Human allogeneic islet cell transplantation as a therapy for cure for type 1 diabetes can be significantly improved if the deleterious effects of indefinite immunosuppression, particularly with their direct toxicity to ? cells, can be eliminated. Therefore, simple and effective donor-specific tolerance induction in such autoimmune diabetic hosts would be highly desirable. We have recently developed a novel tolerance regimen using i.v. infusion of donor splenocytes that are treated with a chemical cross-linker termed 1- ethyl-3-(3'-dimethylaminopropyl)-carbodiimide, or ECDI, and found that in the absence of any immunosuppression, this regimen is highly efficient in inducing durable donor- specific tolerance in allogeneic islet cell transplantation in the chemically-induced (streptozotocin) diabetes model. Similarly, soluble self-antigens such as insulin chemically fixed to syngeneic antigen presenting cells by ECDI have been independently shown to induce robust self-tolerance in the autoimmune diabetes NOD model. However, considerable obstacles exist in translating this methodology to a model harboring both alloimmunity and autoimmunity, i.e. in allogeneic islet transplantation for diabetic NOD mice, a model that is highly clinically relevant to patients with type 1 diabetes receiving deceased donor islet transplantation. This application proposes to take an integrated approach to identify crucial cellular components and signaling pathways required for tolerance by this protocol, as well as critical differences that exist in the autoimmune NOD hosts responsible for the ineffective tolerance induction. The application further proposes to study tolerance in the context of novel routes for islet allograft delivery that are potentially clinically applicable in humans. The ultimate goal of this study is to engineer novel tolerance regimen that is tailored to the specifics of islet allograft delivery, and is efficient and clinically feasible for human allogeneic islet cell transplantation. Successful completion of the proposed study will have significant impact on therapeutic options for patients with type 1 diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
NIH Director’s New Innovator Awards (DP2)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-B (O1))
Program Officer
Spain, Lisa M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Kang, Hee Kap; Wang, Shusen; Dangi, Anil et al. (2017) Differential Role of B Cells and IL-17 Versus IFN-? During Early and Late Rejection of Pig Islet Xenografts in Mice. Transplantation 101:1801-1810
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
Lerret, Nadine M; Li, Ting; Wang, Jiao-Jing et al. (2015) Recipient Myd88 Deficiency Promotes Spontaneous Resolution of Kidney Allograft Rejection. J Am Soc Nephrol 26:2753-64
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 35:8887-8894
Wang, Shusen; Tasch, James; Kheradmand, Taba et al. (2013) Transient B-cell depletion combined with apoptotic donor splenocytes induces xeno-specific T- and B-cell tolerance to islet xenografts. Diabetes 62:3143-50
Kheradmand, Taba; Wang, Shusen; Bryant, Jane et al. (2012) Ethylenecarbodiimide-fixed donor splenocyte infusions differentially target direct and indirect pathways of allorecognition for induction of transplant tolerance. J Immunol 189:804-12
Lerret, N M; Houlihan, J L; Kheradmand, T et al. (2012) Donor-specific CD8+ Foxp3+ T cells protect skin allografts and facilitate induction of conventional CD4+ Foxp3+ regulatory T cells. Am J Transplant 12:2335-47
Chen, G; Kheradmand, T; Bryant, J et al. (2012) Intragraft CD11b(+) IDO(+) cells mediate cardiac allograft tolerance by ECDI-fixed donor splenocyte infusions. Am J Transplant 12:2920-9
Kheradmand, Taba; Wang, Shusen; Gibly, Romie F et al. (2011) Permanent protection of PLG scaffold transplanted allogeneic islet grafts in diabetic mice treated with ECDI-fixed donor splenocyte infusions. Biomaterials 32:4517-24

Showing the most recent 10 out of 14 publications