Administration of silica particles or anti-Lyt2 antibody prevents beta-cell destruction in NOD mice given cyclophosphamide.
The cellular pathway of beta-cell destruction in type I (insulin-dependent) diabetes is still undefined. L3T4+ T-lymphocytes have a role in both the initiation of insulitis and in recurrent disease in transplanted allogeneic islets in nonobese diabetic (NOD) mice. The roles of macrophages and Lyt2+ T-lymphocytes in beta-cell destruction were studied in cyclophosphamide-induced diabetic NOD mice with silica particles and a rat anti-Lyt2 monoclonal antibody. After administration of cyclophosphamide, 10 of 26 untreated mice and 1 of 21 anti-Lyt2-treated mice became diabetic. Insulitis was significantly reduced in anti-Lyt2-treated mice, and immunocytochemical staining showed a lack of Lyt2+ cells. Only 1 of 19 silica-treated mice became diabetic, compared to 8 of 19 control mice. This study demonstrates that both Lyt2+ T-lymphocytes and macrophages are necessary, but not sufficient, for beta-cell destruction in NOD mice. Therefore, we propose that macrophages present beta-cell antigen to L3T4+ cells, which induce cytotoxic Lyt2+ cells to specifically destroy beta-cells.
Charlton
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Transplantation Unit, Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Victoria, Australia.
Bacelj
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Mandel
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D000818:Animals; D000911:Antibodies, Monoclonal; D003520:Cyclophosphamide; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D007124:Immunoenzyme Techniques; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D007518:Isoantibodies / Q000502:physiology*; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D012822:Silicon Dioxide / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
D000911:Antibodies, Monoclonal; D007518:Isoantibodies; C029805:Lyt antibodies; D012822:Silicon Dioxide; D003520:Cyclophosphamide