Anti-CD3 immunotoxin prevents low-dose STZ/interferon-induced autoimmune diabetes in mouse.
Autoimmune diabetes was induced with an established model in which 3 daily injections of 95 mg/kg body wt/day streptozocin (STZ) and 2 x 10(4) U interferon-gamma (IFN-gamma) were administered to C57BL/6 mice. Diabetes onset was accompanied by precipitous increases in serum glucose levels and validated by immunoperoxidase studies showing diminished islets in pancreatic tissue sections. Administration of two to three doses of a monoclonal antibody (MoAb) or an immunotoxin (IT) directed against the CD3 epsilon-chain before STZ/IFN-gamma treatment prevented increases in serum glucose and protected islets from damage. IT was made by crosslinking anti-CD3 to a low oligosaccharide-containing fraction of purified ricin toxin A chain (RTA; a catalytic inhibitor of protein synthesis) with a stabilized derivative of 2-iminothiolane. Protection was complete, long-lived, and selective because two different control ITs did not prevent diabetes onset. A second pan T-cell-reactive IT was synthesized by linking the MoAb anti-Ly1 to the same RTA toxin. Anti-Ly1 reacts with the murine homologue of human CD5. Anti-Ly1 RTA also protected against diabetes onset in a dose-dependent manner requiring higher doses and a longer schedule than anti-CD3 or anti-CD3 RTA. These studies demonstrate for the first time the importance of CD3+ and CD5+ cells in diabetes onset in the low-dose STZ/IFN-gamma model and show that anti-CD3, anti-CD3 RTA, or anti-CD5 RTA may be useful in vivo for the treatment of diabetes or perhaps other T-cell-mediated autoimmune diseases. These data may have important therapeutic implications for early autoimmune diabetes in humans.
Vallera
D A
DA
Department of Therapeutic Radiology, University of Minnesota Hospital and Clinic, Minneapolis 55455.
Carroll
S F
SF
Brief
S
S
Blazar
B R
BR
D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D001786:Blood Glucose / Q000032:analysis; D017252:CD3 Complex; D018956:CD5 Antigens; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D000922:Immunotoxins / Q000276:immunology / Q000502:physiology*; D007328:Insulin / Q000032:analysis; D007372:Interferons / Q000009:adverse effects* / Q000494:pharmacology; D007515:Islets of Langerhans / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013311:Streptozocin / Q000009:adverse effects* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D001786:Blood Glucose; D017252:CD3 Complex; D018956:CD5 Antigens; D000922:Immunotoxins; D007328:Insulin; D011948:Receptors, Antigen, T-Cell; D013311:Streptozocin; D007372:Interferons