PREVENTION OF AUTOIMMUNE ISLET ALLOGRAFT DESTRUCTION BY ENGRAFTMENT OF DONOR T CELLS1

Abstract

The results of clinical islet transplantation have remained poor when compared with the consistent success of pancreas transplantation. Autoimmunity has usually been discounted as a cause of islet transplant failure. Previously, we demonstrated that pancreas transplants from the diabetes resistant BB rat (BB-DR) function indefinitely in autoimmune diabetic hosts, but islets from the same donor are vulnerable to recurrent autoimmunity. Addition of 100 million pancreatic lymph node cells (PLNC) to BB-DR islets restores resistance to autoimmunity and leads to repletion of a T cell subset (RT6.1) in the recipients. Autoimmune (BB-Ac) and streptozocin (BB-Sz) diabetic BB rats were recipients of Wistar Furth (WF) intraportal islet or islets plus PLNC transplants with cyclosporine 5 mg/kg/day recipient treatment. One cohort of Brown Norway (BN) islet transplants to BB-Ac with CsA was performed. At the termination of the experiment, recipient peripheral blood lymphocytes (PBL) were characterized by flow cytometry (FACS) for class I, CD4, CD8, RT6.1, and RT6.2, a T cell maturation marker found in WF but not BB rats. All (14/14) WF and 75% (6/8) BN islet transplants to BB-Ac recipients failed after a mean of 42 and 36 days, respectively, despite CsA immunosuppression. WF islets were successful in 6/8 (75%) transplants to BB-Sz recipients (P<0.001 vs. BB-Ac recipients), confirming that autoimmunity is the major cause of islet failure in BB-Ac rats. Addition of PLNC to WF islets increased the survival in BB-Ac to 82% (9/11) (P<0.0001 vs. WF islets alone). Recipients of islet+PLNC express 19.7% RT6.2 compared with 4.6% and 4.0% for WF islets alone in BB-Ac (P<0.01) and BB-Sz (P<0.01), respectively. Autoimmunity is an important factor leading to islet transplant failure in autoimmune diabetic BB rats. Addition of donor PLNC prevent islet allograft failure and leads to recipient chimerism for a donor T cell subset (RT6.2) associated with resistance to autoimmunity.