Recurrent autoimmunity is pivotal in the accelerated destruction of cultured major histo-incompatible islet grafts in nod mice

Abstract

Introduction: Recent data from Edmonton shows a disappointing 10% five-year clinical islet graft survival. Of many factors, autoimmunity may play a pivotal role. Evidence suggests a strong role for autoimmunity in MHC-matched murine islet transplants, but the data for MHC-mismatched grafts is less clear. To address this issue, we utilized pretransplant in vitro culture to delete intraislet APCs in order to diminish or eliminate alloimmunity. Then, we compared the survival time of cultured B10.BR islets in streptozocin-induced and spontaneously diabetic NOD mice using a clinically relevant intraportal islet transplant site. Methods: B10.BR mouse islets were prepared and cultured at 24°C 95% air and 5% CO2 for 7 days prior to transplantation. Cultured B10.BR mouse islets were transplanted intraportally into recipient animals. Four experimental groups were performed: Group 1, islet transplantation in streptozocin-induced diabetic BALB/c mice without further therapy; Group 2, islet transplantation in streptozocin-induced diabetic NOD mice; Group 3, islet transplantation in streptozocin-induced diabetic NOD mice with anti-lymphocyte serum (ALS) treatment on pre-transplant days −6, −4, and −2; Group 4, islet transplantation in spontaneously-developed diabetic NOD mice with ALS treatment as above. Graft function was assessed by blood glucose monitoring. Results: Cultured B10.BR islet grafts survived indefinitely in BALB/c mice without further treatment. While the mean survival time (MST) of cultured B10.BR islets in chemically-induced diabetic NOD mice was 13.5 days, addition of ALS treatment significantly prolonged the survival time of cultured B10.BR islets in chemically-induced diabetic NOD mice (MST=51 days). However, addition of ALS treatment had little effect in prolongation of survival of cultured B10.BR islets in spontaneously developed diabetic NOD mice (MST 17 days). Conclusions: Culturing B10.BR islets can abrogate alloimmunity in BALB/c mice, but not in NOD mice. ALS is required to prolong islet graft survival in chemically-induced diabetic NOD mice, a unique finding for this strain. In addition, autoimmune diabetic NOD hosts do not allow prolonged islet graft survival despite conditions that are favorable in non-autoimmune diabetic MHC-mismatched hosts or chemically diabetic NOD mice. These data suggest that recurrent autoimmunity occurs regardless of the degree of MHC-mismatch. Autoimmunity must be overcome to achieve long term success of islet grafts.