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PURPOSE OF REVIEW: Solid organ transplantation is the most effective treatment for end-stage organ failure, but the long-term outcomes remain suboptimal. CD4 regulatory T cells (Tregs) are emerging as a potential therapy to facilitate long-term allograft survival. This review provides a general overview of the biology of CD4 Tregs and then goes on to discuss the most relevant and recent experimental and clinical evidence for their therapeutic use in solid organ transplantation. RECENT FINDINGS: There have been major advances in our understanding of Tregs, including improvements in methods for their isolation and expansion. Experimental models are providing very important data on the in-vitro and in-vivo behavior of Tregs in transplantation, while recent clinical trials of Treg cellular therapy in graft-versus-host disease are offering a valuable insight into the efficacy of Treg adoptive cellular therapy. SUMMARY: Data in favor of Treg cellular therapy in transplantation are mounting, and we predict that their use in clinical trials is on the horizon.

Purpose of review Fundamental discoveries during the 1990s revolutionized our understanding of transplantation tolerance and our ability to create it in animal models. The Immune Tolerance Network (ITN) and Reprogramming the Immune System for the Establishment of Tolerance (RISET) consortia were created to leverage these advances and work towards the goal of achieving clinical tolerance in transplantation. This article highlights their accomplishments and challenges during the past decade. Recent findings In interventional trials, renal allograft tolerance has been achieved using bone marrow transplantation with nonmyeloablative protocols to induce transient hematopoietic chimerism. Drug minimization in renal transplantation was achieved with Campath-1H induction therapy and also with cellular therapy using 'transplant acceptance inducing cells'. Successful drug withdrawal was accomplished in long-term stable pediatric liver transplant recipients. Finally, 'registry' trials of tolerant kidney recipients revealed a B-cell signature of tolerance, which will form the basis for future investigations of its use as a biomarker for drug minimization or withdrawal in selected patients. Summary Although transplantation tolerance is not yet reliably achieved in a clinical setting, collaborative efforts, such as those of the ITN and RISET networks, are an effective means to synergize intellectual and financial resources to bring this goal closer to reality.

Purpose of review In recent years there has been increased interest in understanding the physiology and function of regulatory T cells. In this review we focus on the characterization of regulatory T-cell subsets and their potential therapeutic use in organ transplantation. Recent findings Regulatory T cells can play an instrumental role in the establishment of operational tolerance to allografts. The level of expression and the extent of posttranslational acetylation of the regulatory T-cell specific transcription factor Foxp3 are important modulators of their suppressive activity. Low expression of CD127 can be used as a novel marker to define pure regulatory T-cell populations and the expression of CD45RA on CD4CD25 regulatory T cells characterizes a population with a more stable phenotype upon expansion in vitro. Interleukin-35 is a recently discovered immunosuppressive cytokine secreted by CD4CD25 regulatory T cells. Although the presence of allospecific memory T cells in the pretransplant period and the use of immunosuppressants might interfere with the effectiveness of regulatory T-cell-based therapies, encouraging results indicate that the immunosuppressive drug rapamycin does not affect the expansion and function of regulatory T cells and could be included in a combined therapy. Summary Important advances have been made towards establishing regulatory T cells as a viable therapy in transplantation and the first clinical trials using human regulatory T cells are currently underway. There are, however, important limitations and safety issues that have to be addressed before this therapy can be fully translated into the clinic.

PURPOSE OF REVIEW Cell-based immunotherapy offers a novel approach to minimize the need for immunosuppressive drugs and to promote a state of immunological tolerance to a transplanted organ. We review the most promising biomarkers and functional assays able to identify patients tolerant to their graft. Such a signature of tolerance is essential in the assessment of the efficacy with which trials of cellular therapies promote immunoregulation and minimize graft rejection. RECENT FINDINGS A multitude of novel cellular therapies have entered early-phase clinical trials in solid-organ transplant patients. Recent multicentre collaborations have enabled the determination of distinct tolerance profiles for both liver and kidney transplant recipients. These have been shown to be highly predictive of tolerance in certain settings and show utility in identifying patients in whom immunosuppressive drugs can be weaned or discontinued. SUMMARY In order to become a viable treatment option in solid-organ transplantation, the latest large, multicentre clinical trials of cellular therapies must utilize, validate and discover the biomarkers with the capacity to reliably identify a signature of immune tolerance.

The induction of donor-specific tolerance remains an important objective in transplantation to obviate the need for immunosuppression and prevent chronic rejection. Operational tolerance to cardiac allografts can certainly be induced in small animal models. Recent interest has focused on refining the tolerance induction regimens to minimize toxicity and on examining the mechanisms responsible for donor-specific unresponsiveness in these experimental systems. Particular progress has been made on strategies to block T-cell costimulation and on delivery of alloantigens via donor-specific transfusion or bone marrow infusion. Interactions between various forms of immunotherapy and conventional immunosuppression are being studied and there is early evidence of synergy, as well as data suggesting inhibition of tolerance induction by calcineurin inhibitors.

PURPOSE OF REVIEW: This review focuses on the immunogenicity of embryonic stem cell (ESC)-derived progenitors and the impact of the immune response on applications of cell replacement therapy (CRT). Possible strategies to induce immunological tolerance to ESC-derived progenitor cells will also be discussed. RECENT FINDINGS: Evidence for the differential epigenetic control of major histocompatibility (MHC) and antigen processing molecules in ESCs and differentiated ESCs has recently been described. The presence of T cells recognizing the pluripotency-associated transcription factor octamer-binding transcription factor 4 (OCT4) in healthy patient-derived peripheral blood mononuclear cells adds further complexity to the immune response against ESCs and ESC-derived progenitors. SUMMARY: Although ESCs and ESC-derived progenitors appear to exert some level of immune privilege in specific circumstances, these allogeneic cells are indeed recognized by the immune system and can be subject to mechanisms of rejection. Herein, we discuss the importance of the recent reports describing an immunosuppressive capacity of ESCs, and the epigenetic control of MHC in ESCs and how these characteristics may be harnessed in the development of strategies to induce immunological tolerance.

PURPOSE OF REVIEW: Donor reactive regulatory T cells (Treg) play an important role in tolerance induction and maintenance in experimental transplant models. In this review we focus on the formation of the donor reactive Treg pool and explore the potential of these cells for therapeutic application in clinical transplantation. RECENT FINDINGS: Donor reactive Treg can arise by both conversion of alloreactive nonregulatory cells and expansion of naturally occurring Treg (nTreg) cross-reactive with donor alloantigen but the quantitative contribution of each of these pathways is at present unclear. However, the fact that donor reactive Treg can be driven both in vivo and ex vivo by alloantigen challenge of nonregulatory precursors is encouraging as it demonstrates that the functional potential of these cells for use in clinical transplantation will not be limited by fortuitous cross-reactivity between nTreg and donor alloantigens. Treg can be generated in vivo by transplantation or alloantigen challenge in combination with Treg-permissive immunosuppression, or ex vivo by phenotypic selection or by polyclonal or antigen-specific stimulation. A number of ex-vivo protocols exist for the enrichment of Treg in the laboratory and in many cases these cells have demonstrable function both in vitro and in relevant graft-versus-host disease (GVHD) or organ transplant models. The challenge now is to understand the clinical opportunities and limitations that these populations present. SUMMARY: Combined with appropriate immunosuppression, Treg generated/expanded in vivo or ex vivo may hold the final key to operational tolerance in clinical setting.

The induction of tolerance in an adult immune system, although possible in animal models, remains an elusive goal in clinical medicine. The study of cytokine expression may help to define the requirements for reliably directing the immune system toward tolerance against either self antigens in autoimmune disease or foreign antigens in transplantation. Recent studies indicate a clear role for various cytokines in this increasingly complex process.

Intrathymic administration of antigen is a versatile strategy for the induction of tolerance to a wide range of allo-, xeno-, and autoantigens. Interest has now turned to developing methods allowing efficient delivery of antigen to the thymus, and to elucidating the mechanisms responsible for tolera