The family of class I major histocompatibility complex (MHC) antigens includes highly polymorphic, classical class Ia and the more conserved, non-classical class Ib glycoproteins. Members of both subfamilies interact with cytotoxic T cells and NK cells via activating and inhibitory receptors and contribute to elimination of pathogens and tumors by a variety of different pathways.
Our current efforts focus on the biology of class I MHC proteins 1) during experimental cancer rejection, where it is advantageous to enhance immune response against malignant cells, 2) in gut tissues, where immune system needs to distinguish between harmless commensal flora and harmful pathogens and 3) during transplantation of foreign cells, where tolerance to MHC molecules is desired clinically, but is not favored by normal immune response.
(1) One goal of our research is to understand how nonclassical class Ia antigens, Qa-2, promote tumor rejection. We have shown that transcription of Qa-2 genes (Q8, Q9) is silenced in in-vivo arising tumors, but their re-expression on malignant cells provokes tumor elimination. Immunization with Qa-2 positive cancer cells induces anti-tumor CTL, which can destroy diverse types of malignant cells, including melanomas, lymphomas and lung carcinomas. We are currently investigating the mechanisms responsible for silencing of Qa-2 genes in tumors and studying molecular approaches for their reactivation. We are also examining the role that canonical and alternatively spliced isoforms of Qa-2 perform in regulation of T and NK anti-tumor responses. A future challenge will be to identify the tumor/stress antigens presented by Qa-2 restriction elements and to apply these findings in the design of anti-cancer vaccines.
(2) Another interest of our laboratory is to understand the role of class I MHC pathways in the immunobiology of liver and gut, the two organs in which locally induced tolerance dominates over immune response to non-self antigens. The immune system of gastrointestinal tract and liver is the first line of defense against orally ingested pathogens but is, at the same time, maintaining tolerance to commensal flora and food. We have recently discovered several class Ib MHC proteins synthesized solely in these tissues and characterized the classical class I antigen assembly and presentation pathway in liver. We will now investigate how liver and gut-specific class Ib MHC molecules interact with receptors on the immune cells populating these tissues and how they influence tolerance/immune response to tumors and pathogens in the local environment.
(3) While expression of MHC antigens is required for elimination of diseased cells, it is a hindrance during organ transplantation. We are interested in developing molecular approaches to decrease immunogenicity of human cells for transplantation. Preliminary collaborative efforts focus on reducing class I and class II MHC cell surface display and on engineering of inhibitory class I MHC, which will tolerize cytotoxic lymphocytes.
Our experiments employ molecular, biochemical, biophysical, cellular and transgenic approaches.
RESEARCH INTERESTS
Cancer Immunology
Mucosal Immunity
Host-Pathogen Interactions
RECENT PUBLICATIONS
Chiang, E. Y. and Stroynowski, I., "A nonclassical class I MHC molecule restricts CTL-mediated rejection of a syngeneic melanoma tumor." J. Immunol., 173:4394-4401, 2004
Chiang, E. Y. and Stroynowski, I., "Protective immunity to disparate tumors is mediated by a nonpolymorphic class I MHC molecule." J. Immunol., 174:5367-5374, 2005
Chen, M., Tabaczewski, P., Truscott , S., Van Kaer L. and Stroynowski, I., "Hepatocytes express abundant surface class I MHC and efficiently utilize TAP, TPN and LMP components of Ag presentation and processing pathway" J. Immunol., 175:1047-1055, 2005
Guidry P. and Stroynowski, I., "A murine family of gut-expressed class Ib MHC includes alternatively spliced isoforms of the proposed HLA-G homolog." J. Immunol., 175:5248-5259, 2005
SIGNIFICANT PUBLICATIONS
Stroynowski, I., Soloski, M., Low, M.G. and Hood, L., "A single gene encodes soluble and membrane-bound forms of the major histocompatibility Qa-2 antigen: anchoring of the product by a phospholipid tail." Cell, 50:759-768, 1987
Korber, B., Mermod, N., Hood, L. and Stroynowski, I., "Regulation of gene expression by interferons: control of the H-2 promoter responses." Science, 239:1302-1306, 1988
Joyce, S., Tabaczewski, P., Angeletti, R.H., Nathenson, S.G. and Stroynowski, I., "A non-polymorphic MHC class Ib molecule binds a large array of diverse self peptides" J.Exp. Med., 179:579-588, 1994
Tabaczewski, P., Shirwan, H., Lewis, K. and Stroynowski, I., "Alternative splicing of class Ib MHC transcripts in vivo leads to the expression of soluble Qa-2 molecules in murine blood." Proc. Natl. Acad. Sci. USA, 91:1883-1887, 1994
Chiang, E.Y., Henson, M. and Stroynowski, I., "Correction of defects responsible for impaired Qa-2 class Ib MHC expression on melanoma cells protects mice from tumor growth." J.Immunol., 170:4515-4523, 2003
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