Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes

Joffre, Olivier; Santolaria, Thibault; Calise, Denis; Saati, Talal Al; Hudrisier, Denis; Romagnoli, Paola; Meerwijk, Joost P. M. van

doi:10.1038/nm1688

Cited by 474 publications

(421 citation statements)

References 30 publications

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“…Moreover, the generation of alloreactive Treg cells from non-Treg precursors by stimulation with alloantigens may offer immunological advantages over polyclonal expansion of naturally occurring Treg cells, as indicated by other authors [67,68]. We have shown that the presence of RA, TGF-β1, and IL-2 consistently induces the de novo generation of regulatory RA-iTreg cells.…”

Section: Discussionmentioning

confidence: 51%

Alloreactive regulatory T cells generated with retinoic acid prevent skin allograft rejection

et al. 2014

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CD4 + CD25 + Foxp3 + regulatory T (Treg) cells mediate immunological self-tolerance and suppress immune responses. Retinoic acid (RA), a natural metabolite of vitamin A, has been reported to enhance the differentiation of Treg cells in the presence of TGF-β. In this study, we show that the co-culture of naive T cells from C57BL/6 mice with allogeneic antigen-presenting cells (APCs) from BALB/c mice in the presence of TGF-β, RA, and IL-2 resulted in a striking enrichment of Foxp3 + T cells. These RA in vitro-induced regulatory T (RA-iTreg) cells did not secrete Th1-, Th2-, or Th17-related cytokines, showed a nonbiased homing potential, and expressed several cell surface molecules related to Treg-cell suppressive potential. Accordingly, these RA-iTreg cells suppressed T-cell proliferation and inhibited cytokine production by T cells in in vitro assays. Moreover, following adoptive transfer, RA-iTreg cells maintained Foxp3 expression and their suppressive capacity. Finally, RA-iTreg cells showed alloantigen-specific immunosuppressive capacity in a skin allograft model in immunodeficient mice. Altogether, these data indicate that functional and stable allogeneic-specific Treg cells may be generated using TGF-β, RA, and IL-2. Thus, RA-iTreg cells may have a potential use in the development of more effective cellular therapies in clinical transplantation. Keywords: Allogeneic regulatory T cells r Homing r Retinoic acid r Tolerance r TransplantationAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionRegulatory T (Treg) cells are responsible for inducing and maintaining peripheral tolerance [1]. Treg cells are classified into two Correspondence: Dr. Daniela Sauma e-mail: dsauma@u.uchile.cl major subpopulations: thymus-derived Treg cells, which are generated in the thymus and circulate in the periphery as functional mature Treg cells [2][3][4], and peripherally derived Treg cells, which are generated in the periphery from CD4 + CD25 − naive * These authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 452-463 Immunomodulation 453T cells [5][6][7]. Treg cells target effector T cells and dendritic cells (DCs) by modulating their maturation and function through several mechanisms that suppress immune responses [8][9][10]; these include secretion of inhibitory cytokines (IL-10, IL-35, and TGF-β), granzyme/perforin-dependent mediated cytolysis, metabolic disruption [11][12][13][14][15], and the expression of LAG3 and CTLA4, which alter DC function [16,17]. In addition to the aforementioned mechanisms, Treg-cell suppressive capacity is dependent on Treg-cell migration and retention in the microenvironment where regulation is required. Differential expression patterns of chemokine receptors (such as CCR4, CCR5, and CCR9), integrins (α4β7), and selectins (CD62L) contribute to selective retention and trafficking of Treg cells and allow their appropriate localization during ...

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Section: Discussionmentioning

confidence: 51%

Alloreactive regulatory T cells generated with retinoic acid prevent skin allograft rejection

et al. 2014

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“…Foxp3 has important roles not only as a key molecule in the development of regulatory T cells, but also as an inhibitor of T-cell activation and a repressor of transcription factors (31)(32)(33). Regulatory T cells have been widely used in experimental models for treating autoimmune diseases including IBD (13), arthritis (17), diabetes (18,34), and atherosclerosis (35), allergic diseases including asthma (36) and dermatitis (37), and in preventing transplantation rejection (38,39).…”

Section: Discussionmentioning

confidence: 99%

Cell-permeable Foxp3 protein alleviates autoimmune disease associated with inflammatory bowel disease and allergic airway inflammation

Choi

Shin

Sohn

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Foxp3 is a key transcription factor for differentiation and function of regulatory T (Treg) cells that is critical for maintaining immunological self-tolerance. Therefore, increasing Treg function by Foxp3 transduction to regulate an inflammatory immune response is an important goal for the treatment of autoimmune and allergic diseases. Here we have generated a cell-permeable Foxp3 protein by fusion with the unique human HHph-1-PTD (protein transduction domain), examined its regulatory function in T cells, and characterized its therapeutic effect in autoimmune and allergic disease models. HHph-1-Foxp3 was rapidly and effectively transduced into cells within 30 min and conferred suppressor function to CD4 + CD25 − T cells as well as directly inhibiting T-cell activation and proliferation. Systemic delivery of HHph-1 Foxp3 remarkably inhibited the autoimmune symptoms of scurfy mice and the development of colitis induced by scurfy or wild-type CD4 T cells. Moreover, intranasal delivery of HHph-1-Foxp3 strongly suppressed ovalbumin-induced allergic airway inflammation. These results demonstrate the clinical potential of the cell-permeable recombinant HHph-1-Foxp3 protein in autoimmune and hypersensitive allergic diseases.

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“…In contrast, indirect presentation of alloantigens by host regulatory APCs probably is the predominant tolerance mechanism. Other models of allogeneic transplantation also indicate that the indirect pathway plays a critical role in donor-specific tolerance (30,31). Recent data in the EAE model suggest that host plasmacytoid dendritic cells are crucial in this tolerogenic cross-presentation and that the tolerogenic interactions probably occur in the spleen (S.D.M., unpublished observations).…”

Section: Discussionmentioning

confidence: 95%

ECDI-fixed allogeneic splenocytes induce donor-specific tolerance for long-term survival of islet transplants via two distinct mechanisms

Luo

Pothoven

McCarthy

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

158

233

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A major challenge for human allogeneic islet transplantation is the development of effective methods to induce donor-specific tolerance to obviate the need for life-long immunosuppression that is toxic to the insulin-producing ␤ cells and detrimental to the host. We developed an efficient donor-specific tolerance therapy that utilizes infusions of ethylene carbodiimide (ECDI)-treated donor splenic antigen-presenting cells that results in indefinite survival of allogeneic islet grafts in the absence of immunosuppression. Furthermore, we show that induction of tolerance is critically dependent on synergistic effects between an intact programmed death 1 receptorprogrammed death ligand 1 signaling pathway and CD4 ؉ CD25 ؉ Foxp3 ؉ regulatory T cells. This highly efficient antigen-specific therapy with a complete avoidance of immunosuppression has significant therapeutic potential in human islet cell transplantation.anergy ͉ programmed death-1 ͉ regulatory T cells ͉ transplantation ͉ islet transplantation

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Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes

Cited by 474 publications

References 30 publications

Alloreactive regulatory T cells generated with retinoic acid prevent skin allograft rejection

Alloreactive regulatory T cells generated with retinoic acid prevent skin allograft rejection

Cell-permeable Foxp3 protein alleviates autoimmune disease associated with inflammatory bowel disease and allergic airway inflammation

ECDI-fixed allogeneic splenocytes induce donor-specific tolerance for long-term survival of islet transplants via two distinct mechanisms

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