| Laura Timares, Ph.D. |
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University of Alabama at Birmingham Office: (205)934-7545
B.S. University of California at Los Angeles, 1982 Academic Appointments
With the goal of developing effective topical vaccines, we are currently studying cutaneous (a.k.a., skin-derived) DCs, termed Langerhans cells (LCs). This subset of DCs may have a specialized function in delivering cutaneous antigens to draining lymph nodes where they orchestrate either tolerogenic or immunogenic responses. Recently, we discovered that murine LCs undergo cell death after successful antigen presentation to naive T cells and this limits their immunogenic potential to combat infectious diseases or cancer. We have identified the pertinent apoptosis-signaling cascade used by LCs in response to T cells as "Type II", requiring the pro-apoptotic molecule Bid. In the absence of Bid, LCs are resistant to T cell-induced death as well as mechanisms of UV radiation-induced tolerance and perform as superior vaccinating agents. How such gene-modified, apoptosis-resistant DCs induce enhanced T cell responses, evade induction of regulatory T cells (Treg) development, and the molecular signals used by T cells to trigger DC death are under current investigation. We have also shown that epidermal keratinocytes depend on Bid expression as a tumor suppressor to protect against the development of UV-induced cutaneous neoplasias. We have evidence that Bid has a novel pro-survival function that may promote cell cycle checkpoints to promote DNA repair after UV damage. We are investigating the novel molecular mechanism by which Bid promotes cell survival in normal and skin tumor cells with the hope of identifying a new pathway that may be important to target with anti-cancer drugs. In addition, we are developing and testing novel adenoviral vectors that target delivery of genes to dendritic cells and epidermal skin cells to modulate the immune system or ameliorate disease. We are working closely with colleagues in the Gene Therapy Center to test the efficacy of these adenoviral vectors in unique and clinically relevant animal models.
Selected Peer Reviewed Publications Timares L, Takashima A, Johnston SA. Quantitative analysis of the immunopotency of genetically transfected dendritic cells. Proc Nat Acad Sci USA 22:13147-13152, 1998. Timares L, Safer KM, Qu B, Takashima A, Johnston SA. Drug-inducible, dendritic cell-based genetic immunization. J. Immunol. 170:5483-5490, 2003. Timares L, Douglas J, Perebeov A, Krasnych V, Tillman BW, Curiel DT. Adenovirus-mediated gene transfer into dendritic cells . In: Methods in Molecular Biology vol. 246. Gene Delivery to Mammalian Cells Volume 2: Viral Gene Transfer Techniques. Hunana Press. Totowa, NJ Ed. W.C. Heiser pgs. 139-154, 2004. Krishnan R, Pradhan S, Timares L., Katiyar SK, Elmets CA, Nordlund TM: Fluorescence of sunscreens adsorbed to dielectric nanospheres: Parallel to optical behavior on HaCat cells and skin. Photocemistry Photobiology, 82(6): 1557-65, 2006. Pradhan, SJ, Genebriera, J, Felix, K, Denning, W, Elmets, CA, and Timares L: CD4 T cell-induced, Bid-dependent apoptosis in cutaneous dendritic cells regulates T cell expansion and immune responses. J. Immunol. 177: 5956-5967, 2006. Timares, L, Katiyar SK, Elmets CA. DNA Damage, apoptosis and Langerhans Cells - Activators of UV-induced immune tolerance. Photochemistry and Photobiology 84(2):422-36, 2008. PMID 1824850 Pradhan S, Kim HK, Thrash CJ, Cox MA, Manena S, Wu JH, Athar M, Katiyar SK, Elmets CA and Timares L. A critical role for the proapoptotic protein Bid in UV-induced immune suppression and cutaneous apoptosis. J Immunol 1;181(5):3077-88, 2008, PMID 18713978.
National Institutes of Health/National Institute of Allergy and Infectious Diseases National Institutes of Health/National Institute of Allergy and Infectious Diseases
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