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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-MFH-I (M1))
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Emory University
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Kean, Leslie S; Turka, Laurence A; Blazar, Bruce R (2017) Advances in targeting co-inhibitory and co-stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy. Immunol Rev 276:192-212
Kwun, Jean; Manook, Miriam; Page, Eugenia et al. (2017) Crosstalk Between T and B Cells in the Germinal Center After Transplantation. Transplantation 101:704-712
Manook, M; Kwun, J; Burghuber, C et al. (2017) Thrombalexin: Use of a Cytotopic Anticoagulant to Reduce Thrombotic Microangiopathy in a Highly Sensitized Model of Kidney Transplantation. Am J Transplant 17:2055-2064
Mathews, D V; Wakwe, W C; Kim, S C et al. (2017) Belatacept-Resistant Rejection Is Associated With CD28+ Memory CD8 T Cells. Am J Transplant 17:2285-2299
Samy, K P; Anderson, D J; Lo, D J et al. (2017) Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model. Am J Transplant 17:1193-1203
Kwun, Jean; Burghuber, Christopher; Manook, Miriam et al. (2017) Successful desensitization with proteasome inhibition and costimulation blockade in sensitized nonhuman primates. Blood Adv 1:2115-2119
Tkachev, Victor; Furlan, Scott N; Watkins, Benjamin et al. (2017) Combined OX40L and mTOR blockade controls effector T cell activation while preserving Treg reconstitution after transplant. Sci Transl Med 9:
Kwun, Jean; Burghuber, Christopher; Manook, Miriam et al. (2017) Humoral Compensation after Bortezomib Treatment of Allosensitized Recipients. J Am Soc Nephrol 28:1991-1996
Kim, S C; Wakwe, W; Higginbotham, L B et al. (2017) Fc-Silent Anti-CD154 Domain Antibody Effectively Prevents Nonhuman Primate Renal Allograft Rejection. Am J Transplant 17:1182-1192
Schroder, Paul M; Ezekian, Brian; Ford, Mandy et al. (2017) Commentary: Belatacept Does Not Inhibit Follicular T Cell-Dependent B-Cell Differentiation in Kidney Transplantation. Front Immunol 8:1615

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