get their chance to shine.Science. 2011; 332: 1020-1021Crossref PubMed Scopus (54) Google Scholar). Not surprisingly, given the potential market for Treg therapy, there is already considerable commercial interest in novel strategies to produce and manipulate clinical grade Tregs. The first clinical studies of Treg therapy in organ transplantation are already under way in a number of centers around the world and the findings from these are eagerly awaited (8Leslie M Immunology, regulatory T cells get their chance to shine.Science. 2011; 332: 1020-1021Crossref PubMed Scopus (54) Google Scholar). The author of this manuscript has no conflicts of interest to disclose as described by the American Journal of Transplantation.