LONG-TERM GOALS: To improve the results and applicability of islet transplantation early in the course of type 1 diabetes through the attenuation of non-specific inflammatory responses, induction of allo-tolerance, and the restoration of self-tolerance. Unparalleled progress in the conceptual understanding of the mechanisms operative in the induction of allo-tolerance and restoration of self-tolerance has led to the development of selective immunomodulatory strategies. Prime examples of progress made include i) the demonstration of long-term islet allograft survival in non-human primates receiving anti-CD40 Ligand antibody monotherapy, ii) the induction of robust tolerance to murine islet allografts by allo-antigen pretreatment under the cover of short-term anti-CD40L therapy, and iii) the restoration of self-tolerance to beta cell autoantigens in overtly diabetic NOD mice by FcR non-binding anti-CD3 anti bodies. Moreover, blockade of the CD40L/CD40 costimulatory pathway has been shown to prevent inflammatory responses such as cell extravasation, production of inflammatory and chemotactic cytokines, and activation of macrophage effector function. These accomplishments signal a quantum leap in our approaches to circumvent islet graft failure due to non-specific inflammation, autoimmune destruction, and rejection; they now provide realistic opportunities for major advances in clinical islet transplantation. HYPOTHESES: The safety and efficacy of selective immunomodulatory therapies involving FcR non-binding anti-CD3 and anti-CD40L therapy in experimental models of islet transplantation will translate into clinical trials. In addition, implementation of anti-inflammatory, tolerogenic protocols without adverse effects on insulin secretion and action will allow for sustained insulin independence in the majority of type 1 diabetic islet allograft recipients. To test these hypotheses, the incestigators propose the following Specific Aims.
SPECIFIC AIM 1. To establish that induction immunotherapy with the FcR non-binding huOKT3g1 monoclonal antibody prevents autoimmune destruction of human islet grafts.
SPECIFIC AIM 2. To establish that alloantigen pre-treatment under the cover of short-term costimulatory blockade with the anti-CD40L specific monoclonal antibody 5c8 prevents rejection of subsequent human islet allografts.
SPECIFIC AIM 3. To assess the metabolic and immunologic state of islet transplant recipients. The investigators believe that the results of these studies will increase our understanding of the safety, efficacy and underlying mechanisms of selective immunomodulatory therapies aimed at maximizing engraftment and functional survival of allogeneic human islets in type 1 diabetic recipients, and thereby provide a basis for the successful application of minimally invasive means of restoring euglycemia and insulin independence early in the course of diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056963-06
Application #
6932030
Study Section
Special Emphasis Panel (ZRG1-IMS (02))
Program Officer
Eggerman, Thomas L
Project Start
2000-09-30
Project End
2009-07-31
Budget Start
2005-08-01
Budget End
2009-07-31
Support Year
6
Fiscal Year
2005
Total Cost
$831,774
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Surgery
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Loganathan, Gopalakrishnan; Graham, Melanie L; Radosevich, David M et al. (2013) Factors affecting transplant outcomes in diabetic nude mice receiving human, porcine, and nonhuman primate islets: analysis of 335 transplantations. Transplantation 95:1439-47
Radosevich, D M; Jevne, R; Bellin, M et al. (2013) Comprehensive health assessment and five-yr follow-up of allogeneic islet transplant recipients. Clin Transplant 27:E715-24
Hire, Kelly; Ngo, Diem K; Stewart-Maynard, Kristen M et al. (2012) FoxP3+, and not CD25+, T cells increase post-transplant in islet allotransplant recipients following anti-CD25+ rATG immunotherapy. Cell Immunol 274:83-8
Avgoustiniatos, Efstathios S; Scott 3rd, William E; Suszynski, Thomas M et al. (2012) Supplements in human islet culture: human serum albumin is inferior to fetal bovine serum. Cell Transplant 21:2805-14
Bellin, M D; Barton, F B; Heitman, A et al. (2012) Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. Am J Transplant 12:1576-83
Balamurugan, A N; Loganathan, Gopalakrishnan; Bellin, Melena D et al. (2012) A new enzyme mixture to increase the yield and transplant rate of autologous and allogeneic human islet products. Transplantation 93:693-702
Anazawa, Takayuki; Matsumoto, Shuichiro; Yonekawa, Yukihide et al. (2011) Prediction of pancreatic tissue densities by an analytical test gradient system before purification maximizes human islet recovery for islet autotransplantation/allotransplantation. Transplantation 91:508-14
Balamurugan, A N; Breite, Andrew G; Anazawa, Takayuki et al. (2010) Successful human islet isolation and transplantation indicating the importance of class 1 collagenase and collagen degradation activity assay. Transplantation 89:954-61
Loganathan, G; Dawra, R K; Pugazhenthi, S et al. (2010) Culture of impure human islet fractions in the presence of alpha-1 antitrypsin prevents insulin cleavage and improves islet recovery. Transplant Proc 42:2055-7
Hire, Kelly; Hering, Bernhard; Bansal-Pakala, Pratima (2010) Relative reductions in soluble CD30 levels post-transplant predict acute graft function in islet allograft recipients receiving three different immunosuppression protocols. Transpl Immunol 23:209-14

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