PRIMARY FACULTY

Charles S. Via, M.D.
Professor
Pathology
 
4301 Jones Bridge Road
Bethesda MD 20814
Office: 301-295-3801
Fax: 301-295-1996
cvia@nih.gov

My laboratory research effort uses the parent-into-F1 model of graft vs. host disease (GVHD) as an in vivo model to study the development of cytotoxic T lymphocytes (CTL) and the immunopathogenesis of systemic lupus erythematosus, a humoral autoimmune disease that affects primarily young females. GVHD is induced by the transfer of homozygous parental strain T cells into normal F1 mice. Depending on the murine strains used, disease takes one of two outcomes: a) acute GVHD mediated by donor CTL that attack host tissues and b) chronic GVHD, a disease that strongly resembles human lupus. Like naïve T cells, CTL require two signals for activation - an antigen specific signal mediated through the T cell receptor and a second costimulatory signal mediated through CD28 initially. These two signals result in proliferation however maturation to effector CTL also requires a third signal that can be delivered by cytokines. Importantly, defects in CTL development convert acute GVHD to lupus-like chronic GVHD. Conversely, agents that promote CTL convert lupus-like chronic GVHD to acute GVHD. Lastly, lupus-like disease occurring in chronic GVHD mice is more severe in females just as human disease. Our current efforts are focused on: 1) defining the mechanisms responsible for sex-based differences in lupus-like disease; 2) determining the consequences of defects in Fas/FasL and perforin mediated killing on the subsequent development of lupus; 3) defining the role of T cell downregulatory molecules (e.g., Fas, CD80, PD-1) and their suitability as targets for enhancing or reducing CTL function in vivo; 4) defining cytokines and agents that can either deliver signal 3 or induce signal 3 mediating molecules for CTL maturation. Agents identified as having CTL promoting abilities will be tested in spontaneous models of murine lupus for their therapeutic value; and 5) identifying additional cell surface molecules and cytokines with critical roles in enhancing or downregulating CD8 CTL responses. Our laboratory uses multi-color flow cytometry extensively. We have also adapted an in vivo cytotoxic killing assay using non- radioactive parameters. Other methodology used extensively includes real time PCR, ELISA, immunohistology and routine histology. We are developing expertise in confocal microscopy.

Selected Publications

Grader-Beck T, Casciola-Rosen L, Lang T, Rosen A, Via CS. Apoptotic splenocytes drive the autoimmune response to poly (ADP-ribose) polymerase 1 in a murine model of lupus. . J. Immunol. 2007; 178:95-102.
 
Rus V, Nguyen V, Puliaev R, Puliaeva I, Zernetkina V, Luzina I, Papadimitriou JC, Via CS. T cell TRAIL promotes murine lupus by sustaining CD4 T cell help for B cells and inhibiting CD8 cytotoxic T lymphocyte activity. J. Immunol. 2007 178(6):3962-72.
 
Puliaev R, Puliaeva I, Welniak LA, Ryan, AE, Haas M, Murphy WJ, Via CS. Cytotoxic T lymphocyte-promoting effects of CD40 stimulation outweigh B cell stimulatory effects resulting in B cell elimination and disease improvement in a murine model of lupus J. Immunol. 2008 181(1): 47-61
 
Puliaeva I, Puliaev R, Via CS Therapeutic potential of CD8+ cytotoxic T lymphocytes in SLE. Autoimmun Rev. 2008 (in press).
 
Puliaeva I, Puliaev R, Shustov A, Haas M, Via CS. Fas expression on antigen-specific T cells has costimulatory, helper and downregulatory functions in vivo for cytotoxic T cell responses but not for T cell-dependent B cell responses. J. Immunol. 2008 (in press) Fas expression on antigen-specific T cells has costimulatory, helper, and down-regulatory functions in vivo for cytotoxic T cell responses but not for T cell-dependent B cell responses.
 
Puliaeva I, Puliaev R, Shustov A, Haas M, Via CS. J Immunol. 2008 Nov 1;181(9):5912-29.
 
Therapeutic potential of CD8+ cytotoxic T lymphocytes in SLE. Puliaeva I, Puliaev R, Via CS. Autoimmun Rev. 2009 Jan;8(3):219-23.

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