News and Publications

Etiology of Autoimmune Disease and the Actions of Counterregulatory Cytokines

N. Sarvetnick, B. Balasa, J.D. Davies, M. Falcone, C. Fine, M. Flodstrom, W.S. Gallichan, A. Good, C. King, T. Krahl, M. Krakowski, M. Kritzik, M.S. Horwitz, A. Ilic, A. La Cava, J. Lee, G. Patstone, E. O'Conner, E. Rodriguez, C.C. Smith, K. Van Gunst, D. Walker, L. Xu, B. Yeung

During the past year, we have continued our emphasis on the etiology of autoimmune disease and the actions of counterregulatory cytokines. Autoimmune diseases are prevalent in all human populations, but the initiating event that leads to autoimmunity is unknown. Pathogens have been implicated; in particular, coxsackieviruses are thought to be important etiologic agents in insulin-dependent diabetes mellitus (IDDM). To further our understanding of the etiology of autoimmune disease, we are studying the mechanism whereby viruses trigger autopathogenic processes that lead to self-reactivity.

Coxsackievirus infects the exocrine part of the pancreas, leading to a highly destructive inflammatory response and pancreatitis. During this process, the exocrine part is severely damaged. The resulting immune activation and the release of inflammatory mediators and cytokines could affect adjacent pancreatic islets in the endocrine part of the pancreas, leading to the release of sequestered islet antigens and the upregulation of costimulatory and adhesion molecules. These antigens could travel via the blood to organized lymphoid organs, where they could prime naive cells specific for islet antigens. Although coxsackievirus and pancreatic islet antigens are similar antigenically, our data support a "bystander" mechanism for the connection between infection and the development of IDDM.

We have derived support for the hypothesis that islet autoreactivity occurs as a bystander to the inflammation of the exocrine pancreas that initiates the cascade leading to diabetes. This support was established through experiments with a variety of murine strains in which we tested both the bystander and the molecular mimicry hypotheses. Our objective is to elucidate the underlying mechanism of virus-induced autoreactivity in pancreatic islets that is implicated in the etiology of IDDM in humans. Such mechanisms may not be mutually exclusive and could act simultaneously. The knowledge acquired from these studies will expand the understanding of the relationship between coxsackievirus and the development of IDDM.

Autoimmune diseases are mediated by autoreactive T lymphocytes, which lead an attack on self-tissues. The actions of these autoimmune T lymphocytes are regulated by cytokines. Cytokines are involved in both the enhancement of immune responses that generate autoimmunity and the suppression of immune responses that, theoretically, prevent autoimmunity. The exact mechanism of cytokine regulation of T-cell responses in autoimmune diseases is not fully understood and may be complicated by the diverse effects of cytokines in different tissue environments. A greater understanding of cytokine-induced regulation and counterregulation of the disease process may allow advances in treatment of autoimmune disorders.

We seek to understand the mechanisms that explain the counterregulatory activities of cytokines in autoimmune diseases, in particular, diabetes. Cytokine-mediated counterregulation has been evoked to explain the tolerance and disease prevention that occurs after administration of islet antigens. To study the mechanism of counterregulation, we developed a model in which the localized production of IL-4 or transforming growth factor-ß prevents spontaneous autoimmunity in nonobese diabetic mice. Recently, we tested several hypotheses of the mechanism of cytokine-mediated counterregulation that we observed in transgenic nonobese diabetic mice.

We think alteration of lymphocyte half-life and localization of the lymphoid compartment could explain counterregulation. We further think that counterregulation is mediated through the tissue antigen-presenting cells, which alter the T-cell priming capabilities of the tissue. The information obtained from these studies allows an understanding of the mechanism exerted by counterregulatory cytokines within tissue compartments in vivo that may be quite distinct from the properties ascribed to the cytokines on the basis of in vitro studies.

PUBLICATIONS

Balasa, B., Davies, J.D., Lee, J., Good, A., Yeung, B., Sarvetnick, N. Interleukin-10 impacts on autoimmune diabetes via a CD8⁺ T-cell pathway circumventing the requirement for CD4⁺ T and B lymphocytes. J. Immunol., in press.

Balasa, G., Deng, C., Lee, J., Bradley, L.M., Christadoss, P., Sarvetnick, N. IFN- is necessary for the genesis of acetylcholine receptor-induced clinical experimental autoimmune myasthenia gravis in mice. J. Exp. Med. 186:385, 1997.

Balasa, B., Deng, C., Lee, J., Christadoss, P., Sarvetnick, N. The Th2 cytokine IL-4 is not required for the progression of antibody-dependent autoimmune myasthenia gravis. J. Immunol., in press.

Balasa, B., Krahl, T., Patstone, G., Lee, J., Tisch, R., McDevitt, H.O., Sarvetnick, N. CD40 ligand-CD40 interactions are necessary for the initiation of insulitis and diabetes in nonobese diabetic mice. J. Immunol. 159:4620, 1997.

Balasa, B., Sarvetnick, N. Cytokines and insulin-dependent mellitus: Implications for etiology and therapy. Drug News Perspect., in press.

Falcone, M., Lee, J., Patstone, G., Yeung, B., Sarvetnick, N. B lymphocytes are crucial antigen-presenting cells in the pathogenic autoimmune response to GAD65 antigen in nonobese diabetic (NOD) mice. J. Immunol., in press.

Falcone, M., Sarvetnick, N. Transgenic models in autoimmunity. In: Immunologically Mediated Endocrine Diseases. Gill, R., Harmon, J., Maclaren, N. (Eds.). Lippincott-Raven, Philadelphia, in press.

Geiger, K.D., Nash, T.C., Sawyer, S., Krahl, T., Patstone, G., Reed, J.C., Krajewski, S., Dalton, D., Buchmeier, M.J., Sarvetnick, N. Interferon-gamma protects neurons against herpes simplex virus-1 mediated apoptosis. Virology 238:189, 1997.

Gu D.-L., Arnush, M., Sarvetnick, N. Endocrine-exocrine intermediate cells in STZ treated transgenic mice. Pancreas 15:246, 1997.

Horwitz, M.S., Bradley, L.M., Harbertson, J., Krahl, T., Lee, J., Sarvetnick, N. Diabetes induced by Coxsackie virus: Initiation by bystander damage and not molecular mimicry. Nature Med., in press.

Jones, E.M., Sarvetnick, N. Balance between autoimmune destruction and regeneration: Dual activities of IFN in wound healing and inflammation. In: Pancreatic Growth and Regeneration. Sarvetnick, N. (Ed.). R.G. Landes, Georgetown, TX, 1997, p. 108.

Jones, E.M. Sarvetnick, N. Islet regeneration in IFN transgenic mice. Horm. Metab. Res. 29:308, 1997.

King, C., Davies, J., Mueller, R., Lee, M., Krahl, T., Yeung, B., O'Conner, E., Sarvetnick, N. TGF-ß1 alters APC preference, polarizing islet antigen response to Th2. Immunity 8:601, 1998.

King, C., Sarvetnick, N. Organ-specific autoimmunity. Curr. Opin. Immunol. 9:863, 1997.

Krakowski, M., Sarvetnick, N. Perspectives in pancreatic development. In: Pancreatic Growth and Regeneration. Sarvetnick, N. (Ed.). R.G. Landes, Georgetown, TX, 1997, p. xx.

La Cava, A., Sarvetnick, N. The role of cytokines in autoimmune diseases. In: Current Directions in Autoimmunity. Theofilopoulos, A. (Ed.). Karger, Basel, Switzerland, in press.

Lee, M.-S., Sarvetnick, N. Fetal exposure to interferon- leads to induction of antigen-presenting molecules and leukocyte recruitment. Autoimmunity 25:147, 1997.

Lee, M.-S., Wicker, L.S., Peterson, L.B., Sarvetnick, N. Pancreatic IL-10 induces diabetes in NOD-B6-Idd3-Idd10 mice even in the presence of I-E. Autoimmunity 26:215, 1997.

Mueller, R., Bradley, L.M., Krahl, T., Sarvetnick, N. Mechanism underlying counter-regulation of autoimmune diabetes by IL-4. Immunity 7:411, 1997.

Mueller, R., Davies, J.D., Krahl, T., Sarvetnick, N. Interleukin-4 expression by grafts from transgenic mice fails to prevent allograft rejection. J. Immunol. 159:1599, 1997.

Ohasi, P.S., Sarvetnick, N. Autoimmunity a bias from tolerance to immunity [editorial]. Curr. Opin. Immunol. 9:815, 1997.

Sarvetnick, N. (Ed.). Pancreatic Growth and Regeneration. R.G. Landes, Georgetown, TX, 1997.