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Member Information
Andrew Caton, PhD
Associate Professor, Wistar Institute
Office Phone: 215-898-3871
Office Fax: 215-898-3868
Email: caton@wistar.org
Website(s):
Education: PhD 1980, University of Cambridge , UK
Keywords: Immune response, antigens
Research and/or Clinical Interests:
Immune response to viruses
Summary:
The vertebrate immune system is characterized by its ability to generate a repertoire of immunoglobulin (Ig) and T cell receptor (TCR) molecules (expressed by B and T lymphocytes, respectively) that can recognize a and direct the immune system's effector mechanisms toward a vast array of different antigens. When the immune system reacts toward antigens that are present on viruses and other invading microorganisms, these processes are generally beneficial for the host because they lead to the elimination of the infecting agent. Under other scenarios, however, the induction of immune responses can be detrimental to the host. Immune reactions toward the host's own cells and tissues lead to the various syndromes of autoimmunity. Adverse immune responses toward transplanted tissues can cause their rejection, and coversely, successful pregnancy depends on the failure of the maternal immune system to reject the fetus, even though the fetus expresses paternally-inherited antigens that have the potential to be recognized as foreign by the maternal immune system. Our research is aimed toward defining the mechanisms by which the immune system responds to foreign antigens such as viruses, and by which it regulates immune responses to self antigens. We are also examining the extent and outcome of immune responses to fetal antigens during pregnancy.
Our experimental approaches center on a transgenic mouse model system we have developed in which the influenza virus A/PR/8/34 hemagglutinin (PR8 HA) is a model self antigen. The HA provides an extremely powerful system for analyzing the specificity of self recognition, because of our previous studies defining the location and structure of B and T cell determinants on the PR8 HA. We have also previously examined the genetic basis by which HA-specific Ig and TCRs are generated in BALB/c mice. As a result of these past studies, how the HA is recognized in transgenic mice that express the HA as a neo-self antigen (HA Tg mice) can be examined using the wealth of reagents and information we have gained by studying its recognition as a foreign antigen. In our intial studies, HA Tg mice were immunized or infected with influenza virus or with mutant viruses that contain amino acid substitutions in defined T and B cell determinants in the HA. The responses that were induced in HA Tg mice were then compared to the responses that could be induced in non-Tg mice. This approach allowed us to carry out a systematic analysis of the extent, specificity and genetic basis with which T and B cell tolerance is induced to the HA. The major finding that emerged from these studies is that although self-tolerance clearly modifies the anti-HA immune responses of HA Tg mice, HA-reactive T and B cells persist in these mice and can be activated by virus immunization. Our current studies aim, firstly, to determine factors and mechanisms that dictate why different subsets of HA-specific T and B cells differ in their susceptibility to negative selection by the neo-self HA in HA Tg mice. Secondly, we are evaluating the lymphocytes that evade negative selection for their capacity to differentiate and participate in antigen-specific immune responses.
To address these issues, we are utilizing additional lineages of transgenic mice that express HA-specific TCR and Ig molecules in order to study how defined self-reactive T and B cell populations mature in HA Tg mice. For example, we are evaluating whether HA-specific T cells that escape negative selection in HA Tg mice have altered capacities to differentiate into distinct effector phenotypes (e.g. Th1 versus Th2 cells). In addition, we are generating HA Tg mice that express the HA as a neo-self antigen under a variety of different promoters, in order to target expression of the HA to different cell types and tissues. Our long term objective is to use a well characterized and easily manipulable experimental system to examine mechanisms by which tolerance is established in healthy individuals, and to determine processes by which these mechanisms break down and/or can be manipulated in states such as autoimmunity, transplantation and pregnancy.
Representative Publications:
Scott, B., Liblau, R., Degermann, S., Marconi, L.A. , Caton, A.J., McDevitt, H.O., and Lo, D. 1994. A role for non-MHC genetic polymorphism in susceptibility to spontaneous autoimmunity. Immunity 1: 73-82.
Roark, J.H., Kuntz, C., Nguyen, K-A.T., Caton, A.J., and Erikson, J. 1995. Breakdown of B cell tolerance in a mouse model of systemic lupus erythematosus. J. Exp. Med. 181: 1157-1167.
Cerasoli, D.M., McGrath, J., Carding, S.R., Shih, F.F., Knowles, B.B., and Caton, A.J. 1995. Low avidity recognition of a class-II restricted neo-self peptide by virus-specific T cells. Int. Immunol. 7: 935-945.
Cerasoli, D.M., Riley, M., Shih, F.F., and Caton, A.J. 1995. Genetic basis for T cell recognition of a major histocompatability complex class II-restricted neo-self peptide. J. Exp. Med. 182: 1327-1336.
Caton, A.J., Swartzentruber, J.R., Kuhl, A.L., Carding, S.R., and Stark, S.E. 1996. Activation and negative selection of functionally distinct subsets of antibody secreting cells by influenza hemagglutinin as a viral and a neo-self antigen. J. Exp. Med. 183: 13-26.
Shih, F.F, Cerasoil, D.M., and Caton, A.J. 1997. A major T cell determinant from the influenza virus hemagglutinin (HA) can be a cryptic self peptide in HA transgenic mice. Int. Immunol. 9: 249- 261.
