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Member Information
Terri H. Finkel, MD, PhD
Chief, Division of Rheumatology
Hollander Endowed Chair in Pediatric Rheumatology
Director, Rheumatology Fellowship Program
Associate Professor of Pediatrics
Phone: 215-590-7180
Fax: 215-590-1258
Email: finkelt@email.chop.edu
Website(s):
Education: MD 1982, Stanford University; PhD 1984, Stanford University - Biochemistry/Biophysics; Master of Arts (Honorary) 1999, University of Pennsylvania
Keywords: Pediatrics, Pathogenesis, Latency, T-cell Signal Transduction, Apoptosis, Primate Models, Clinical Trials
Research and/or Clinical Interests:
Mechanisms of HIV persistence and immune dysregulation, with emphasis on identification of viral and cellular determinants regulating HIV/SIV-induced apoptosis, immune suppression and latency
Molecular mechanisms of lymphocyte activation
Summary:
The Finkel lab has done extensive work on cell death in AIDS, being the first to show that the HIV surface protein, gp120, primes T cells for cell death by apoptosis. These results suggest a mechanism for the massive CD4 T cell depletion in AIDS, particularly in the face of concurrent infection and antigenic challenge with other organisms. Subsequent in vivo studies showed that this apoptosis occurs predominantly in healthy bystander cells and only rarely in infected cells, suggesting that HIV encodes or induces expression of survival genes. We have identified known and novel cellular gene products that are inversely correlated with, and may regulate, T cell apoptosis in HIV infection. In particular, current specific aims are designed to define the role and mechanism of action of a novel candidate 'survival' gene, DDIT4, in HIV-infected T cells. We hypothesize that expression of T cell DDIT4 (DNA damage inducible transcript 4) inhibits HIV-induced apoptosis via HIF-1 (hypoxia-inducible factor-1) and regulation of toxic ROS. This research has implications for both the cause and cure of AIDS, arguing that rational drug therapy must do two things - destroy the virus and repair the immune system. DDIT4 may also be required for viral latency, since cell viability must be a prerequisite for latent infection. Inhibition of viral anti-apoptotic genes could eliminate the HIV reservoir that remains even after prolonged, aggressive anti-retroviral therapy and thus effect a cure.
We are also investigating a mechanism of HIV-induced T cell unresponsiveness, apoptosis and developmental arrest via inhibition of the Janus kinase, JAK3, and its target transcription factor, STAT5. We have demonstrated reversal of HIV-induced inhibition by IL-2 and other cytokines that bind gamma c-related cytokine receptors. These data suggest novel therapeutic approaches to the early immunodeficiency seen in HIV-infected children. Our ongoing research focuses on the role of JAK3/STAT5 inhibition in HIV latency and chronic infection.
In work relating to T cell signal transduction, anergy, and autoimmunity, the Finkel lab was among the first to show that T cells, like some non-immune cells, use the cytoskeleton to transduce activating signals. Current work addresses mechanisms of initiation of T cell activation, including the role of costimulatory surface receptors, analyses of the spatial distribution and interaction parameters of ligand-receptor interactions at the interface of the immune synapse in real time, and determination of the valency requirement of receptors for membrane-anchored ligands. A novel artificial membrane system has been developed that closely mimics the cell surface and provides a valuable research tool to study subtle differences in intracellular signaling pathways induced by specific ligand/receptor or membrane/membrane interactions.
Representative Publications:
Banda NK, Bernier J, Kurahara DK, Kurrle R, Haigwood N, Sekaly R-P, Finkel TH. Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis. J Exp Med 176:1099-106, 1992.
Finkel TH, Banda NK. Indirect mechanisms of HIV pathogenesis: how does HIV kill T cells? Curr Opin Immunol 6:605-15, 1994.
Finkel TH, Tudor-Williams G, Banda NK, Cotton MC, Curiel T, Monks C, Baba T, Ruprecht R, Kupfer A. Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nat Med 1:129-134, 1995.
Rozdzial MM, Malissen B, Finkel TH. Tyrosine phosphorylated T cell receptor- chain associates with the actin cytoskeleton upon activation of mature T lymphocytes. Immunity 3:623-33, 1995.
Selliah N and Finkel TH. Cutting Edge: JAK3 activation and rescue of T cells from HIV gp120-induced unresponsiveness. J Immunol 160:5697-701, 1998.
Rozdzial MM, Pleiman CP, Cambier JC, Finkel TH. pp56Lck mediates T cell receptor- chain binding to the microfilament cytoskeleton. J Immunol 160:5491-5499, 1998.
Rapaport ER, Casella CR, Ikle D, Mustafa F, Isaak D, and Finkel TH. Mapping of HIV-1 determinants of apoptosis in infected T cells. Virology 252:407-417, 1998.
Marschner S, Freiberg BF, Kupfer A, Finkel TH. Ligation of the HIV-1 CD4 receptor induces downregulation of L-selectin. Proc Nat Acad Sci USA 96:9763-9768, 1999.
Casella CR, Rapaport EL, and Finkel TH. Vpu mediates increased susceptibility of HIV-1 infected cells to Fas killing. J Virol 73:92-100, 1999.
Paterson RK, Bluëthmann H, Tseng P, Dunlap A, Finkel TH. Development and function of autospecific dual TCR+ T lymphocytes. Int Immunol 11:113-19, 1999.
Angkachatchai V, Finkel TH. The small GTP-binding protein, Rho, is required for IL-2 production and sustained calcium flux in activated T cells. J Immunol 163:3819-3825, 1999.
Selliah N, Finkel TH. Role and mechanism of apoptosis in HIV disease. Cell Death and Diff 8:127-136, 2001.
Selliah N, Finkel TH. HIV-1 NL4-3, but not IIIB, inhibits JAK3/STAT5 activation in CD4 T cells. Virology 286:412-421, 2001.
Kovacs B, Maus MV, Riley J, Derimanov GS, Koretzky GA, June CH, Finkel TH. Human CD8+ T cells do not require the polarization of lipid rafts for activation and proliferation. Proc Nat Acad Sci USA 99:15006-15011, 2002.
Feuerstein N, Shivers D, Chen F., Eisenberg RA, Finkel TH. Chronic GVH prevents anergy in bone marrow self-reactive B cells: a selective increase in post-endoplasmic reticulum processing and trafficking to the cell surface of autoreactive IgM receptors. Int Immunol 15:975-985, 2003.
Selliah N, Shackelford J, Wang JF, Traynor F, Yin J, Finkel TH. T cell signaling and apoptosis in HIV disease. Immunol Res 27/2-3:247-260, 2003.
Jiyi Y, Chen MF, Finkel TH. Differential gene expression during HIV-1 infection analyzed by suppression subtractive hybridization. AIDS 18:587-96, 2004.
Wang J-F, Marschner S, Finkel TH. CXCR4 engagement is required for HIV-1 induced L-selectin shedding. Blood 103:1218-21, 2004.
Maus MV*, Kovacs B*, Kwok WW, Nepom GT, Schlienger K, Riley JL, Allman D, Finkel TH, June CH. Extensive replicative capacity of human central memory T cells. J Immunol 172:6675-83, 2004. *These authors contributed equally to this work.
Feuerstein N, DeSimone DC, Eisenberg RA, Finkel TH. Chronic GVH is associated with a decrease in Ig light chain receptor editing in bone marrow self reactive B cells. Eur J Immunol 34:1361-70, 2004.
