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Cellular mechanims of autoimmunity and gene transfer approaches for treatment of autoimmune diseasesCellular events in the induction of Autoimmune Encephalomyelitis (EAE)a. Characterization of the antigen presenting cell (APC) in the brain and in the gut that presents the autoantigen to the pathogenic T cell. We find that APC of bone marrow origin as well as APC of non bone marrow origin such as astrocytes and epithelial cells can present antigen to pathogenic T cells in the brain. However. APC of bone marrow origin are much more efficient in presenting the autoantigen. We are studying the expression of various adhesion molecules on both types of APC. their activation patterns and their lymphokine secretion profile. b. Prevention of EAE induction with antibodies specific for adhesion molecules. We are studying the effects of anti CD11a. anti CD11b. anti-selectine(s) and anti-macrophage activation marker antibodies on the induction phase of EAE. We find that some of these antibodies are potent inhibitors of EAE induction. Induction of depletion/clonal anergy of myelin basic protein (MBP) and proteolipid protein (PLP) in vivo.We are using retroviral vectors to introduce synthetic genes expressing the encephalitogenic determinants of MBP and PLP into resting B cells such that varying levels of the antigens are expressed continuously in the target cells. In some of the constructs the genes encoding the encephalitogenic determinants of MBP and PLP are fused to lysosomal targeting sequences and some of the constructs also contain a B7 anti-sense coding sequences. The target B cells are introduced into susceptible mice in which EAE is then induced either by direct immunizations or by adoptive transfer of encephalitogenic T cell lines. Selected PublicationsMukherjee S, Lee HL, Pacchia AL, Ron Y, Dougherty JP. (2007) A HIV-2-based self-inactivating vector for enhanced gene transduction. J Biotechnol. 127(4):745-57. Zhuang J. Mukherjee S. Ron Y. Dougherty JP. (2006) High rate of genetic recombination in murine leukemia virus: implications for influencing proviral ploidy. J Virol. 80(13):6706-11. Chen CC. Ron Y. (2006) New strategies for immune-mediated anti-viral drug and vaccine development. Curr Pharm Des. 12(11):1391-401. Micheva-Viteva S. Pacchia AL. Ron Y. Peltz SW. Dougherty JP. (2005) Human immunodeficiency virus type 1 latency model for high-throughput screening. Antimicrob Agents Chemother. 49(12):5185-8. Smith KM. Brewer JM. Mowat AM. Ron Y. Garside P. (2004) The influence of follicular migration on T-cell differentiation. Immunology. 111(3):248-51. Chen CC. Rivera A. Dougherty JP. Ron Y. (2004) Complete protection from relapsing experimental autoimmune encephalomyelitis induced by syngeneic B cells expressing the autoantigen. Blood. 103(12):4616-8. Rivera A. Chen CC. Dougherty JP. Ben-Nun A. Ron Y. (2003) Host stem cells can selectively reconstitute missing lymphoid lineages in irradiation bone marrow chimeras. Blood. 101(11):4347-54. Adelson ME. Pacchia AL. Kaul M. Rando RF. Ron Y. Peltz SW. Dougherty JP. (2003) Toward the development of a virus-cell-based assay for the discovery of novel compounds against human immunodeficiency virus type 1. Antimicrob Agents Chemother. 47(2):501-8. Nicot A. Ratnakar PV. Ron Y. Chen CC. Elkabes S. (2003) Regulation of gene expression in experimental autoimmune encephalomyelitis indicates early neuronal dysfunction. Brain. 126(Pt 2):398-412. Zhuang J. Jetzt AE. Sun G. Yu H. Klarmann G. Ron Y. Preston BD. Dougherty JP. (2002) Human immunodeficiency virus type 1 recombination: rate. fidelity. and putative hot spots. J Virol. 76(22):11273-82. O'Neil PK. Sun G. Yu H. Ron Y. Dougherty JP. Preston BD. (2002) Mutational analysis of HIV-1 long terminal repeats to explore the relative contribution of reverse transcriptase and RNA polymerase II to viral mutagenesis. J Biol Chem. 277(41):38053-61. |
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