Targeting Acute Allograft Rejection by Immunotherapy With Ex Vivo-Expanded Natural CD4+CD25+ Regulatory T Cells

Xia, Guliang; He, Jie; Zhang, Zheng Jenny; Leventhal, Joseph R.

doi:10.1097/01.tp.0000250731.44913.ee

Cited by 59 publications

(48 citation statements)

References 45 publications

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“…Furthermore, it has been shown that Tregs are less effective in controlling CD8 responses than CD4 responses in vivo. However, in Rag -/-mice, Tregs that prevented graft rejection mediated by CD4 + T cells only delayed graft rejection mediated by CD8 + T cells, presumably due to linked suppression (20). Besides, it has been shown that independent targeting of CD8 + T cells can convert ineffective into effective therapeutic protocols in several transplant models (21).…”

Section: Tcr-transduced Tregs Can Control Indirect Alloresponses In Vmentioning

confidence: 99%

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Conferring indirect allospecificity on CD4+CD25+ Tregs by TCR gene transfer favors transplantation tolerance in mice

Tsang¹,

Tanriver²,

Jiang³

et al. 2008

J. Clin. Invest.

246

243

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Section: Tcr-transduced Tregs Can Control Indirect Alloresponses In Vmentioning

confidence: 99%

“…However, it has been shown that adoptive transfer of Tregs together with CD4 + effector cells, even at a 1:1 ratio, cannot control CD4-mediated BALB/c rejection in BL/6 Rag -/-recipients (20). Thus, a short course of rapa-…”

Section: Tcr-transduced Tregs Can Control Indirect Alloresponses In Vmentioning

confidence: 99%

Conferring indirect allospecificity on CD4+CD25+ Tregs by TCR gene transfer favors transplantation tolerance in mice

Tsang¹,

Tanriver²,

Jiang³

et al. 2008

J. Clin. Invest.

246

243

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“…Due to low precursor frequency, efficient ex vivo expansion of fresh nT reg is likely essential for generating sufficient cells to therapeutically target a large repertoire of alloreactive T eff clones. AlloAg-nonspecifically expanded CD4 + CD25 + nT reg have previously been shown by us to prevent graftversus-host disease in CD25 −/− allogeneic bone marrow (BM) chimeras following delayed lymphocyte infusion and heart allograft rejection in immunodeficient Rag −/− mice mediated by concurrently cotransferred T eff (19,20). Our current study was to extend the use of ex vivo-expanded CD4 + CD25 + nT reg to therapeutically target heart allograft rejection in wild-type mice.…”

Section: Introductionmentioning

confidence: 99%

Ex Vivo-Expanded Natural CD4+CD25+ Regulatory T Cells Synergize With Host T-Cell Depletion to Promote Long-Term Survival of Allografts

Xia

Leventhal

2008

American Journal of Transplantation

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“…Among the protocols designed to obtain adequate numbers of Treg cells for use in immunotherapy, the polyclonal expansion of Thymus-derived Treg cells using anti-CD3/anti-CD28 beads plus IL-2 has been shown to be the most efficient method for ex vivo expansion of both mouse and human Treg cells [29][30][31][32]. However, the expansion of thymus derived Treg cells and the generation of polyclonal in vitro-induced Treg (iTreg) cells from naive cells have the disadvantage that these cells are expanded/generated from an existing pool, and have a broad rather than a selective reactivity towards alloantigens.…”

Section: Introductionmentioning

confidence: 99%

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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Targeting Acute Allograft Rejection by Immunotherapy With Ex Vivo-Expanded Natural CD4+CD25+ Regulatory T Cells

Abstract: Therapeutic use of ex vivo-expanded natural CD4+ CD25+ Treg may be a feasible and nontoxic modality for controlling allograft rejection or perhaps inducing allograft tolerance.

Cited by 59 publications

References 45 publications

Conferring indirect allospecificity on CD4+CD25+ Tregs by TCR gene transfer favors transplantation tolerance in mice

Conferring indirect allospecificity on CD4+CD25+ Tregs by TCR gene transfer favors transplantation tolerance in mice

Ex Vivo-Expanded Natural CD4+CD25+ Regulatory T Cells Synergize With Host T-Cell Depletion to Promote Long-Term Survival of Allografts

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

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