scholarly journals Infiltrating Foxp3+Regulatory T Cells From Spontaneously Tolerant Kidney Allografts Demonstrate Donor-Specific Tolerance

2013 ◽  
Vol 13 (11) ◽  
pp. 2819-2830 ◽  
Author(s):  
M. Hu ◽  
C. Wang ◽  
G. Y. Zhang ◽  
M. Saito ◽  
Y. M. Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

scholarly journals In situ recruitment of regulatory T cells promotes donor-specific tolerance in vascularized composite allotransplantation

2020 ◽  
Vol 6 (11) ◽  
pp. eaax8429 ◽  
Author(s):  
James D. Fisher ◽  
Wensheng Zhang ◽  
Stephen C. Balmert ◽  
Ali M. Aral ◽  
Abhinav P. Acharya ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Tolerance ◽  
Immunosuppressive Drugs ◽  
Vascularized Composite Allotransplantation ◽  
Local Enrichment ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Vascularized composite allotransplantation (VCA) encompasses face and limb transplantation, but as with organ transplantation, it requires lifelong regimens of immunosuppressive drugs to prevent rejection. To achieve donor-specific immune tolerance and reduce the need for systemic immunosuppression, we developed a synthetic drug delivery system that mimics a strategy our bodies naturally use to recruit regulatory T cells (Treg) to suppress inflammation. Specifically, a microparticle-based system engineered to release the Treg-recruiting chemokine CCL22 was used in a rodent hindlimb VCA model. These “Recruitment-MP” prolonged hindlimb allograft survival indefinitely (>200 days) and promoted donor-specific tolerance. Recruitment-MP treatment enriched Treg populations in allograft skin and draining lymph nodes and enhanced Treg function without affecting the proliferative capacity of conventional T cells. With implications for clinical translation, synthetic human CCL22 induced preferential migration of human Treg in vitro. Collectively, these results suggest that Recruitment-MP promote donor-specific immune tolerance via local enrichment of suppressive Treg.

scholarly journals Resilience of T cell-intrinsic dysfunction in transplantation tolerance

2019 ◽  
Vol 116 (47) ◽  
pp. 23682-23690 ◽  
Author(s):  
Michelle L. Miller ◽  
Christine M. McIntosh ◽  
Ying Wang ◽  
Luqiu Chen ◽  
Peter Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cardiac Transplantation ◽  
T Cell Memory ◽  
Cell Dysfunction ◽  
Antigen Persistence ◽  
T Cell Dysfunction ◽  
Alloreactive T Cell ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Following antigen stimulation, naïve T cells differentiate into memory cells that mediate antigen clearance more efficiently upon repeat encounter. Donor-specific tolerance can be achieved in a subset of transplant recipients, but some of these grafts are rejected after years of stability, often following infections. Whether T cell memory can develop from a tolerant state and whether these formerly tolerant patients develop antidonor memory is not known. Using a mouse model of cardiac transplantation in which donor-specific tolerance is induced with costimulation blockade (CoB) plus donor-specific transfusion (DST), we have previously shown that systemic infection with Listeria monocytogenes (Lm) months after transplantation can erode or transiently abrogate established tolerance. In this study, we tracked donor-reactive T cells to investigate whether memory can be induced when alloreactive T cells are activated in the setting of tolerance. We show alloreactive T cells persist after induction of cardiac transplantation tolerance, but fail to acquire a memory phenotype despite becoming antigen experienced. Instead, donor-reactive T cells develop T cell-intrinsic dysfunction evidenced when removed from the tolerant environment. Notably, Lm infection after tolerance did not rescue alloreactive T cell memory differentiation or functionality. CoB and antigen persistence were sufficient together but not separately to achieve alloreactive T cell dysfunction, and conventional immunosuppression could substitute for CoB. Antigen persistence was required, as early but not late surgical allograft removal precluded the acquisition of T cell dysfunction. Our results demonstrate transplant tolerance-associated T cell-intrinsic dysfunction that is resistant to memory development even after Lm-mediated disruption of tolerance.

scholarly journals Transient antibody targeting of CD45RC inhibits the development of graft-versus-host disease

2020 ◽  
Vol 4 (11) ◽  
pp. 2501-2515 ◽  
Author(s):  
Laetitia Boucault ◽  
Maria-Dolores Lopez Robles ◽  
Allan Thiolat ◽  
Séverine Bézie ◽  
Michael Schmueck-Henneresse ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Rat Model ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Nsg Mice ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Abstract Allogeneic bone marrow transplantation (BMT) is a widely spread treatment of many hematological diseases, but its most important side effect is graft-versus-host disease (GVHD). Despite the development of new therapies, acute GVHD (aGVHD) occurs in 30% to 50% of allogeneic BMT and is characterized by the generation of effector T (Teff) cells with production of inflammatory cytokines. We previously demonstrated that a short anti-CD45RC monoclonal antibody (mAb) treatment in a heart allograft rat model transiently decreased CD45RChigh Teff cells and increased regulatory T cell (Treg) number and function allowing long-term donor-specific tolerance. Here, we demonstrated in rat and mouse allogeneic GVHD, as well as in xenogeneic GVHD mediated by human T cells in NSG mice, that both ex vivo depletion of CD45RChigh T cells and in vivo treatment with short-course anti-CD45RC mAbs inhibited aGVHD. In the rat model, we demonstrated that long surviving animals treated with anti-CD45RC mAbs were fully engrafted with donor cells and developed a donor-specific tolerance. Finally, we validated the rejection of a human tumor in NSG mice infused with human cells and treated with anti-CD45RC mAbs. The anti-human CD45RC mAbs showed a favorable safety profile because it did not abolish human memory antiviral immune responses, nor trigger cytokine release in in vitro assays. Altogether, our results show the potential of a prophylactic treatment with anti-human CD45RC mAbs in combination with rapamycin as a new therapy to treat aGVHD without abolishing the antitumor effect.

Donor-lymphocyte infusion induces transplantation tolerance by activating systemic and graft-infiltrating double-negative regulatory T cells

Blood ◽  
2002 ◽  
Vol 100 (9) ◽  
pp. 3408-3414 ◽  
Author(s):  
Kevin J. Young ◽  
Liming Yang ◽  
M. James Phillips ◽  
Li Zhang
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Nonhuman Primates ◽  
Cell Receptor ◽  
Donor Lymphocyte Infusion ◽  
Transplantation Tolerance ◽  
Double Negative ◽  
Skin Grafts ◽  
Skin Allografts ◽  
Specific Tolerance

Abstract Donor-lymphocyte infusion (DLI) before transplantation can lead to specific tolerance to allografts in mice, nonhuman primates, and humans. We and others have demonstrated a role for regulatory T cells in DLI-induced, donor-specific transplantation tolerance, but it is not known how regulatory T cells are activated and where they execute their function. In this study, we observed, in both transgenic and normal mice, that DLI before transplantation is required for activation of αβ-T-cell-receptor–positive, CD3+CD4−CD8− double-negative (DN) regulatory T cells in the periphery of recipient mice. More interestingly, DLI induced DN regulatory T cells to migrate preferentially to donor-specific allogeneic skin grafts and to form a majority of graft-infiltrating T cells in accepted skin allografts. Furthermore, both recipient-derived peripheral and graft-infiltrating DN T cells were able to suppress and kill antidonor CD8+ T cells in an antigen-specific manner. These data indicate that DLI may induce donor-specific transplantation tolerance by activating recipient DN regulatory T cells in the periphery and by promoting migration of regulatory T cells to donor-specific allogeneic skin grafts. Our results also show that DN regulatory T cells can eliminate antidonor T cells both systemically and locally, a finding suggesting that graft-infiltrating T cells can be beneficial to graft survival.

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