Regulatory T Cells Get Their Chance to Shine

Leslie, Mitch

doi:10.1126/science.332.6033.1020

Cited by 55 publications

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“…44: 2592-2602 Cellular immune response 2593 graft-versus-leukemia responses [11,12]. Therefore, polyspecific CD4 + CD25 high cells are currently being evaluated after stem cell transplantation [13]. However, under nonlymphopenic conditions as seen in patients with autoimmune diseases or in patients after organ transplantation, polyspecific Treg cells have so far been largely ineffective in controlling immune responses [5,14,15] [24], and CD137 (4-1BB) [25] were described as Treg-cell activation markers after polyspecific Treg-cell activation.…”

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confidence: 99%

Isolation of human antigen‐specific regulatory T cells with high suppressive function

et al. 2014

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Adoptive transfer of regulatory T (Treg) cells could be an alternative to chronic immunosuppression for prevention of allogeneic graft rejection. While polyspecific Treg cells can prevent immune responses under lymphopenic conditions, Ag-specific Treg cells are needed to treat autoimmunity and graft rejection. Yet, reliable markers for Ag-specific Treg cells are missing. We report that latency-associated peptide (LAP) and glycoprotein A repetitions predominant (GARP) can identify human Ag-specific Treg cells. In addition,we show that the depletion of CD154 + cells from LAP + or GARP + Treg cells increases the Treg-cell purity to over 90%, as assessed by epigenetic analysis. These Ag-specific Treg cells can be isolated magnetically and might contribute to the development of GMP-based protocols. In addition, Ag-specific Treg cells are functionally far superior to CD4 + CD25 high or CD4 + CD25 high CD127 low Treg cells in vitro and in preventing strong alloreactions in humanized mice. They could, therefore, have a high therapeutic potential for the control of alloimmune, autoimmune, and allergic immune responses in patients.Keywords: Antigen-specific r CD154 r GARP r LAP r Regulatory T (Treg) cells Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIn organ transplantation, acute rejection can be prevented by a combination of nonspecific immunosuppressive drugs and immunomodulatory induction therapies, yet chronic rejection and chronic graft dysfunction remain a clinical problem [1]. In addition, chronic nonspecific immunosuppression causes renal dysfunction and predisposes patients to infections and increased Correspondence: Dr. Elmar Jaeckel e-mail: Jaeckel.Elmar@mh-hannover.de risk of malignancies [1]. Innate and adaptive immune responses can be controlled by Treg cells, thereby offering new therapeutic options after organ transplantation [2][3][4][5][6]. CD4 + CD25 high FOXP3 + Treg cells have been shown to be of major importance in allospecific tolerance in animal models and to influence donor-specific immune responses in transplant patients [7][8][9][10]. After allogeneic hematopoietic stem cell transplantation, polyspecific Treg cells can prevent GVH disease without influencing * These authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 2592-2602 Cellular immune response 2593 graft-versus-leukemia responses [11,12]. Therefore, polyspecific CD4 + CD25 high cells are currently being evaluated after stem cell transplantation [13]. However, under nonlymphopenic conditions as seen in patients with autoimmune diseases or in patients after organ transplantation, polyspecific Treg cells have so far been largely ineffective in controlling immune responses [5,14,15] [24], and CD137 (4-1BB) [25] were described as Treg-cell activation markers after polyspecific Treg-cell activation.In this manuscript, we demonstrated for the first time that LAP and GARP can be use...

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Isolation of human antigen‐specific regulatory T cells with high suppressive function

et al. 2014

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“…Such an approach would permit autologous or matched allogeneic cells with defined characteristics (e.g., cell surface markers, cytokine profile) and purity to be introduced into T1D patients, and restore self tolerance by the same mechanism used by inverse vaccination, but in a more controlled fashion, in a way mimicking the blockade of adoptive transfer described with T cells isolated from antigen-tolerized NOD mice. As more knowledge becomes available regarding the safety of Tregs that have been expanded ex vivo, and techniques to define and isolate the appropriate cell populations, the feasibility of Treg therapy will also be applied to autoimmune diabetes [Hippen et al, 2011;Leslie, 2011]. Regardless of how they are harnessed, in vivo by inverse vaccination or ex vivo by expansion and reintroduction, regulatory T cells appear to be the best chance for an autoimmune diabetes cure at this point.…”

Section: Discussionmentioning

confidence: 97%

Inverse vaccination with islet autoantigens to halt progression of autoimmune diabetes

Hinke

2011

Drug Development Research

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The incidence of autoimmune diabetes mellitus is growing worldwide; currently the only treatment is injection of insulin formulations to maintain glycemic control. Islet transplantation has been examined as a potential cure for diabetes. However, it has several limitations, including side effects of immunosuppressive agents required to prevent graft rejection. Other approaches have been to examine immune modulation to halt or prevent the autoimmune attack, with the hope that by preventing tissue damage, it will eventually regenerate and permit patients to be free from insulin injections. The focus of the current review is the three major antigen-based vaccines, insulin, glutamic acid decarboxylase 65 (GAD65; Diamyd), and heat shock protein 60 (Hsp60; DiaPep277), with respect to their mechanism of action, preclinical results, and published results from clinical trials. Despite promising results with these three antigens in mice and humans, efficacy has been limited in clinical trials. Drug Dev Res 72: 788-804, 2011. r

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“…It thus remains to be seen whether autoimmune liver diseases are associated with an impairment of Tregs that recognize the disease-driving autoantigens. Nonetheless, even if Treg impairment was not responsible for the pathogenesis of AIH or the other autoimmune liver diseases, there are reasons to believe that therapeutic Treg augmentation might be an effective treatment [37] . As it was shown that functional autoantigen-specific Tregs derived from the blood of AIH patients can be expanded in vitro [36] , re-infusion of such expanded Tregs may be a promising option.…”

Section: Tregs and Autoimmune Liver Diseasesmentioning

confidence: 99%

“…As it was shown that functional autoantigen-specific Tregs derived from the blood of AIH patients can be expanded in vitro [36] , re-infusion of such expanded Tregs may be a promising option. However, the purity and stability of in vitro generated or expanded Tregs are yet unresolved issues that may limit the use of such therapies [37] . Various approaches are being explored to overcome these obstacles in an attempt to develop Treg-based treatments for autoimmune diseases [37,38] , including autoimmune liver diseases [39,40] .…”

Section: Tregs and Autoimmune Liver Diseasesmentioning

confidence: 99%

“…However, the purity and stability of in vitro generated or expanded Tregs are yet unresolved issues that may limit the use of such therapies [37] . Various approaches are being explored to overcome these obstacles in an attempt to develop Treg-based treatments for autoimmune diseases [37,38] , including autoimmune liver diseases [39,40] . To obtain effective treatments, it is important to utilize Tregs that specifically recognize the disease-driving autoantigens, because, as explained earlier, Tregs need to be activated by their cognate antigens to perform their suppressive activities.…”

Section: Tregs and Autoimmune Liver Diseasesmentioning

confidence: 99%

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Regulatory T Cells in Hepatic Immune Tolerance and Autoimmune Liver Diseases

Herkel¹

2015

Dig Dis

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Regulatory T cells (Tregs) have a profound ability to control immune responses. A majority of Tregs are derived from the thymus; yet a substantial Treg fraction is derived from the periphery. The liver seems to be an important source of peripherally derived Tregs. Indeed, the liver's well-known ability to induce immune tolerance is at least partly based on hepatic Treg generation. With recently developed tools to deliver antigens to tolerance-inducing liver cells, it is now possible to harness liver-derived Tregs for specific control of unwanted immune responses. Indeed, the selective delivery of autoantigens to liver sinusoidal endothelial cells could induce autoantigen-specific Tregs in vivo, providing effective treatment of autoimmune disease. Owing to the fundamental role Tregs play in controlling immune responses, an impairment of Tregs seems to be a plausible explanation for the development of autoimmune diseases, for example, in the liver. However, the actual role of Treg impairment in autoimmune liver diseases, such as autoimmune hepatitis (AIH), remains controversial. Major obstacles for clarifying the role of Tregs in autoimmune liver diseases are related to the difficulty to identify human Tregs unambiguously and to the difficulty to identify those Tregs and effector T cells that specifically recognize disease-driving autoantigens. However, even if AIH turned out to be a disease that is not driven by Treg impairment, Treg-based therapies for autoimmune liver diseases might still be effective, provided the Tregs for therapeutic use recognize the relevant antigens.

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Regulatory T Cells Get Their Chance to Shine

Abstract: Researchers are encouraged by results from initial safety trials of regulatory T cells in graft-versus-host disease and are embarking on trials testing their ability to fight type 1 diabetes and forestall rejection of transplanted kidneys.

Cited by 55 publications

References 0 publications

Isolation of human antigen‐specific regulatory T cells with high suppressive function

Isolation of human antigen‐specific regulatory T cells with high suppressive function

Inverse vaccination with islet autoantigens to halt progression of autoimmune diabetes

Regulatory T Cells in Hepatic Immune Tolerance and Autoimmune Liver Diseases

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