Research Group

  • Dr Gregg A. Hadley, Principal Investigator

Location

  • The Ohio State University, Columbus, USA

Title

  • Mechanisms Underlying Immune Destruction of Pancreatic Islet Transplants

Despite recent progress in the field of clinical pancreatic islet transplantation, only a small minority of diabetic recipients achieve insulin independence in the long term. While there is compelling evidence that CD8+ T cells contribute to this abysmal success rate, the specificity of such cells, and the efferent pathways by which they compromise long-term graft survival remain obscure. Insight into this important clinical problem is provided by recent studies from the principal investigator’s laboratory documenting a pivotal role for the integrin CD103 in promoting destruction of islet allografts by CD8+ T cells. These data suggest that blockade of CD103 as an adjunct to conventional immunosuppressive strategies provides feasible means of preserving long-term function of clinical islet transplants.

The current proposal focuses on four issues critical to advancing this objective. These studies will utilize a clinically relevant mouse model in which islet allografts are transplanted into diabetic NOD mouse recipients. In aim 1, we will determine if CD103+CD8+ effectors are present within islet allografts at the time of rejection in clinically relevant transplant scenarios. In aim 2, we will determine whether CD103+CD8+ effectors that infiltrate islet allografts in diabetic hosts recognize foreign or self antigens expressed by the pancreatic islets. In aim 3, we will determine how CD103+CD8+ effectors compromise the function of islet allografts. In aim 4, we will use mice with targeted disruption of the CD103 gene to provide proof-of-principle that blockade of CD103+CD8+ effectors as an adjunct to conventional immunosuppressive strategies provides a feasible means of preserving long-term function of islet allografts transplanted into diabetic hosts. The information gained from these studies will elucidate the cellular/molecular pathways of islet allograft destruction in diabetic hosts in clinically relevant transplant scenarios, and reveal novel targets for therapeutic intervention in this important clinical problem.

Progress Report (I)
Progress Report (II)
Final Report