Neonatal injection of CD3 antibody into nonobese diabetic mice reduces the incidence of insulitis and diabetes.
Over 80% of nonobese diabetic (NOD) mice develop lymphocytic infiltrates of their pancreatic islets (insulitis) by 6 wk of age and 50% of the females are diabetic by 6 mo of age. The incidence of insulitis in NOD mice injected once as neonates with 250 micrograms of the CD3 antibody, 145.2C11, was 8% at 10 wk of age, increasing to 25% at 32 wk of age. Fewer than 10% of these animals developed diabetes by 8 mo of age. Neonatal administration of 145.2C11 reduced the proliferative responses of spleen cells to mitogen stimulation 2 and 4 wk postinjection and expression of TCR was reduced 1 to 5 wk postinjection. The percentage of CD4 and CD8 cells in the spleen was transiently reduced after injection and the frequency of Pgp-1+-high cells (putative memory cells) was increased 2 to 4 wk postinjection, suggesting that in vivo administration of the antibody caused some T cells to divide as well as transiently reducing T cell numbers. IL-2R expression was not detected on spleen cells in the 4 wk after antibody injection. The phenotypic and functional changes after neonatal CD3 antibody injection resolved by 8 wk of age. The control and injected mice grew normally and made equivalent IgG antibody responses to injected human IgG. Neonatally injected 145.2C11 antibody was cleared from the circulation with a terminal half-life approximating to 21 days but greater than 90% of antigen binding activity was lost 6 days after injection. Protection from diabetes did not follow neonatal elimination of T cells with CD4 and CD8 antibodies, nor the injection of a TCR subset antibody, F23.1. Our data suggest that the neonatal T cell repertoire is open to modulation by a single injection of a CD3 antibody and they offer a new experimental approach to immunotherapy in an animal model of type 1 diabetes.
Hayward
A R
AR
Department of Pediatrics, University of Colorado School of Medicine, Denver 80262.
Shreiber
M
M
D000818:Animals; D000831:Animals, Newborn / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D017252:CD3 Complex; D006224:Cricetinae; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D007515:Islets of Langerhans / Q000473:pathology*; D008213:Lymphocyte Activation; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008815:Mice, Inbred Strains; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell