The role of autoimmunity in islet allograft destruction. Major histocompatibility complex class II matching is necessary for autoimmune destruction of allogeneic islet transplants after T-cell costimulatory blockade

• Published in: Diabetes (New York, N.Y.) Vol. 51; no. 11; pp. 3202 - 3210
• Main Authors: MAKHLOUF, Leila, KISHIMOTO, Koji, SMITH, Rex N, ABDI, Reza, KOULMANDA, Maria, WINN, Henry J, AUCHINCLOSS, Hugh JR, SAYEGH, Mohamed H
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.11.2002
• Subjects: Animals; Autoimmune Diseases - immunology; Autoimmune Diseases - pathology; Autoimmunity; Biological and medical sciences; Care and treatment; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - surgery; Diabetes. Impaired glucose tolerance; Disease Models, Animal; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Female; Glucagon - analysis; Graft Survival - immunology; Histocompatibility; Histocompatibility Antigens Class II - immunology; Histocompatibility Testing; Insulin - analysis; Islands of Langerhans; Islets of Langerhans; Islets of Langerhans Transplantation - immunology; Islets of Langerhans Transplantation - pathology; Management. Various non-drug treatments. Langerhans islet grafts; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Inbred Strains; Physiological aspects; Species Specificity; T-Lymphocytes - immunology; Time Factors; Transplantation, Homologous - immunology; Transplantation, Homologous - pathology; Type 1 diabetes; Endocrinopathy; Autoimmunity; Immunopathology; Major histocompatibility system; Rodentia; Langerhans islet; Homograft; Autoimmune disease; Transplantation; Vertebrata; Mammalia; Treatment; Mouse; Animal; T-Lymphocyte; Insulin dependent diabetes; Endocrine pancreas
• ISSN: 0012-1797
• DOI: 10.2337/diabetes.51.11.3202

Although it has often been assumed that transplanted allogeneic islets can be destroyed by recurrent autoimmunity in recipients with type 1 diabetes, definitive evidence is lacking and the settings in which this may occur have not been defined. To address these issues, we compared the survival of islet transplants (subject to tissue-specific autoimmunity) with cardiac transplants (not subject to tissue-specific autoimmunity) from various major histocompatibility complex (MHC)-matched and -mismatched donors transplanted into autoimmune NOD recipients. We found that when recipients were treated with combined B7 and CD154 T-cell costimulatory blockade, hearts survived best with better MHC matching, whereas islets survived worst when the donor and recipient shared MHC class II antigens. In the absence of full or MHC class II matching, there was no difference in the survival of islet and cardiac allografts. We also found that the tendency of NOD mice to resist tolerance induction by costimulation blockade is mediated by both CD4+ and CD8+ T-cells, not directly linked to the presence of autoimmunity, and conferred by non-MHC background genes. These findings have clinical importance because they suggest that under some circumstances, avoiding MHC class II sharing may provide better islet allograft survival in recipients with autoimmune diabetes, since mismatched allogeneic islets may be resistant to recurrent autoimmunity. Our results may have implications for the design of future clinical trials in islet transplantation.