Pilot Study Evaluating Regulatory T Cell–Promoting Immunosuppression and Nonimmunogenic Donor Antigen Delivery in a Nonhuman Primate Islet Allotransplantation Model

Ji, Lei; Kim, J. I.; Shi, Shuai; Zhang, X.; Machaidze, Zurab; Lee, S.; Schuetz, Christian; Martins, Paulo Ney Aguiar; Oura, Tetsu; Farkash, Evan A.; Rosales, Ivy A.; Smith, Rex Neal; Stott, Ryan; Lee, K. M.; Soohoo, Julie; Bosković, S; Cappetta, K.; Nadazdin, O.; Yamada, Yasuaki; Yeh, Heidi; Kawai, Tatsuo; Sachs, David H.; Bénichou, Gilles; Markmann, James F.

doi:10.1111/ajt.13329

Cited by 26 publications

(29 citation statements)

References 26 publications

(27 reference statements)

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“…23 When infused intravenously, they are readily phagocytized by recipient splenic APCs, 19 and induce robust donor-specific tolerance in murine models of allogeneic and xenogeneic transplantation. 18,20,33 This approach has also demonstrated promising efficacy in a nonhuman primate model of allogeneic islet transplantation, 34 and the same concept has been successfully applied to treating autoimmunity 35 in a clinical trial for multiple sclerosis. 36 Independently, a recent phase I/IIa clinical trial using a single infusion of donor early apoptotic cells for prophylaxis of GVHD in 13 patients receiving allogeneic bone marrow transplantation has demonstrated remarkable safety and potential efficacy of this approach in reducing acute GVHD.…”

Section: Efficacy Of Donor Ecdi-sp In Mertk −/− Recipients Can Be Rmentioning

confidence: 99%

Receptor tyrosine kinase MerTK suppresses an allogenic type I IFN response to promote transplant tolerance

Zhang

DeBerge

Wang

et al. 2019

American Journal of Transplantation

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Recipient infusion of donor apoptotic cells is an emerging strategy for inducing robust transplantation tolerance. Daily clearance of billions of self-apoptotic cells relies on homeostatic engagement of phagocytic receptors, in particular, receptors of the tyrosine kinase family TAM (Tyro3, Axl, and MerTK), to maintain self-tolerance. However, an outstanding question is if allogeneic apoptotic cells trigger the same receptor system for inducing allogeneic tolerance. Here, we employed allogeneic apoptotic splenocytes and discovered that the efferocytic receptor MerTK on recipient phagocytes is a critical mediator for transplantation tolerance induced by this strategy. Our findings indicate that the tolerogenic properties of allogeneic apoptotic splenocytes require MerTK transmission of intracellular signaling to suppress the production of inflammatory cytokine interferon α (IFN-α). We further demonstrate that MerTK is crucial for subsequent expansion of myeloid-derived suppressor cells and for promoting their immunomodulatory function, including maintaining graft-infiltrating CD4 CD25 Foxp3 regulatory T cells. Consequently, recipient MerTK deficiency resulted in failure of tolerance by donor apoptotic cells, and this failure could be effectively rescued by IFN-α receptor blockade. These findings underscore the importance of the efferocytic receptor MerTK in mediating transplantation tolerance by donor apoptotic cells and implicate MerTK agonism as a promising target for promoting transplantation tolerance.

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Section: Efficacy Of Donor Ecdi-sp In Mertk −/− Recipients Can Be Rmentioning

confidence: 99%

Receptor tyrosine kinase MerTK suppresses an allogenic type I IFN response to promote transplant tolerance

Zhang

DeBerge

Wang

et al. 2019

American Journal of Transplantation

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“…Our lab has experimented with donor splenocytes treated with 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (ECDI-SPs) as a highly effective modality for tolerance induction in murine models of allogeneic and xenogeneic islet transplantation, 188,189 allogeneic heart, 190 and kidney transplantation (Luo et al, unpublished data), as well as in nonhuman primate allogeneic islet transplantation. 191 Graft protection in these studies correlates with a remarkable inhibition of allospecific T cell immune response. [184][185][186] Specifically, donor ECDI-SPs differentially target T cells with indirect versus direct allospecificities.…”

Section: Donor Negative Vaccinationmentioning

confidence: 81%

Impact of infection on transplantation tolerance

Luo

2019

Immunological Reviews

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Allograft tolerance is the ultimate goal of organ transplantation. Current strategies for tolerance induction mainly focus on inhibiting alloreactive T cells while promoting regulatory immune cells. Pathogenic infections may have direct impact on both effector and regulatory cell populations, therefore can alter host susceptibility to transplantation tolerance induction as well as impair the quality and stability of tolerance once induced. In this review, we will discuss existing data demonstrating the effect of infections on transplantation tolerance, with particular emphasis on the role of the stage of infection (acute, chronic, or latent) and the stage of tolerance (induction or maintenance) in this infection‐tolerance interaction. While the deleterious effect of acute infection on tolerance is mainly driven by proinflammatory cytokines induced shortly after the infection, chronic infection may generate exhausted T cells that could in fact facilitate transplantation tolerance. In addition to pathogenic infections, commensal intestinal microbiota also has numerous significant immunomodulatory effects that can shape the host alloimmunity following transplantation. A comprehensive understanding of these mechanisms is crucial for the development of therapeutic strategies for robustly inducing and stably maintaining transplantation tolerance while preserving host anti‐pathogen immunity in clinically relevant scenarios.

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“…The modulation of the host immune response through the transfusion of ECDI‐SP is a simple and non‐cytoreductive strategy to induce donor‐specific tolerance . ECDI‐treated leukocytes are known to undergo rapid apoptosis, although the precise mechanism remains unclear.…”

Section: Discussionmentioning

confidence: 99%

ECDI‐fixed donor splenocytes prolong skin allograft survival by promoting M2 macrophage polarization and inducing regulatory T cells

Zhou

Zhang

et al. 2019

FASEB BioAdvances

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Rejection is a common complication of allogeneic tissue transplantation. Fixation of splenocytes (SP) with 1‐ethyl‐3‐(3'‐dimethylaminopropyl)‐carbodiimide (ECDI) induces immune tolerance in recipients post‐transplantation; however, the mechanism underlying this effect remains unclear. Here, we determined the mechanisms of ECDI‐fixed donor SP (ECDI‐SP) in inducing tolerance in skin allograft transplantation. C57BL/6‐recipient mice that received Balb/c full‐thickness skin transplants with two infusions of donor‐derived ECDI‐SP, along with rapamycin showed superior skin allograft survival and lower inflammatory cell infiltration than mice that received rapamycin‐only treatment. In ECDI‐SP‐treated mice, the levels of anti‐inflammatory cytokines such as interleukin (IL)‐10 in sera were markedly increased, whereas the expression of inflammatory cytokines was significantly suppressed. Splenic macrophages were significantly polarized to the alternative activated macrophage (M2) phenotype, with expansion of CD4+Foxp3+ regulatory T cells (Tregs) in the spleen and draining lymph nodes. Allostimulatory activity of ECDI‐SP in vitro and donor‐specific ex vivo hyporesponsiveness were observed. C57BL/6 macrophages engulfed allogeneic Balb/c‐derived ECDI‐SP, polarized to the M2 phenotype, with pronounced cAMP response element‐binding (CREB) protein phosphorylation. By facilitating increased IL‐10 expression, ECDI‐SP induced M2 polarization and Treg production, inhibiting effector T‐cell proliferation. Thus, ECDI‐SP modulates macrophage M2 polarization by increasing CREB phosphorylation and promoting Treg production to suppress allogeneic skin graft rejection.

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Pilot Study Evaluating Regulatory T Cell–Promoting Immunosuppression and Nonimmunogenic Donor Antigen Delivery in a Nonhuman Primate Islet Allotransplantation Model

Cited by 26 publications

References 26 publications

Receptor tyrosine kinase MerTK suppresses an allogenic type I IFN response to promote transplant tolerance

Receptor tyrosine kinase MerTK suppresses an allogenic type I IFN response to promote transplant tolerance

Impact of infection on transplantation tolerance

ECDI‐fixed donor splenocytes prolong skin allograft survival by promoting M2 macrophage polarization and inducing regulatory T cells

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