Research / Clinical
Summary
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Diseases/Research Topics
Autoimmunity, Cytokines, Diabetes, Host Defense, Immune Regulation, Treg, Antigen Specific Immunotherapy
The main theme of Dr. von Herrath's research program is to understand the regulation of autoimmune and anti-viral responses.
Their work has shown that the amount of immunopathology or tissue injury is determined not only by the magnitude of a localized or systemic immune process, but also to a large extent by its components or the class(es) of responses it encompasses. Thus, each immune or auto-immune reaction has at least a more aggressive and a more regulatory component that balance each other and, in this way, have a strong effect on the duration or magnitude of the response and resulting tissue injury.
In autoimmune diseases, it is possible to take therapeutic advantage of this paradigm and generate autoreactive regulatory cells (Tregs) by targeted immunization with self-antigens. They have shown that such cells can be induced by mucosal immunization and DNA vaccination. Antigen-induced autoreactive Tregs are able to site-specifically suppress ongoing autoimmune reactions, because they are preferentially retained in the draining lymph node closest to the target organ where they exert their regulatory function.
Ongoing and future studies are focused on:
1. The role of key cytokines (TGF-beta, IL-4/IL-5 and IL-10), transcription factors (T-bet) and chemokines (IP-10) in regulating autoimmunity and virally-induced immunopathology. Pertinent issues are modulation of antigen presenting cells, in vivo trafficking of Tregs and their in vitro propagation and antigen specificities (Juedes J. Exp.Med. 2004, Homann Immunity 1999, 2002 and Bot JI 2001).
2. Dissecting how autoantigen-induced Tregs act in immune-competent hosts in vivo and how they can be used in the clinic to prevent diabetes. Combination of antigen-induced Tregs with systemic therapies, such as anti-CD3 that favor a ‘Treg-friendly’ environment, will be further developed (see von Herrath JI 2002 and Nature reviews from 2003 and 2004).
3. The Role of viral immunopathology in autoimmunity. Viral infections can enhance and abrogate autoimmune processes and Dr. von Herrath and his colleagues will continue to evaluate mechanistically how this occurs. Furthermore, persistent infection systems are being investigated to define approaches that ameliorate immunopathology and facilitate vaccine development (Christen JCI 2-2004 and 11-2004, Christen, Diabetes 2004, Bot J. Virol 2003). Paradigms developed from these studies will not only be useful in selectively suppressing autoimmune diseases, but can also be employed to lower immunopathology that accompanies viral infections.
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