The overall goal of this proposal is the induction of tolerance simultaneously to both renal and pancreatic islet transplants across an allogeneic barrier in baboons. The studies are based upon the following previous observations: 1) tolerance to fully mismatched renal allografts can be achieved in juvenile miniature swine by a short course of high-dose tacrolimus, and preliminary data indicate that this methodology is also successful in juvenile baboons; 2) in contrast to free islet grafts, composite """"""""islet kidneys"""""""" (I-K), prepared by transplantation of autologous swine islets under the kidney capsule two months prior to transplantation of the composite organ into nephrectomized, pancreatectomized allogeneic recipients, restore euglycemia immediately and maintain both renal and islet function long-term; and 3) tolerance to renal allografts can be achieved in adult animals by induction of mixed hematopoietic chimerism. We propose here to extend these studies to the induction of tolerance to I-K in baboons, with the intent of developing a clinically relevant treatment protocol for end stage diabetic nephropathy. Specifically, we will: 1) Establish a non-human primate model of renal allograft tolerance in juvenile baboons; 2) Assess the association of biologic and molecular markers with tolerance and rejection in baboons undergoing tolerance-induction protocols; 3) Test the ability of composite islet-kidney transplants to treat both diabetes and renal failure in nephrectomized, juvenile baboons, made diabetic through STZ treatment; and 4) Extend treatment of diabetes and renal failure by I-K transplantation to adult baboons using tolerance induction through a mixed chimerism approach and assess the validity of biologic and molecular biomarkers of tolerance induction developed in Aim 2 for assessment of tolerance induction. We anticipate that the combination of tolerance induction and the use of pre-vascularized islets in these approaches could provide a new and effective treatment modality for patients with type I diabetes and end-stage renal disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK080653-02
Application #
7487886
Study Section
Special Emphasis Panel (ZAI1-PA-I (M1))
Program Officer
Appel, Michael C
Project Start
2007-08-20
Project End
2012-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$797,884
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Pathiraja, V; Villani, V; Tasaki, M et al. (2017) Tolerance of Vascularized Islet-Kidney Transplants in Rhesus Monkeys. Am J Transplant 17:91-102
Vallabhajosyula, Prashanth; Hirakata, Atsushi; Shimizu, Akira et al. (2013) Assessing the effect of immunosuppression on engraftment of pancreatic islets. Transplantation 96:372-8
Matar, Abraham J; Pathiraja, Vimukthi; Wang, Zhirui et al. (2012) Effect of pre-existing anti-diphtheria toxin antibodies on T cell depletion levels following diphtheria toxin-based recombinant anti-monkey CD3 immunotoxin treatment. Transpl Immunol 27:52-4
Yamada, K; Hirakata, A; Tchipashvili, V et al. (2011) Composite islet-kidneys from single baboon donors cure diabetes across fully allogenic barriers. Am J Transplant 11:2603-12
Kawai, Tatsuo; Cosimi, A Benedict; Sachs, David H (2011) Preclinical and clinical studies on the induction of renal allograft tolerance through transient mixed chimerism. Curr Opin Organ Transplant 16:366-71
Tena, Aseda; Vallabhajosyula, Prashanth; Hawley, Robert J et al. (2011) Quantification of baboon thymopoiesis in porcine thymokidney xenografts by the signal-joining T-cell receptor excision circle assay. Transplantation 91:639-44