Treg-mediated prolonged survival of skin allografts without immunosuppression

Pilat, Nina; Wiletel, Mario; Weijler, Anna Marianne; Steiner, Romy; Mahr, Benedikt; Warren, Joanna; Corpuz, Theresa M.; Wekerle, Thomas; Webster, Kylie E.; Sprent, Jonathan

doi:10.1073/pnas.1903165116

Cited by 38 publications

(45 citation statements)

References 52 publications

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“…The main highlight of this study was the early and continued presence of CD4 and CD8 Tregs within the NPSC grafts. CD4 Tregs have been implicated in prolongation of allograft survival and recently have been demonstrated to improve survival of xenografts 20 – 24 , 40 . Tregs have been shown to mediate immune tolerance and homeostasis by suppressing T effector cells, inhibiting cell–cell contact with APCs, and secreting regulatory cytokines 41 , 42 .…”

Section: Discussionmentioning

confidence: 99%

Neonatal Pig Sertoli Cells Survive Xenotransplantation by Creating an Immune Modulatory Environment Involving CD4 and CD8 Regulatory T Cells

et al. 2020

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The acute cell-mediated immune response presents a significant barrier to xenotransplantation. Immune-privileged Sertoli cells (SC) can prolong the survival of co-transplanted cells including xenogeneic islets, hepatocytes, and neurons by protecting them from immune rejection. Additionally, SC survive as allo- and xenografts without the use of any immunosuppressive drugs suggesting elucidating the survival mechanism(s) of SC could be used to improve survival of xenografts. In this study, the survival and immune response generated toward neonatal pig SC (NPSC) or neonatal pig islets (NPI), nonimmune-privileged controls, was compared after xenotransplantation into naïve Lewis rats without immune suppression. The NPSC survived throughout the study, while NPI were rejected within 9 days. Analysis of the grafts revealed that macrophages and T cells were the main immune cells infiltrating the NPSC and NPI grafts. Further characterization of the T cells within the grafts indicated that the NPSC grafts contained significantly more cluster of differentiation 4 (CD4) and cluster of differentiation 8 (CD8) regulatory T cells (Tregs) at early time points than the NPI grafts. Additionally, the presence of increased amounts of interleukin 10 (IL-10) and transforming growth factor (TGF) β and decreased levels of tumor necrosis factor (TNF) α and apoptosis in the NPSC grafts compared to NPI grafts suggests the presence of regulatory immune cells in the NPSC grafts. The NPSC expressed several immunoregulatory factors such as TGFβ, thrombospondin-1 (THBS1), indoleamine-pyrrole 2,3-dioxygenase, and galectin-1, which could promote the recruitment of these regulatory immune cells to the NPSC grafts. In contrast, NPI grafts had fewer Tregs and increased apoptosis and inflammation (increased TNFα, decreased IL-10 and TGFβ) suggestive of cytotoxic immune cells that contribute to their early rejection. Collectively, our data suggest that a regulatory graft environment with regulatory immune cells including CD4 and CD8 Tregs in NPSC grafts could be attributed to the prolonged survival of the NPSC xenografts.

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Section: Discussionmentioning

confidence: 99%

Neonatal Pig Sertoli Cells Survive Xenotransplantation by Creating an Immune Modulatory Environment Involving CD4 and CD8 Regulatory T Cells

et al. 2020

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“…The authors suggested that blocking IL-6 production and IL-6 signaling in combination with co-stimulatory blockade inhibited Th1 responses, and promoted transplant tolerance (Zhao et al, 2012). Recently, the role of IL-6 in allograft rejection was revisited (Pilat et al, 2019). These authors showed that in combination with rapamycin and an anti-IL-2 monoclonal antibody plus IL-2-complex, blocking IL-6 prolonged MHC mismatched skin transplants for greater than 75 days (Pilat et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, the role of IL-6 in allograft rejection was revisited (Pilat et al, 2019). These authors showed that in combination with rapamycin and an anti-IL-2 monoclonal antibody plus IL-2-complex, blocking IL-6 prolonged MHC mismatched skin transplants for greater than 75 days (Pilat et al, 2019). Here, we show that T cell derived IL-6 production was inhibited in the presence of Treg EVs, suggesting one way that these vesicles may have abrogate T cell alloresponses seen in our mouse model.…”

Section: Discussionmentioning

confidence: 99%

“…Regulatory T cells (Tregs) are essential for the maintenance of tolerance to self-antigens and immune homeostasis (Shevach, 2018). In humans, a link between the frequency of Tregs within allografts and longevity has been described (Pearce et al, 1993), whilst the adoptive transfer of ex vivo expanded murine, or human Tregs, in preclinical murine transplant models significantly prolonged the survival of murine and human skin allografts, respectively (Sagoo et al, 2011;Boardman et al, 2017;Pilat et al, 2019). Given their efficacy in vivo, we are currently conducting Phase I/II clinical trials to investigate the therapeutic potential of autologous Treg therapy to promote transplant survival rates in kidney (The ONE Study: NCT02129881) and liver (ThRIL: NCT02166177) transplant recipient patients (Romano et al, 2017;Sánchez-Fueyo et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Regulatory T Cell Extracellular Vesicles Modify T-Effector Cell Cytokine Production and Protect Against Human Skin Allograft Damage

Tung

Fanelli

Matthews

et al. 2020

Front. Cell Dev. Biol.

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Regulatory T cells (Tregs) are a subpopulation of CD4 + T cells with a fundamental role in maintaining immune homeostasis and inhibiting unwanted immune responses using several different mechanisms. Recently, the intercellular transfer of molecules between Tregs and their target cells has been shown via trogocytosis and the release of small extracellular vesicles (sEVs). In this study, CD4 + CD25 + CD127 lo human Tregs were found to produce sEVs capable of inhibiting the proliferation of effector T cells (Teffs) in a dose dependent manner. These vesicles also modified the cytokine profile of Teffs leading to an increase in the production of IL-4 and IL-10 whilst simultaneously decreasing the levels of IL-6, IL-2, and IFNγ. MicroRNAs found enriched in the Treg EVs were indirectly linked to the changes in the cytokine profile observed. In a humanized mouse skin transplant model, human Treg derived EVs inhibited alloimmune-mediated skin tissue damage by limiting immune cell infiltration. Taken together, Treg sEVs may represent an exciting cell-free therapy to promote transplant survival.

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“…Despite prolonging the survival of islet allografts, IL-2 mab complexes failed to augment the survival of skin allografts as monotherapy ( 53 ). However, later experiments showed that modification of the treatment protocol led to prolonged skin allograft survival.…”

Section: Treg Expansion In Vivomentioning

confidence: 99%

Treg Therapies Revisited: Tolerance Beyond Deletion

Pilat

Sprent

2021

Front. Immunol.

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Induction of immune tolerance is the Holy Grail in transplantation medicine and autoimmunity. Currently, patients are required to use immunosuppressive drugs for the rest of their lives, resulting in unwanted side effects and complication from global suppression of the immune response. It is well established that regulatory T cells (Tregs) are critical for the maintenance of immune tolerance towards self-antigens by several mechanisms of immune regulation, in parallel with intrathymic deletion of self-reactive T cells during ontogeny. Therefore, approaches for increasing Treg numbers or function in vivo could provide an all-purpose solution for tolerance induction. Currently, most state-of-the-art therapeutics for treating autoimmune diseases or preventing allograft rejection work either by general immunosuppression or blocking inflammatory reactions and are non-specific. Hence, these approaches cannot provide satisfactory long-term results, let alone a cure. However, in animal models the therapeutic potential of Treg expansion for inducing effective tolerance has now been demonstrated in various models of autoimmunity and allogeneic transplantation. Here, we focus on therapies for increasing the size of the Treg pool by expanding endogenous Treg numbers in vivo or by adoptive transfer of Tregs. In particular, we discuss IL-2 based approaches (low dose IL-2, IL-2 complexes) for inducing Treg expansion in vivo as well as cell-based approaches (polyclonal, antigen specific, or cell engineered) for adoptive Treg therapy. We also mention new questions arising from the first clinical studies on Treg therapy in the fields of transplantation and autoimmunity.

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Treg-mediated prolonged survival of skin allografts without immunosuppression

Cited by 38 publications

References 52 publications

Neonatal Pig Sertoli Cells Survive Xenotransplantation by Creating an Immune Modulatory Environment Involving CD4 and CD8 Regulatory T Cells

Neonatal Pig Sertoli Cells Survive Xenotransplantation by Creating an Immune Modulatory Environment Involving CD4 and CD8 Regulatory T Cells

Regulatory T Cell Extracellular Vesicles Modify T-Effector Cell Cytokine Production and Protect Against Human Skin Allograft Damage

Treg Therapies Revisited: Tolerance Beyond Deletion

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