Insulin selectively primes Th2 responses and induces regulatory tolerance to insulin in pre-diabetic mice.
Little is known about the immunological impact of insulin administration other than it can boost insulin autoantibody levels. In particular, while the subcutaneous administration of a soluble foreign antigen (without adjuvant) is generally only weakly immunogenic in a naive animal, it is unknown what effect the subcutaneous administration of a soluble self-antigen has in animals with established autoimmune responses to the antigen. Addressing these questions in pre-diabetic nonobese diabetic (NOD) mice, we examined the effects of administering insulin, as well as the metabolically inactive B-chain of insulin, on insulin-specific cellular and humoral immune responses. We show that pre-diabetic NOD mice have a spontaneous Th1-biased response against insulin. Administering insulin, or the insulin B-chain, rather than boosting the established Th1 response, primed Th2 cellular and humoral immunity to insulin, shifting the predominant insulin response toward a Th2 phenotype. Despite the presence of a Th1 response against insulin, insulin treated mice failed to mount proliferative T-cell responses following immunization and challenge with insulin, demonstrating that the treatment induced an active form of tolerance to this autoantigen. Thus, the subcutaneous administration of a soluble antigen can engage Th2 responses and induce self-tolerance, even after the establishment of autoreactive Th-1 responses. Such immune deviation and induced regulatory tolerance may contribute to the protective effects of prophylactic insulin therapy, as well as the establishment of a "honeymoon" phase in new-onset insulin-dependent diabetic patients.
Tian
J
J
Department of Molecular and Medical Pharmacology, University of California, Los Angeles 90095-1735, USA.
Chau
C
C
Kaufman
D L
DL
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology; D007328:Insulin / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D011236:Prediabetic State / Q000276:immunology*; D012995:Solubility; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology*
D001324:Autoantigens; D007328:Insulin