Tolerance to Rat Heart Grafts Induced by Intrathymic Immunomodulation Is Mediated by Indirect Recognition Primed CD4+CD25+ Treg Cells

Köksoy, Sadi; Elpek, Kutlu G.; Yolcu, Esma S.; Shirwan, Haval

doi:10.1097/01.tp.0000159870.01567.02

Cited by 18 publications

(14 citation statements)

References 34 publications

(54 reference statements)

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“…2). Although IL-10 production has been reported to be of importance in tolerance transfer in some models (11), in our hands, IL-10 mRNA levels were not significantly changed in the tissue harvested from primary/secondary recipients and neutralization of IL-10 demonstrated no effect on tolerance transfer. In contrast, antiYTGF-A completely abolished transfer of graft acceptance (Fig.…”

Section: Discussioncontrasting

confidence: 77%

“…After intrathymic immunomodulation with donor antigens to prolong survival of cardiac allografts, long-term survivors were reported to develop a CD4 + CD25 + T regulatory cell population that prevented both short-term and long-term rejection when adoptively transferred into secondary graft recipients (11). Tolerance transfer was associated with high levels of IL-10 from Tregs induced after indirect antigen presentation.…”

Section: Discussionmentioning

confidence: 98%

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Persistence of Gene Expression Profile in CD200 Transgenic Skin Allografts Is Associated With Graft Survival on Retransplantation to Normal Recipients

Yang

Gorczynski

2012

Transplantation

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Adoptive transfer of tolerance in MLC to BL/6 grafts was most evident when both skin and splenocytes were transferred from primary BALB/c recipients, although there was an attenuation of MLC responses after graft transfer alone. Adoptive transfer of tolerance occurred concomitant with persistent overexpression of genes encoding Foxp3, transforming growth factor β, interleukin 10, and PD-1 (and PD-L1/PD-L2) in tolerant skin grafts and increased expression of mRNAs for indoleamine 2,3-dioxygenase and the subunits encoding interleukin 35. Infusion of anti-CD4 or anti-transforming growth factor β to secondary recipients on retransplantation abolished increased graft survival, suggesting the importance of each to the final outcome.

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Section: Discussioncontrasting

confidence: 77%

Section: Discussionmentioning

confidence: 98%

Persistence of Gene Expression Profile in CD200 Transgenic Skin Allografts Is Associated With Graft Survival on Retransplantation to Normal Recipients

Yang

Gorczynski

2012

Transplantation

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“…Treg cells have anti-inflammatory functions and can promote tolerance to “self” by contact-mediated suppression or secretion of the anti-inflammatory cytokines IL-10 and TGF-β [67–71]. We demonstrated previously that expression of Treg cells is one of the mechanism by which BMMSCs display their immunosuppressive effect after SBTx [34].…”

Section: Discussionmentioning

confidence: 99%

Heme oxygenase-1-transduced bone marrow mesenchymal stem cells in reducing acute rejection and improving small bowel transplantation outcomes in rats

et al. 2016

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BackgroundWe determined whether bone marrow mesenchymal stem cells (BMMSCs) transduced with heme oxygenase-1 (HO-1), a cytoprotective and immune-protective factor, could improve outcomes for small bowel transplantation (SBTx) in rats.MethodsWe performed heterotopic SBTx from Brown Norway rats to Lewis rats, before infusing Ad/HO-1-transduced BMMSCs (Ad/HO-1/BMMSCs) through the superficial dorsal veins of the penis. Respective infusions with Ad/BMMSCs, BMMSCs, and normal saline served as controls. The animals were sacrificed after 1, 5, 7, or 10 days. At each time point, we measured small bowel histology and apoptosis, HO-1 protein and mRNA expression, natural killer (NK) cell activity, cytokine concentrations in serum and intestinal graft, and levels of regulatory T (Treg) cells.ResultsThe saline-treated control group showed aggravated acute cellular rejection over time, with mucosal destruction, increased apoptosis, NK cell activation, and upregulation of proinflammatory and immune-related mediators. Both the Ad/BMMSC-treated group and the BMMSC-treated group exhibited attenuated acute cellular rejection at an early stage, but the effects receded 7 days after transplantation. Strikingly, the Ad/HO-1/BMMSC-treated group demonstrated significantly attenuated acute cellular rejection, reduced apoptosis and NK cell activity, and suppressed concentrations of inflammation and immune-related cytokines, and upregulated expression of anti-inflammatory cytokine mediators and increased Treg cell levels.ConclusionOur data suggest that Ad/HO-1-transduced BMMSCs have a reinforced effect on reducing acute rejection and protecting the outcome of SBTx in rats.

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“…Deficiencies in the development or function of these cells are associated with severe autoimmunity in humans and various animal models of congenital and acquired diseases (5)(6)(7). Treg cells are also involved in immune tolerance to allogeneic Ags in settings of transplantation and graft-vs-host disease (3,8,9) and are implicated in immune evasion mechanisms used by tumors and pathogens (10 -12). These findings provide support for the central role played by these cells in regulating peripheral mechanisms of immune tolerance.…”

Section: N Aturally Occurring Cd4mentioning

confidence: 99%

Ex Vivo Expansion of CD4+CD25+FoxP3+ T Regulatory Cells Based on Synergy between IL-2 and 4-1BB Signaling

Elpek

Yolcu

Franke

et al. 2007

The Journal of Immunology

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126

143

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Naturally occurring CD4+CD25+FoxP3+ T regulatory (Treg) cells require three distinct signals transduced via TCR, CD28, and IL-2R for their development and maintenance. These requirements served as the basis for several recently developed ex vivo expansion protocols that relied on the use of solid support-bound Abs to CD3 and CD28 in the presence of high dose IL-2. We report in this study that Treg cells up-regulate the expression of inducible costimulatory receptor 4-1BB in response to IL-2, and stimulation using this receptor via a novel form of 4-1BB ligand (4-1BBL) fused to a modified form of core streptavidin (SA-4-1BBL) was effective in expanding these cells up to 110-fold within 3 wk. Expanded cells up-regulated CD25, 4-1BB, and membranous TGF-β, suppressed T cell proliferation, and prevented the rejection of allogeneic islets upon adoptive transfer into graft recipients. Importantly, SA-4-1BBL rendered CD4+CD25− T effector cells refractive to suppression by Treg cells. This dual function of signaling via 4-1BB, vis-à-vis Treg cell expansion and licensing T effector cells resistant to Treg cell suppression, as well as the up-regulation of 4-1BB by IL-2 may serve as important regulatory mechanisms for immune homeostasis following antigenic challenge. Stimulation using a soluble form of SA-4-1BBL represents a novel approach to expand Treg cells with potential therapeutic applications in autoimmunity and transplantation.

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Tolerance to Rat Heart Grafts Induced by Intrathymic Immunomodulation Is Mediated by Indirect Recognition Primed CD4+CD25+ Treg Cells

Abstract: Our data demonstrate that cardiac allograft tolerance in this model is mediated by CD4+CD25+ Treg cells primed by indirect recognition and is associated with high levels of IL-10.

Cited by 18 publications

References 34 publications

Persistence of Gene Expression Profile in CD200 Transgenic Skin Allografts Is Associated With Graft Survival on Retransplantation to Normal Recipients

Persistence of Gene Expression Profile in CD200 Transgenic Skin Allografts Is Associated With Graft Survival on Retransplantation to Normal Recipients

Heme oxygenase-1-transduced bone marrow mesenchymal stem cells in reducing acute rejection and improving small bowel transplantation outcomes in rats

Ex Vivo Expansion of CD4+CD25+FoxP3+ T Regulatory Cells Based on Synergy between IL-2 and 4-1BB Signaling

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