Research Group

  • Dr Gregg A. Hadley, Principal Investigator


  • The Ohio State University, Columbus, USA


  • 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.