The long-term goal of the proposed preclinical studies is to develop a clinically applicable tolerogenic protocol for use in human islet allotransplantatin in T1D. The central component of our strategy is the delivery of antigens on leukocytes treated with the chemical cross linker 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (ECDI). Autoantigen-coupled splenocytes given IV prevent and treat autoimmunity in mice. In transplant models, ECDI-fixed donor splenocytes given IV on days -7 and +1 - as induce long-term donor-specific tolerance to islet allografts, and when combined with short-term rapamycin (RAPA), also to heart allografts in mice. A first-in-human clinical trial of autologous, peptide-coupled cels in multiple sclerosis (MS) recently established the clinical feasibility of this novel tolerogenic strategy. To test whether the profound tolerogenic efficacy of alloantigen delivery via ECDI-fixed cells (ADEC) will translate to islet transplantation in nonhuman primates (NHP), we will study the following specific aims:
AIM #1 : To manufacture ADEC products meeting prospectively defined release criteria for evaluation as tolerogens in islet allotransplantation in RM.
AIM #2 : T determine the efficacy of ADEC in inducing tolerance to islet allografts in RM with low and high memory alloreactivity transiently treated with RAPA, sTNFR, ?-IL-6R, and LFA3-Ig.
AIM #3 : To examine the effects of the immunotherapeutic protocol on mechanisms underlying the induction, maintenance, and/or loss of donor-specific tolerance to islet allografts in RM. The innovation of this proposal lies expressly in the preemptive use of potent, yet safe, cellular immunotherapeutics as antigen-specific, negative vaccines. Our protocol targets innate, heterologous, and adaptive direct and indirect pathway immunity (and can be extended to target autoimmunity) and has, despite complete avoidance of generalized T and/or B cell depletion and costimulation blockade, a high potential for inducing durable tolerance to islet allografts in NHP. The proposed studies will provide novel insights into the role of ADEC and concomitant immunotherapy for tolerance induction to islet allografts, a critical step toward clinical translaton of this antigen-specific tolerance strategy.

Public Health Relevance

Human islet allotransplantation restores insulin independence and near normoglycemia, protects from severe hypoglycemia and slows the progression of microvascular complications in those people with type 1 diabetes (T1D). The numerous undesirable side effects and the high costs of chronic immunosuppression limit the applicability of islet transplants. To overcome this limitation, the goal of this proposal is to develop in a pre clinical model of T1D (diabetic non-human primates) tolerogenic protocol(s) for use in human islet allotransplantation in T1D.

Agency
National Institute of Health (NIH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI102463-03
Application #
8706034
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Kraemer, Kristy A
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Wang, Shusen; Zhang, Xiaomin; Zhang, Lei et al. (2015) Preemptive Tolerogenic Delivery of Donor Antigens for Permanent Allogeneic Islet Graft Protection. Cell Transplant 24:1155-65
Bryant, Jane; Lerret, Nadine M; Wang, Jiao-Jing et al. (2014) Preemptive donor apoptotic cell infusions induce IFN-?-producing myeloid-derived suppressor cells for cardiac allograft protection. J Immunol 192:6092-101
Bryant, Jane; Hlavaty, Kelan A; Zhang, Xiaomin et al. (2014) Nanoparticle delivery of donor antigens for transplant tolerance in allogeneic islet transplantation. Biomaterials 35:8887-94