title: Endogenous immune response to glutamic acid decarboxylase (GAD67) in NOD mice is modulated by adjuvant immunotherapy.
abstract: We have shown that immunization of non-obese diabetic (NOD) mice with adjuvants (CFA or BCG) prevents the onset of diabetes by induction of regulatory cells. Since autoimmune responses to glutamic acid decarboxylase (GAD) are up-regulated in insulin-dependent diabetes mellitus (IDDM), in this study GAD67-specific antibody, T cell proliferation and lymphokine production patterns were analysed in the adjuvant-treated mice to characterize the regulatory mechanisms underlying the protection. We used both spontaneous diabetes and syngeneic islet transplantation models in NOD mice. Protection against spontaneous diabetes and prevention of syngeneic islet graft rejection by CFA or BCG treatment was found to be accompanied by the production of long lasting and high titre anti-GAD67 antibody of IgG1 isotype in the sera. Upon in vitro stimulation with GAD67, draining lymph node and spleen cells from CFA-immunized NOD mice or syngeneic islet-grafted and BCG-protected NOD mice produced much more IL-4, whereas there was no significant change in IFN-gamma production. The strong early T cell proliferative response to GAD67 in CFA or BCG-immunized NOD mice was followed by a low or unresponsiveness state. Taken together, these results suggest a shift in Th1/Th2 balance in the GAD67-specific endogenous immune response to a change in Th2 levels after adjuvant treatment. We postulate that the protective effect of CFA or BCG is due to the diversion of GAD-specific endogenous cellular immune response to a non-pathogenic humoral response.
authors.affiliation: Department of Microbiology and Immunology, University of Western Ontario, Canada.
authors.forename: H Y
authors.initials: HY
authors.lastname: Qin
authors.forename: J F
authors.initials: JF
authors.lastname: Elliott
authors.forename: J R
authors.initials: JR
authors.lastname: Lakey
authors.forename: R V
authors.initials: RV
authors.lastname: Rajotte
authors.forename: B
authors.initials: B
authors.lastname: Singh
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D000918:Antibody Specificity; D001323:Autoantibodies / Q000096:biosynthesis* / Q000276:immunology; D001500:BCG Vaccine / Q000276:immunology / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D005620:Freund's Adjuvant / Q000276:immunology / Q000627:therapeutic use*; D005968:Glutamate Decarboxylase / Q000276:immunology / Q000627:therapeutic use*; D007132:Immunoglobulin Isotypes; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000276:Adjuvants, Immunologic; D001323:Autoantibodies; D001500:BCG Vaccine; D016207:Cytokines; D007132:Immunoglobulin Isotypes; D005620:Freund's Adjuvant; D005968:Glutamate Decarboxylase