Renal transplantation represents first-line therapy for patients with ESRD, with the most recent data documenting significant one-year success rates (with 94% graft survival for deceased donor transplants, and 98% graft survival with living donor allografts). However, patients continue to face high morbidity and mortality after transplant, both from chronic allograft rejection and from the toxicities associated with standard immunosuppressive regimens. Given these dual risks, the ultimate goal in this field is the induction of immune tolerance after transplantation, which promises life-long acceptance of an allograft, without the need for ongoing immunosuppression and importantly, with preservation of protective immunity. While novel pharmacologic and antibody-based therapies represent real promise in terms of greatly prolonging allograft survival and reducing off-target toxicities, murine studies strongly suggest that the most robust strategies for inducing immune tolerance incorporate cellular therapies, including both mixed chimerism induction (especially in combination with T cell costimulation blockade) and reaulatory T cell (Treq)-based approaches. Both of these therapies hold the promise of fundamentally resetting recipient immunity in favor of allograft acceptance and thus provide a direct pathway towards immune tolerance induction. Therefore, in this application, we will address mixed-chimerism- and Treg-based tolerance induction through the following Specific Aims:
Specific Aim #1 : To induce immune tolerance to a renal allograft through the induction of stable, full spectrum mixed-hematopoietic chimerism in the setting of T cell costimulation blockade.
Specific Aim #2 : To utilize regulatory T cells to consolidate mixed-chimerism and to induce immune tolerance during renal transplantation.

Public Health Relevance

Renal transplantation represents first-line therapy for patients with end-stage renal disease, with over 16,000 transplants being performed each year. While most patients initially do well post-transplant, they almost invariably face significant toxicities, including off-target complications of non-specific immunosuppression and the constant risk of chronic rejection. The ultimate answer for all of these issues is immune tolerance induction. This application seeks to define clinically-relevant cellular therapies for tolerance-induction, which could improve the lives of tens of thousands of transplant patients each year.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI051731-13
Application #
8705984
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Type
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Lo, D J; Anderson, D J; Song, M et al. (2015) A pilot trial targeting the ICOS-ICOS-L pathway in nonhuman primate kidney transplantation. Am J Transplant 15:984-92
Lei, J; Kim, J I; Shi, S et al. (2015) Pilot Study Evaluating Regulatory T Cell-Promoting Immunosuppression and Nonimmunogenic Donor Antigen Delivery in a Nonhuman Primate Islet Allotransplantation Model. Am J Transplant :

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