Intrathymic transplantation of islet antigen affects CD8+ diabetogenic T-cells resulting in tolerance to autoimmune IDDM.
The acquisition of T-cell tolerance in the thymus is limited to those antigens expressed in the thymus at the time of T-cell development. Normally, islet antigens that are involved in insulin-dependent diabetes mellitus (IDDM) are not present in the thymus, but we have previously shown that transplantation of islets expressing relevant antigens into the thymus at the time of T-cell maturation results in prevention of IDDM in the multidose streptozotocin model of diabetes mellitus (MDSDM). Although both CD4+ and CD8+ T-cells are involved in the pathogenesis of this disease, the cells affected by intrathymic transplantation of islets are unknown. In this study, we have identified which T-cell subsets are affected by intrathymic islet antigens. Streptozotocin (STZ)-treated syngeneic islets were transplanted into the thymuses of C57BL/KsJ mice, and CD4+, CD8+, or both subsets of cells were transiently depleted with monoclonal antibodies (mAbs). After T-cell repopulation, animals that had received intrathymic islets followed by anti-CD8 mAb (P < 0.05) or both anti-CD4 and anti-CD8 mAbs (P < 0.01) but not anti-CD4 mAb alone were resistant to the development of autoimmune diabetes after five low doses of STZ. Insulitis was also reduced in mice receiving intrathymic islets and anti-CD8 (P < 0.025) or both anti-CD4 and anti-CD8 mAbs (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Baumann
E E
EE
Department of Pediatrics, University of Chicago, Illinois 60637, USA.
Buckingham
F
F
Herold
K C
KC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D017252:CD3 Complex / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D005434:Flow Cytometry; D007108:Immune Tolerance; D007515:Islets of Langerhans / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000276:immunology; D013311:Streptozocin / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*; D013934:Thymectomy; D013950:Thymus Gland; D016042:Transplantation, Heterotopic
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D013311:Streptozocin