Alan M. Kaplan, Ph.D.
Professor and Chairman
Doctoral Studies: Purdue University.
Postdoctoral: University of Toronto.
Research Statement:
My laboratory is focussed on understanding the mechanisms of pulmonary immunity and pulmonary fibrosis and on studying the regulation and development of anti-leukemic activity in syngeneic graft versus-host disease.
Experiments from our laboratory were the first to show that BLM-induced pulmonary fibrosis could be induced in SCID mice in the absence of lymphocytes and that fibrosis under those conditions were associated with profound eosinophilia. More recent studies have shown that BLM-induced fibirosis occurred in anti-IL-5 knockout mice in the absence of eosinophilia as well as in NK deficient mice suggesting that neither cell type was required for the induction of fibrosis. Currently, the levels and kinetics of fibrogenic and anti-inflammatory cytokines are being elucidated to determine their role in fibrosis. In addition, we have adopted a transgenic mouse strategy to deplete monocytes and consequently inflammatory macrophages by expressing an inducible suicide gene for the macrophage specific promoter, cfms, to express green fluorescent protein (GFP) and a suicide gene containing two units of FK506 binding protein (FKBP) fused to the cytoplasmic region of Fas. Dimerization of the FKBP with the drug AP20187 activates fas-mediated apoptosis and results in a dramatic reduction in GFP+ macrophages. In addition, these Tg mice develop an interesting clinical syndrome that includes massive adhesions and inflammation, the mechanism of which is currently under study.
We are also studying the mechanisms responsible for the induction of murine cyclosporine A-induced syngeneic graft-versus-host disease (SGVHD). Ongoing work in this model has ranged from describing the regulation and pathogenesis associated with the induction and adoptive transfer of this disease, to analysis of T cell clones isolated from diseased animals. It has been shown clinically that a beneficial consequence of GVHD following bone marrow transplantation (BMT) is the generation of anti-tumor or graft-versus-leukemia (GVL) responses and similarly mice with SGVHD have demonstrated the ability to reject syngeneic tumors. We are currently studying three aspects of SGVHD: 1) the immunoregulatory events that are responsible for induction of the disease; 2) the mechanism of GVL activity with particular focus on innate immunity; and 3) the induction and regulation of a Crohn’s/colitis like autoimmune disease which appears to be a prominent feature of SGVHD.
Selected Recent Publications:
Burnett, S., Zhang, J., Kaplan, A.M., and Cohen, D.A. Conditional macrophage ablation in transgenic mice expressing a Fas-based suicide gene. In preparation.
Bryson, J.S., Zhang, L., Goes, S.W., Jennings , C.D., Caywood, B.E., Carlson, S.L. and Kaplan, A.M. CD4+ T cells mediate murine syngeneic graft-versus-host disease-associated colitis. Submitted
Fernandez, S., Jose, P., Avdiushko, M., Kaplan, A.M. and Cohen, D.A. Inhibition of IL-10 receptor function in the lung by Toll-Like receptor agonists. Submitted.
Lowery-Flanagan, D.M., Jennings , C.D., Caywood, B.E., Gross, R., Goes, S., Kaplan, A.M. and Bryson, J.S. Nitric oxide mediates intestinal pathology of murine cyclosporine-induced syngeneic-graft-versus-host disease. J. Leukocyte Biology. 72:762-768, 2002. PDF
Lowery-Flanagan, D.M., Gross, R., Jennings , C.D., Caywood, B.E., Goes, S., Kaplan, A.M. and Bryson, J.S. Induction of syngeneic graft-versus-host disease in LPS hyporesponsive C3H/HeJ mice. J. Leukocyte Biol. 70:873-880, 2001. PDF
Avduishko, R., Hongo, D., Lake-Bullock, H., Kaplan, A.M. and Cohen, D.A. IL-10 receptor dysfunction in macrophages during chronic inflammation. J. Leukocyte Biol., 70:624-632, 2001. PDF
Hao, H., Cohen, D.A., Jennings , C.D., Bryson, S.J., and Kaplan, A.M. Lack of a role of eosinophils in bleomycin-induced pulmonary fibrosis. J. Leukocyte Biol. 68:515-521, 2000. PDF
Lake-Bullock, H.V., Zhu, J., Hao, J., Cohen, D.A., and Kaplan, A.M. T Cell Independence of Bleomycin-Induced Pulmonary Fibrosis. J. Leukocyte Biology 65:187-195, 1999. PDF
Bryson, J.S., Jennings, C.D., Lowery, D.M., Carlson, S.L., Pflugh, D.L., Caywood, B.E. and Kaplan, A.M. Rejection of an MHC Class II negative tumor following induction of murine syngeneic graft-versus-host disease. Bone Marrow Transplantation 23:363-372, 1999. PDF
Lake-Bullock, H.V., Bryson, J.S., Jennings , C.D., Kaplan, A.M. Inhibition of graft-versus-host disease: Use of a T-cell controlled suicide gene. J. Immunol. 158:5079-5082, 1997. PDF
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