Regulatory T-Cell Counter-Regulation by Innate Immunity Is a Barrier to Transplantation Tolerance

Kim, James I.; Lee, Major K.; Moore, Daniel J.; Sonawane, Samsher; Duff, Patrick E.; O’Connor, Matthew; Yeh, Heidi; Lian, Moh Moh; Deng, Shaoping; Caton, Andrew J.; Markmann, James F.

doi:10.1111/j.1600-6143.2009.02847.x

Cited by 18 publications

(9 citation statements)

References 27 publications

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“…Nevertheless, the expression of Foxp3 is unstable and will be down-regulated in an IL-6-rich, Th17-promoting environment. When such Treg ‘deprogramming’ occurs, Tregs fail to exert their original immunoinhibitory role [ 20 , 21 ] and may convert into competent Foxp3- effector T cells, which up-regulate the RORγt expression [ 11 ]. Inflammation-dampening strategies, particularly manipulating the inflammation occurring in the graft and draining lymph nodes, may guide the host immunity from an adverse effect toward tissue-protective phenotypes.…”

Section: Discussionmentioning

confidence: 99%

All-trans retinoid acid promotes allogeneic corneal graft survival in mice by regulating Treg-Th17 balance in the presence of TGF-β

Wang

et al. 2015

BMC Immunol

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BackgroundAll-trans retinoid acid (ATRA) has been proven to skew Regulatory T cell-T helper 17 cell (Treg-Th17) balance toward Treg in vitro, favoring graft acceptance. However, its in vivo effect after solid organ transplantation is under investigation.ResultsBALB/c mice were given orthotopic corneal grafts from C57BL/6 donors, and recipient mice were administered with ATRA, TGF-β, and the combination of both agents for 8 weeks after surgery. We found that a mixed treatment of ATRA and TGF-β significantly promoted graft survival. Moreover, with the presence of TGF-β, ATRA upregulated CD4+CD25+Foxp3+Treg cells and suppressed Th17 cells in the blood, spleen and draining lymph nodes of recipient mice, as well as enhanced the Foxp3 expression and inhibited the RORγt expression in grafts and peripheral blood mononuclear cells (PBMCs). Simultaneously, increased number of Foxp3+ cells and decreased number of IL-17+ cells in conjunctiva were found in recipients with mixed treatment, along with reduced IL-17 level in serum and aqueous humor and increased IL-10 level in aqueous humor. Tregs isolated from recipient mice treated with ATRA + TGF-β presented the strongest suppressive activity in vitro.ConclusionsCombined application of ATRA and TGF-β may shift the Th17-Treg balance toward Tregs, hence facilitating the induction of immunological tolerance after allogenic corneal transplantation and representing a potential therapeutic approach in the treatment of posttransplant rejection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-015-0082-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

All-trans retinoid acid promotes allogeneic corneal graft survival in mice by regulating Treg-Th17 balance in the presence of TGF-β

Wang

et al. 2015

BMC Immunol

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“…Deletion of activated T cells is necessary, but not sufficient, for induction of transplantation tolerance, since T cells from tolerant recipients are able to reject allografts adoptively transferred into new recipients within 3 weeks after transplantation (48). On the other hand, antigen-specific Tregs do not seem to participate during the early phase of tolerance induction (49), as it takes 3 weeks for Tregs to fully develop in the periphery of tolerant recipients (50,51). These observations suggest that additional mechanisms of early immune regulation must exist that protect the allograft from being acutely rejected by day 10 after transplant.…”

Section: Discussionmentioning

confidence: 99%

Monocytic suppressive cells mediate cardiovascular transplantation tolerance in mice

Garcia¹,

Ledgerwood²,

Yu³

et al. 2010

J. Clin. Invest.

194

221

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One of the main unresolved questions in solid organ transplantation is how to establish indefinite graft survival that is free from long-term treatment with immunosuppressive drugs and chronic rejection (i.e., the establishment of tolerance). The failure to achieve this goal may be related to the difficulty in identifying the phenotype and function of the cell subsets that participate in the induction of tolerance. To address this issue, we investigated the suppressive roles of recipient myeloid cells that may be manipulated to induce tolerance to transplanted hearts in mice. Using depleting mAbs, clodronate-loaded liposomes, and transgenic mice specific for depletion of CD11c + , CD11b + , or CD115 + cells, we identified a tolerogenic role for CD11b + CD115 + Gr1 + monocytes during the induction of tolerance by costimulatory blockade with CD40L-specific mAb. Early after transplantation, Gr1 + monocytes migrated from the bone marrow into the transplanted organ, where they prevented the initiation of adaptive immune responses that lead to allograft rejection and participated in the development of Tregs. Our results suggest that mobilization of bone marrow CD11b + CD115 + Gr1 + monocytes under sterile inflammatory conditions mediates the induction of indefinite allograft survival. We propose that manipulating the common bone marrow monocyte progenitor could be a useful clinical therapeutic approach for inducing transplantation tolerance.

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“…Current translational transplant studies are focused upon the delivery of T-regs with direct allospecificity ( 97 , 99 , 108 – 112 ), partly because these can be generated more readily than indirect pathway T-regs. These are likely to be most effective in preventing early acute rejection, albeit the strong pro-inflammatory environment immediately after transplantation may favor deleterious trans-differentiation of the administered T-regs to T effector status ( 113 ). Control of acute rejection is not a major clinical problem, and while early administration of direct pathway T-regs may have long-lasting consequences ( 114 ), based on the above consideration of expression of target epitope at late time points, one would predict that chronic rejection will be better controlled by iT-regs with indirect allospecificity.…”

Section: Targeting Late T Cell Alloresponses To Prevent Progression Omentioning

confidence: 99%

T cell Allorecognition Pathways in Solid Organ Transplantation

et al. 2018

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Transplantation is unusual in that T cells can recognize alloantigen by at least two distinct pathways: as intact MHC alloantigen on the surface of donor cells via the direct pathway; and as self-restricted processed alloantigen via the indirect pathway. Direct pathway responses are viewed as strong but short-lived and hence responsible for acute rejection, whereas indirect pathway responses are typically thought to be much longer lasting and mediate the progression of chronic rejection. However, this is based on surprisingly scant experimental evidence, and the recent demonstration that MHC alloantigen can be re-presented intact on recipient dendritic cells—the semi-direct pathway—suggests that the conventional view may be an oversimplification. We review recent advances in our understanding of how the different T cell allorecognition pathways are triggered, consider how this generates effector alloantibody and cytotoxic CD8 T cell alloresponses and assess how these responses contribute to early and late allograft rejection. We further discuss how this knowledge may inform development of cellular and pharmacological therapies that aim to improve transplant outcomes, with focus on the use of induced regulatory T cells with indirect allospecificity and on the development of immunometabolic strategies.KEY POINTS Acute allograft rejection is likely mediated by indirect and direct pathway CD4 T cell alloresponses.Chronic allograft rejection is largely mediated by indirect pathway CD4 T cell responses. Direct pathway recognition of cross-dressed endothelial derived MHC class II alloantigen may also contribute to chronic rejection, but the extent of this contribution is unknown.Late indirect pathway CD4 T cell responses will be composed of heterogeneous populations of allopeptide specific T helper cell subsets that recognize different alloantigens and are at various stages of effector and memory differentiation.Knowledge of the precise indirect pathway CD4 T cell responses active at late time points in a particular individual will likely inform the development of alloantigen-specific cellular therapies and will guide immunometabolic modulation.

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Regulatory T-Cell Counter-Regulation by Innate Immunity Is a Barrier to Transplantation Tolerance

Cited by 18 publications

References 27 publications

All-trans retinoid acid promotes allogeneic corneal graft survival in mice by regulating Treg-Th17 balance in the presence of TGF-β

All-trans retinoid acid promotes allogeneic corneal graft survival in mice by regulating Treg-Th17 balance in the presence of TGF-β

Monocytic suppressive cells mediate cardiovascular transplantation tolerance in mice

T cell Allorecognition Pathways in Solid Organ Transplantation

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