[Show abstract][Hide abstract] ABSTRACT: The identification of T-helper 9 (Th9), Th17, Th22 cells as distinct subsets of CD4(+) T cells has extended the Th1/Th2 paradigm in the adaptive immunity. In the past decade, many studies in animal models and clinical transplantation have demonstrated that interleukin-17 (IL-17) is involved in allograft rejection. It appears that Th17 cells together with Th1 and Th2 cells play an important role in mediating allograft rejection. Here, we summarize our current knowledge on the contribution of Th1, Th2, Th9, Th17, Th22, and follicular T-helper (Tfh) cells in allograft rejection. We also discuss the regulation of CD4(+) T-cell subsets by CD4(+) Foxp3(+) regulatory T cells (Tregs) in the context of transplantation tolerance.
[Show abstract][Hide abstract] ABSTRACT: To respond to infection, resting or naïve T cells must undergo activation, clonal expansion, and differentiation into specialized functional subsets of effector T cells. However, to prevent excessive or self-destructive immune responses, regulatory T cells (T(regs)) are instrumental in suppressing the activation and function of effector cells, including effector T cells. The transcription factor Forkhead box P3 (Foxp3) regulates the expression of genes involved in the development and function of T(regs). Foxp3 interacts with other transcription factors and with epigenetic elements such as histone deacetylases (HDACs) and histone acetyltransferases. T(reg) suppressive function can be increased by exposure to HDAC inhibitors. The individual contributions of different HDAC family members to T(reg) function and their respective mechanisms of action, however, remain unclear. A study showed that HDAC6, HDAC9, and Sirtuin-1 had distinct effects on Foxp3 expression and function, suggesting that selectively targeting HDACs individually or in combination may enhance T(reg) stability and suppressive function. Another study showed that the receptor programmed death 1 (PD-1), a well-known inhibitor of T cell activation, halted cell cycle progression in effector T cells by inhibiting the transcription of the gene encoding the substrate-recognition component (Skp2) of the ubiquitin ligase SCF(Skp2). Together, these findings reveal new signaling targets for enhancing T(reg) or effector T cell function that may be helpful in designing future therapies, either to increase T(reg) suppressive function in transplantation and autoimmune diseases or to block PD-1 function, thus increasing the magnitude of antiviral or antitumor immune responses of effector T cells.
[Show abstract][Hide abstract] ABSTRACT: The pursuit of transplantation tolerance is the holygrail in clinical organ transplantation. It has been established that regulatory T cells (Tregs) can confer donor-specific tolerance in mouse models of transplantation. However, this is crucially dependent on the strain combination, the organ transplanted and most importantly, the ratio of Tregs to alloreactive effector T cells. The ex vivo expansion of Tregs is one solution to increase the number of alloantigen specific cells capable of suppressing the alloresponse. Indeed, ex vivo expanded, alloantigen specific murine Tregs are shown to preferentially migrate to, and proliferate in, the graft and draining lymph node. In human transplantation it has been proposed that depletion of the majority of direct pathway alloreactive T cells will be required to tip the balance in favour of regulation. Ex vivo expansion of alloantigen specific, indirect pathway human Tregs, which can cross regulate the residual direct pathway has been established. Rapid expansion of these cells is possible, whilst they retain antigen specificity, suppressive properties and favourable homing markers. Furthermore, considerable progress has been made to define which immunosuppressive drugs favour the expansion and function of Tregs. Currently a series of clinical trials of adoptive Treg therapy in combination with depletion of alloreactive T cells and short term immunosuppression are underway for human transplantation with the aim of minimizing immunosuppressive drugs and completely withdrawal.
Seminars in Immunology 09/2011; 23(6):453-61. DOI:10.1016/j.smim.2011.08.012 · 5.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Immune-suppressive cellular immunotherapy requires large numbers of antigen-specific regulatory T cells (T(reg) cells), lymphocytes that suppress certain immune responses. Together, three papers in this issue of Science Translational Medicine describe protocols for the ex vivo expansion of human T(reg) cells and assess the immune-suppressive function of ex vivo-manipulated T(reg) cells after transfer into humanized mouse disease models. Along with recent phase I clinical trial results, these new data provide a platform for clinical use of T(reg) cells as personalized therapeutic agents for the treatment of autoimmune diseases, graft-versus-host disease, and transplant rejection.
Science translational medicine 05/2011; 3(83):83ps19. DOI:10.1126/scitranslmed.3001819 · 15.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Substantial advances in our understanding of the developmental and functional relationship between regulatory T cells (T(regs)) and T helper 17 (T(H)17) cells and their potential clinical applications have been made. In response to these breakthroughs, the second international conference entitled "China Tregs/Th17 2010 Shanghai Conference," held in Shanghai, China, was dedicated to this topic. Various types of T(regs) and T(H)17 cells, as well as their relevant cytokines, were discussed. Here, we summarize some of the findings shared at the conference, specifically focusing on the biology of T(H)17 cells, including interleukin-17 (IL-17)-producing innate cells, T(regs), and the factors that control the critical balance between T(regs) and cells of the T(H)17 lineage.
[Show abstract][Hide abstract] ABSTRACT: In the past decade it has been established that regulatory T cells (Tregs) control all immune responses. As the induction and effector mechanisms used by Tregs are being unraveled, it is emerging that a reciprocal population of CD4(+) T lymphocytes exists in the immune system that produces inflammatory cytokine IL-17, and coined "Th17 cells". Th17 cells have been implicated in the pathogenesis of many forms of human disease. The development, function, mechanism of action, and homeostasis of Tregs and Th17 cells, and the reciprocal control between Tregs and Th17 cells were presented at the Second International Conference on Regulatory T Cells and Th17 Cells and Clinical Application in Human Diseases in Shanghai on 17-20 July 2010 (China Tregs/Th17 2010). In this Special Issue of International Immunopharmacology, several paper submitted to the conference will highlight the biology of Tregs and Th17 cells, and their clinical application in human disease.
International immunopharmacology 02/2011; 11(5):533-5. DOI:10.1016/j.intimp.2011.02.020 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The emergence of TH17 cells as a distinct subset of effector T cell has led to a revised model of the adaptive immune system. In experimental
and clinical transplantation, the TH17-producing cytokine, interleukin (IL)-17, is evident in allograft rejection. It is conceivable that TH17 cells could play a specific role in pathogenic process of allograft rejection. This chapter summarizes the current spectrum
of TH17 cells in transplant rejection. The tolerance and regulation of TH17 response in the allogeneic context is also discussed.
TH17 Cells in Health and Disease, 12/2010: pages 319-339;
[Show abstract][Hide abstract] ABSTRACT: Recent studies in animal models have demonstrated that adoptive transfer of antigen-specific CD4+CD25+ regulatory T cells (Tregs) can prevent or even cure autoimmune diseases, and appear to induce transplantation tolerance. Thus, adoptive cell therapy using ex vivo induced and expanded patient-specific CD4+CD25+Tregs has emerged as a promising individualized medicine for the treatment of inflammatory disease. Here we discuss our current efforts on the pursuit of regulatory T cell therapy for the induction of transplantation tolerance.
International immunopharmacology 12/2010; 10(12):1486-90. DOI:10.1016/j.intimp.2010.08.007 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: CD4(+)CD25(+) regulatory T cells (Tregs) play a crucial role in controlling immune responses. It is an appealing strategy to harness Tregs for adoptive cell therapy to induce tolerance to allografts. Several approaches have been developed to expand antigen-specific Tregs. Despite the large body of experimental data from murine studies demonstrating the great potential of these cells for clinical application, Treg adoptive transfer therapy was used in immunodeficient animals or in strain combinations with limited histiocompatibility. The aim of this study was to investigate whether Treg lines can protect from allograft rejection in a fully MHC-mismatched strain combination and whether the presence of Tregs with indirect allospecificity offered an advantage compared to self-reactive Tregs. Treg lines with self-specificity or with indirect allospecificity were generated by stimulating BL/6 CD4(+)CD25(+) T cells with autologous immature DCs either unpulsed or pulsed with K(d) peptide. The Treg lines were injected into recipient mice in combination with temporary depletion of CD8(+) T cells and a short course of Rapamycin. The data demonstrate that Treg lines with indirect allospecificity can be generated and most importantly they can induce indefinite survival of BALB/c hearts transplanted into BL/6 recipients when combined with short term immunosuppression. However, the Treg lines with self-specificity were only slightly less effective. The data presented in this study demonstrate the potential of ex vivo expanded Treg lines for adoptive cell therapy to promote transplantation tolerance.
[Show abstract][Hide abstract] ABSTRACT: Regulatory T cells (Tregs) are subsets of T cells that are specifically dedicated to controlling immune responses. It has been established that Tregs play a key role in regulating autoimmune disease, allergy, cancer, infectious disease, and in the induction of transplantation tolerance. The latest progress in the development, function, mechanism of action, and homeostasis of regulatory T cells, and their translation to the clinic were presented at the International Conference on Regulatory T Cells and Clinical Application in Human Diseases in Beijing on 25-27 October 2008 (China Tregs 2008). In this Special Issue of International Immunopharmacology, several papers submitted to the China Tregs 2008 will highlight some of the recent advances in the biology of regulatory T cells and current strategies to translate regulatory T cells into the clinic.
International immunopharmacology 04/2009; 9(5):515-7. DOI:10.1016/j.intimp.2008.01.038 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: T cell responses to MHC-mismatched transplants can be mediated via direct recognition of allogeneic MHC molecules on the cells of the transplant or via recognition of allogeneic peptides presented on the surface of recipient APCs in recipient MHC molecules - a process known as indirect recognition. As CD4(+)CD25(+) Tregs play an important role in regulating alloresponses, we investigated whether mouse Tregs specific for allogeneic MHC molecules could be generated in vitro and could promote transplantation tolerance in immunocompetent recipient mice. Tregs able to directly recognize allogeneic MHC class II molecules (dTregs) were obtained by stimulating CD4(+)CD25(+) cells from C57BL/6 mice (H-2(b)) with allogeneic DCs from BALB/c mice (H-2(d)). To generate Tregs that indirectly recognized allogeneic MHC class II molecules, dTregs were retrovirally transduced with TCR genes conferring specificity for H-2K(d) presented by H-2A(b) MHC class II molecules. The dual direct and indirect allospecificity of the TCR-transduced Tregs was confirmed in vitro. In mice, TCR-transduced Tregs, but not dTregs, induced long-term survival of partially MHC-mismatched heart grafts when combined with short-term adjunctive immunosuppression. Further, although dTregs were only slightly less effective than TCR-transduced Tregs at inducing long-term survival of fully MHC-mismatched heart grafts, histologic analysis of long-surviving hearts demonstrated marked superiority of the TCR-transduced Tregs. Thus, Tregs specific for allogeneic MHC class II molecules are effective in promoting transplantation tolerance in mice, which suggests that such cells have clinical potential.
[Show abstract][Hide abstract] ABSTRACT: So profound is the potential for regulatory T cells (Tregs) to control unwanted immune responses that in 2008 an entire conference was dedicated to them. The underlying concept of this conference, "China Tregs 2008," was that unraveling the cellular biology of Tregs will lead to important advances for therapies in virtually all human disease processes and in transplantation. The master-switch of immune regulation is the forkhead transcription factor Foxp3; in mice, Foxp3 is a sine qua non for regulatory activity. At "China Tregs 2008," the cell signaling events leading to the expression of Foxp3 and those events downstream were explored together with presentations on how the latest knowledge of the biology of Tregs is being translated in the clinic.
[Show abstract][Hide abstract] ABSTRACT: The pursuit of transplantation tolerance is still in progress some 53 years after Medawar and colleagues’ first description.
It has been established beyond doubt that regulatory T cells can confer donor-specific tolerance in mouse models of transplantation.
However, this is crucially dependent on the strain combination, the organ transplanted and most importantly, the ratio of
Tregs to alloreactive effector T cells. The ex-vivo expansion of Tregs is one solution to increase the number of alloantigen
specific cells capable of suppressing the alloresponse. This technique has been used to demonstrate long term graft survival
in mouse models, where ex-vivo expanded, alloantigen specific T cells are shown to preferentially migrate to, and proliferate
in, the graft and draining lymph node. When such models are selected to test the role of the different allorecognition pathways
for Treg induced graft survival, it appears that only a modest direct pathway alloresponse is sufficient to abrogate tolerance
in immunocompetent mice. This remains the case when Tregs are expanded with both direct and indirect pathway allospecificity.
Therefore, in human transplantation it is likely that depletion of the majority of direct pathway alloreactive T cells will
be required to tip the balance in favour of regulation. Ex-vivo expansion of alloantigen specific, indirect pathway human
Tregs, which can cross regulate the residual direct pathway has been established. Rapid expansion of these cells is possible,
while they retain antigen specificity, suppressive properties and favourable homing markers. Furthermore, considerable progress
has been made in the last few years to define which immunosuppressive drugs favour the expansion and function of Tregs. It
is proposed that a trial of Treg therapy in combination with depletion of alloreactive T cells and short term immunosuppression
is on the near horizon for human transplantation.
[Show abstract][Hide abstract] ABSTRACT: CD4+CD25+ regulatory T (Treg) cells play a critical role in the induction and maintenance of peripheral immune tolerance. In experimental transplantation models in which tolerance was induced, donor-specific Treg cells could be identified that were capable of transferring the tolerant state to naive animals. Furthermore, these cells appeared to have indirect allospecificity for donor antigens. Here we show that in vivo alloresponses can be regulated by donor alloantigen-specific Treg cells selected and expanded in vitro. Using autologous dendritic cells pulsed with an allopeptide from H2-Kb, we generated and expanded T-cell lines from purified Treg cells of CBA mice (H2k). Compared with fresh Treg cells, the cell lines maintained their characteristic phenotype, suppressive function, and homing capacities in vivo. When cotransferred with naive CD4+CD25- effector T cells after thymectomy and T-cell depletion in CBA mice that received CBK (H2k+Kb) skin grafts, the expanded Treg cells preferentially accumulated in the graft-draining lymph nodes and within the graft while preventing CBK but not third-party B10.A (H2k+Dd) skin graft rejection. In wild-type CBA, these donor-specific Treg cells significantly delayed CBK skin graft rejection without any other immunosuppression. Taken together, these data suggest that in vitro-generated tailored Treg cells could be considered a therapeutic tool to promote donor-specific transplant tolerance.
[Show abstract][Hide abstract] ABSTRACT: Despite the success of organ transplantation, most transplant patients are susceptible to variety of infections and cancer due to the use of potent immunosuppressive drugs for life to prevent transplant rejection. Regulatory T cells are capable of preventing transplant rejection while leaving the immune system's function against infection intact. Thus, adoptive cell therapy using patient-specific regulatory T cells as individualized medicine could promote clinical transplantation tolerance without the use of nonspecific immunosuppressive agents.
Discovery medicine 01/2007; 6(36):239-42. · 3.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Harnessing naturally arising CD4+ CD25+ regulatory T cells (Tregs) for potential adoptive cell therapy is hampered by their innate autoreactivity and their limited number.
CD4+ CD25+ Tregs were purified from peripheral blood of human leukocyte antigen (HLA) DR1*0101+ A2- individuals, and stimulated with autologous monocyte-derived dendritic cells (DCs).
Here we show that CD4+ CD25+ Tregs specific for an HLA A2 (103-120) peptide can be selected from the peripheral blood CD4+ CD25+ T cell population of a healthy individual and detected using a tetramer comprised of HLA DRB1*0101 and the A2 peptide. The selected cells can be expanded substantially (i.e., a 1600-fold increase over a two-week period) by T-cell receptor (TCR) stimulation and high-doses of interleukin-2 (IL-2). The CD4+ CD25+Tregs with indirect allospecificity for the A2 peptide showed more potent antigen-specific suppression than polyclonal CD4+ CD25+ Tregs.
These data may pave the way for clinical studies using CD4+ CD25+ Tregs with indirect allospecificity as therapeutic reagents for the induction of donor-specific transplantation tolerance.
[Show abstract][Hide abstract] ABSTRACT: Naturally arising CD4(+)CD25(+) regulatory T cells play a pivotal role in the prevention of autoimmunity and in the induction of donor-specific transplantation tolerance. Harnessing regulatory cells for potential adoptive cell therapy is hampered by their lack of antigen-specificity and their limited numbers. Here we describe the generation and expansion of murine CD4(+)CD25(+) T cells with antigen-specificity for an K(d) peptide as potential reagents for adoptive cell therapy in promoting donor-specific transplantation tolerance. Using bone marrow-derived autologous dendritic cells pulsed with the K(d) peptide, we generated T cell lines from purified CD4(+)CD25(+) T cells from C56BL/6 mice. The T cell lines expressed high level of CD25 and low level of CD45RB and CD69. They maintained the expression of CD62L, GITR, CTLA-4 and more importantly FoxP3. The CD4(+)CD25(+) T cell lines were anergic after TCR stimulation and produced little cytokine such as IL-2 and IFN-gamma. Importantly, they were more potent than freshly isolated CD4(+)CD25(+) T cells in suppressing proliferation and cytokine secretion by effector CD4(+) T cells. Furthermore, the CD4(+)CD25(+) T cell lines could be expanded to large cell numbers and maintained in culture up to 1 year. The K(d)-specific CD4(+)CD25(+) T cell lines will be invaluable in devising a strategy for the induction of cardiac transplantation tolerance in wild-type B6 mice carrying a full mismatch BALB/c heart.
International Immunopharmacology 01/2007; 6(13-14):1883-8. DOI:10.1016/j.intimp.2006.07.032 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The key goal in clinical transplantation is the induction of donor-specific transplantation tolerance to minimise the morbidity and mortality associated with long-term immunosuppression. Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) expressing forkhead transcript factor FoxP3 play a crucial role in the prevention of autoimmunity, and appear to mediate transplantation tolerance, and these cells can have indirect allospecificity for donor antigens. Here we show that self-reactive human CD4(+)CD25(+) Tregs can be subverted into allopeptide-specific cells in vitro and be expanded to large cell numbers, and that similar in vitro expanded murine CD4(+)CD25(+) Tregs with indirect allospecificity were capable of inducing donor-specific experimental transplantation tolerance. These data provide a platform for clinical studies using CD4(+)CD25(+) Tregs with indirect allospecificity as potential reagents for the induction of donor-specific transplantation tolerance.
International Immunopharmacology 01/2007; 6(13-14):1879-82. DOI:10.1016/j.intimp.2006.07.025 · 2.47 Impact Factor