Insulin selectively primes Th2 responses and induces regulatory tolerance to insulin in pre-diabetic mice

Diabetologia. 1998 Feb;41(2):237-40. doi: 10.1007/s001250050896.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibody Formation / drug effects
  • Antibody Formation / immunology
  • Autoantigens / immunology
  • Autoimmunity / immunology*
  • Diabetes Mellitus, Type 1 / immunology*
  • Female
  • Immunity, Cellular / drug effects
  • Immunity, Cellular / immunology
  • Insulin / immunology*
  • Insulin / pharmacology
  • Mice
  • Mice, Inbred NOD
  • Prediabetic State / immunology*
  • Solubility
  • Th1 Cells / drug effects
  • Th1 Cells / immunology
  • Th2 Cells / drug effects
  • Th2 Cells / immunology*


  • Autoantigens
  • Insulin