News and Publications

Immunotherapy of Autoimmune Diabetes in a Transgenic Model

M.G. von Herrath, D. Homann, A. Holz, B. Coon, T. Wolfe

Our goal is to define and test novel immunotherapies for type I autoimmune diabetes (insulin-dependent diabetes mellitus, IDDM) that selectively influence key "players" in the autoimmune process (Fig. 1) without markedly affecting overall immunocompetence. We use the well-established RIP-LCMV transgenic mouse model of virus-induced diabetes. These transgenic mice express proteins from lymphocytic choriomeningitis virus as self-antigens in their pancreatic ß-cells. Infection with the virus results in activation of an immune response, including cytotoxic T lymphocytes (CTLs), that not only eliminates the virus but also attacks the islets. This situation leads to a slowly progressive autoimmune syndrome that culminates in IDDM. We focus on modulating 2 key events.

The first event is local activation and expansion of autoreactive cells in pancreatic islets. We seek to inhibit this event by blocking costimulatory molecules expressed on "professional" antigen-presenting cells (Fig. 1). Treatment of RIP-LCMV mice with antibodies to the costimulatory molecules B7.1, B7.2, or CD40L completely prevented IDDM. Interestingly, the therapy did not affect the generation of primary antiself CD8 CTLs and consequently did not interfere with the elimination of the viral infection. However, memory lymphocytes and production of cytokines by these lymphocytes were reduced. Little or no insulitis developed. Of importance, the antibodies had to be administered during a susceptible phase after induction of CTLs but before development of clinical IDDM.

Our second approach is to interfere with cytokine regulation of the autoimmune process by giving self (autoimmune targeted) antigens orally. Recent studies in mice deficient in stat-4 (IL-12 signaling) and stat-6 (IL-4 signaling) indicated that slowly progressive RIP-LCMV IDDM is regulated by these cytokine pathways and does not occur in the absence of cytokines such as IFN- or IL-12 associated with type 1 helper T cells.

Further, we showed that oral administration of insulin prevents diabetes in RIP-LCMV mice and is associated with a shift in the islets from an inflammatory cytokine profile associated with type 1 helper T cells to a regulatory profile associated with type 2 helper T cells. The putative mechanism is the induction of insulin-reactive regulatory lymphocytes that migrate from the gut to the targeted organ (pancreas) and locally abrogate the autoimmune process by secreting regulatory cytokines such as IL-4 or TGF-ß, a phenomenon termed "bystander suppression." Indeed, oral administration of antigen is not effective in IL-4-- or stat-6--deficient mice; this finding pinpoints a crucial role for this cytokine.

Our most recent studies showed that the amount of antigen required for oral therapy can be drastically reduced by adding the B-subunit of cholera toxin or by coupling the subunit to the antigen. This finding suggests that increased uptake of antigen through M cells in the gut that bind the B-subunit enhances efficacy. When the mechanism is fully understood, this approach should be beneficial for preventing IDDM in persons at risk.

PUBLICATIONS

von Herrath, M.G. Bystander suppression induced by oral tolerance. Res. Immunol. 148:541, 1997.

von Herrath, M.G. Strengths and pitfalls in immunotherapy of IDDM: Novel insights from the RIP-LCMV transgenic mouse model of virus-induced diabetes. Tranplant. Proc., in press.

von Herrath, M.G., Coon, B., Lewicki, H., Mazarguil, H., Gairin, J.E., Oldstone, M. In vivo treatment with a MHC class I restricted blocking peptide can prevent virus-induced autoimmune diabetes. J. Immunol., in press.

von Herrath, M.G., Holz, A., Homann, D., Oldstone, M. Role of viruses in type I diabetes. Semin. Immunol. 10:87, 1998.

von Herrath, M.G., Homann, D. Treatment of virus-induced IDDM by oral administration of insulin: Study on the mechanism by which oral antigens can abrogate autoimmunity. Endocrinol. Diabetes 105:24, 1997.