Diabetes induced with low doses of streptozotocin is mediated by V beta 8.2+ T-cells.
T-cells have been shown to cause insulitis and ultimately be responsible for the destruction of beta-cells in animal models of insulin-dependent diabetes mellitus (IDDM). In one murine model, insulitis and hyperglycemia occur after administration of five low doses of streptozotocin (STZ) (multidose STZ-induced diabetes mellitus [MDSM]). Insulitis can first be identified in the islets after the final (fifth) daily dose of STZ is given. We have studied the T-cells that infiltrate the islets of Langerhans during the early stages of diabetes by preparing Southern blots of T-cell receptor (TCR) beta-chain genes amplified by polymerase chain reaction (PCR) from islets from C57BL/KsJ mice given multiple doses of STZ. The relative abundance of TCR gene products in islets was compared with spleen cells stimulated with anti-CD3 monoclonal antibody (mAb). We found that after the fourth dose of STZ, there was a striking increase in the amount of V beta 8.2 TCR gene product (37 +/- 4% of total PCR signal) compared with T-cells in the spleen (9 +/- 2%, P < 0.01), which increased further 2 days after the final dose of STZ (47 +/- 5%, P < 0.001). We studied the heterogeneity of the size of the V beta 8.2 TCR CDR3 region and found primarily products with only two lengths compared with a heterogeneous population in the spleen. Treatment with anti-V beta 8 mAb, but not anti-V beta 9 and anti-V beta 13 mAbs, prevented development of hyperglycemia (P < 0.0001) and insulitis (P < 0.0005) after STZ administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Herold
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KC
Department of Medicine, University of Chicago, Illinois 60637.
Bloch
T N
TN
Vezys
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V
Sun
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D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000096:biosynthesis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis*; D013154:Spleen / Q000276:immunology; D013311:Streptozocin / Q000008:administration & dosage / Q000633:toxicity*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D013997:Time Factors
D017931:DNA Primers; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D013311:Streptozocin