title: A multivalent vaccine for type 1 diabetes skews T cell subsets to Th2 phenotype in NOD mice.
abstract: Previous studies by our group, using an experimental autoimmune thyroiditis (EAT) model in Strain 13 inbred guinea pigs, resulted in T cell-mediated delayed hypersensitivity; however, autoantibodies proved not to be cytotoxic to thyroid epithelial cells in the presence or absence of complement proteins. Albeit, T cell-mediated lymphocyte cytotoxicity began to diminish sharply concomitantly with increasing titers of circulating autoantibodies, indicating a skewing of the self-reactive response and amelioration of the EAT. Furthermore, immunization of guinea pigs with thyroglobulin in incomplete Freund's adjuvant (IFA) generated a high titer of antithyroglobulin antibodies and proved to inhibit thyroiditis. These observations indicated that the shift in the immune response from Th1 to Th2 and the production of antibodies were likely responsible for ameliorating EAT. Based upon these results, we extrapolated our studies to design a multivalent vaccine, which shows promise in preventing/reversing T1D in NOD mice. A small pilot study was conducted in which a total of 34 mice, 20 non-immunized controls and 14 immunized with syngeneic islet lysate, were monitored for mean day to diabetes for a total of 28 weeks. Immunization of NOD animals with syngeneic islet lysates resulted in a significant delay in diabetes onset (P < 0.001) as compared to non-immunized controls. To further assess the vaccine's efficacy, robustness, and delay of disease, a large-scale experiment was conducted and monitored for 32 weeks using 106 mice, 64 non-immunized controls and 42 immunized with syngeneic islet lysate. At the end of the study, 90% of the non-immunized group developed diabetes, while less than 25% of the immunized group became diabetic (P < 0.0001). The protective effect, as a result of vaccination, correlated with an increase in the levels of IL-10 and IL-4 cytokines as well as a skewing to Th2-dependent isotype antibodies in serum. Strikingly, adoptive transfer of spleen cells from immunized animals into NOD.scid recipients provided protection against transfer of diabetes by diabetogenic spleen cells. The results of this study provide evidence that vaccination with islet lysate leads to a Th2-dependent skewing of the immune response to islet beta cells as a possible mechanism of protection. This strategy may be implemented as a possible vaccination protocol for arresting and/or preventing T1D in patients.
authors: Immunogenetics/Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh and University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh 15224, USA.
authors: Ming S
authors: MS
authors: Lin
authors: Hubert M
authors: HM
authors: Tse
authors: Meghan M
authors: MM
authors: Delmastro
authors: Suzanne
authors: S
authors: Bertera
authors: Caterina T
authors: CT
authors: Wong
authors: Robert
authors: R
authors: Lakomy
authors: Jing
authors: J
authors: He
authors: Martha M
authors: MM
authors: Sklavos
authors: Gina M
authors: GM
authors: Coudriet
authors: Massimo
authors: M
authors: Pietropaolo
authors: Massimo M
authors: MM
authors: Trucco
authors: Jon D
authors: JD
authors: Piganelli
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control; D005260:Female; D007114:Immunization; D007328:Insulin / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D012583:Schwann Cells / Q000276:immunology; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D007328:Insulin