scholarly journals Treg-inducing microparticles promote donor-specific tolerance in experimental vascularized composite allotransplantation

2019 ◽  
Vol 116 (51) ◽  
pp. 25784-25789 ◽  
Author(s):  
James D. Fisher ◽  
Stephen C. Balmert ◽  
Wensheng Zhang ◽  
Riccardo Schweizer ◽  
Jonas T. Schnider ◽  
...  
Keyword(s):  
T Cells ◽  
Therapeutic Approach ◽  
Solid Organ Transplantation ◽  
Solid Organ ◽  
Donor Strain ◽  
Vascularized Composite Allotransplantation ◽  
Skin Grafts ◽  
Systemic Immunosuppression ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

For individuals who sustain devastating composite tissue loss, vascularized composite allotransplantation (VCA; e.g., hand and face transplantation) has the potential to restore appearance and function of the damaged tissues. As with solid organ transplantation, however, rejection must be controlled by multidrug systemic immunosuppression with substantial side effects. As an alternative therapeutic approach inspired by natural mechanisms the body uses to control inflammation, we developed a system to enrich regulatory T cells (Tregs) in an allograft. Microparticles were engineered to sustainably release TGF-β1, IL-2, and rapamycin, to induce Treg differentiation from naïve T cells. In a rat hindlimb VCA model, local administration of this Treg-inducing system, referred to as TRI-MP, prolonged allograft survival indefinitely without long-term systemic immunosuppression. TRI-MP treatment reduced expression of inflammatory mediators and enhanced expression of Treg-associated cytokines in allograft tissue. TRI-MP also enriched Treg and reduced inflammatory Th1 populations in allograft draining lymph nodes. This local immunotherapy imparted systemic donor-specific tolerance in otherwise immunocompetent rats, as evidenced by acceptance of secondary skin grafts from the hindlimb donor strain and rejection of skin grafts from a third-party donor strain. Ultimately, this therapeutic approach may reduce, or even eliminate, the need for systemic immunosuppression in VCA or solid organ transplantation.

scholarly journals The Need for Inducing Tolerance in Vascularized Composite Allotransplantation

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Kadiyala V. Ravindra ◽  
Hong Xu ◽  
Larry D. Bozulic ◽  
David D. Song ◽  
Suzanne T. Ildstad
Keyword(s):  
Solid Organ Transplantation ◽  
Tolerance Induction ◽  
Mixed Chimerism ◽  
Future Research ◽  
Solid Organ ◽  
Vascularized Composite Allotransplantation ◽  
Split Tolerance ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Successful hand and face transplantation in the last decade has firmly established the field of vascularized composite allotransplantation (VCA). The experience in VCA has thus far been very similar to solid organ transplantation in terms of the morbidity associated with long-term immunosuppression. The unique immunological features of VCA such as split tolerance and resistance to chronic rejection are being investigated. Simultaneously there has been laboratory work studying tolerogenic protocols in animal VCA models. In order to optimize VCA outcomes, translational studies are needed to develop less toxic immunosuppression and possibly achieve donor-specific tolerance. This article reviews the immunology, animal models, mixed chimerism & tolerance induction in VCA and the direction of future research to enable better understanding and wider application of VCA.

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.

Low-dose of tacrolimus favors the induction of functional CD4+CD25+FoxP3+ regulatory T cells in solid-organ transplantation

2009 ◽  
Vol 9 (5) ◽  
pp. 564-569 ◽  
Author(s):  
Zhen Wang ◽  
Bingyi Shi ◽  
Hailong Jin ◽  
Li Xiao ◽  
Yongwei Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Organ Transplantation ◽  
Low Dose ◽  
Solid Organ Transplantation ◽  
Solid Organ

scholarly journals Future of Solid Organ Transplantation: Organ-Specific Tolerance

KIDNEYS ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 130-136
Author(s):  
Yusuf Ercin Sonmez
Keyword(s):  
Immune System ◽  
Solid Organ Transplantation ◽  
Organ Transplant ◽  
Immunological Tolerance ◽  
The Body ◽  
Solid Organ ◽  
Donor Organ ◽  
Organ Specific ◽  
Specific Tolerance

A transplant between two people who are not genetically identical is called an allotransplant and the process is called allotransplantation. Donor organs and tissues can be from people who are living, or people who have died because of a significant brain injury or lack of circulation. Allotransplantation can create a rejection process where the immune system of the recipient attacks the foreign donor organ or tissue and destroys it. The recipient may need to take immunosuppressive medication for the rest of their life to reduce the risk of rejection of the donated organ. In general, deliberately induced immunosuppression is performed to prevent the body from rejecting an organ transplant. The adverse effects associated with these agents and the risks of long-term immunosuppression present a number of challenges for the clinician. Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response in a given organism.

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.

Sign in / Sign up

Export Citation Format

Share Document