SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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T U M O R I M M U N O L O G Y P R O G R A M SELECTED PUBLICATIONS 2002 Strbo, N, Yamazaki, K, Lee, KP, Rukavina, D, and Podack, ER. Heat shock fusion protein gp96-Ig mediates strong CD8 CTL expansion in vivo. American Journal of Reproductive Immunology 48:220-25, 2002. Bahlis, NJ, McCafferty-Grad, J, Jordan- McMurry, I, Neil, J, Reis, I, Kharfan-Dabaja, M, Eckman, J, Goodman, M, Fernandez, HF, Boise, LH, and Lee, KP. Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma. Clinical Cancer Research 8:3658-68, 2002. Gray, Parkin K, Stephan, RP, Apilado, RG, Lill- Elghanian, DA, Lee, KP, Saha, B, and Witte, PL. Expression of CD28 by bone marrow stromal cells and its involvement in B lymphopoiesis. Journal of Immunology 169:2292-302, 2002. Baumgartner, R, Durant, P, van Gessel, Y, Chattopadhyay, S, Beswick, RL, Tadaki, DK, Lasbury, M, Lee, CH, Perrin, P, and Lee, KP. Evidence for the requirement of T cell costimulation in the pathogenesis of natural Pneumocystis carinii pulmonary infection. Microbial Pathogenesis 33:193-201, 2002. 2003 Tadaki, DK, Williams, A, Lee, KP, Kirk, AD, and Harlan, DM. Porcine CD80: cloning, characterization, and evidence for its role in direct human T-cell activation. Xenotransplantation 10:252-58, 2003. McCafferty-Grad, J, Bahlis, NJ, Krett, N, Aguilar, TM, Reis, I, Lee, KP, and Boise, LH. Arsenic trioxide utilizes caspase-dependent and caspase-independent death pathways in myeloma cells. Molecular Cancer Therapeutics 2:1155-64, 2003. Hernandez, A, Lindner, I, Blomberg, BB, Hussini, S, Burger, M, Mathew, JM, Carreno, M, Garcia-Morales, R, Fuller, L, Jin, Y, Rosen, A, Lee, KP, Miller, J, and Esquenazi, V. Suppression of allogeneic T cell proliferation through blocking of NF-KB in the differentiation process of human dendritic cells. Human Immunology 64:S128, 2003. HIGHLIGHTS/DISCOVERIES • Direct activation of PKC causes normal human hematopoietic CD34 + stem cells to differentiate into DC. • PKC activation causes many myeloid leukemias to differentiate into immunologically functional “leukemic” DC. These cells have potential utility as “cellular” anti-leukemia vaccines. • Specific intracellular signaling pathways downstream of PKC activation control specific aspects of DC differentiation. • Arsenic trioxide + ascorbic acid is an effective combination in the treatment of refractory/relapsed myeloma. Lindner, I, Kharfan-Dabaja, MA, Ayala, E, Kolonias, D, Carlson, LM, Beazer-Barclay, Y, Scherf, U, Hnatyszyn, JH, and Lee, KP. Induced dendritic cell differentiation of chronic myeloid leukemia blasts is associated with down-regulation of BCR-ABL. Journal of Immunology 171:1780-91, 2003. UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 111
T U M O R I M M U N O L O G Y P R O G R A M ROBERT B. LEVY, PH.D. Professor of Microbiology and Immunology DESCRIPTION OF RESEARCH Researchers in Dr. Levy’s laboratory study the immunological responses following allogeneic bone marrow transplantation (BMT), which determine the success or failure of the hematopoietic graft. The primary objective of these studies is to define how different effector molecules produced by transplanted donor T cells and by barrier cells in the recipient regulate the development of graft versus host disease (GVHD) and control hematopoietic engraftment, respectively. The work concerning GVHD has focused on elucidating the role of donor-mediated cytotoxicity against recipient cells following the transplant. Their findings have demonstrated that differing pathways of cytotoxicity play different roles in the GVHD process. Granule dependent cytotoxicity dependent on perforin function is important in the development and onset of the disease. Cytotoxicity mediated by CD95L (FasL) is an important pathway in the pathogenesis occurring in the liver during GVHD and also can contribute to cutaneous GVHD. Most interestingly, even when both of these molecular pathways are absent in donor T cells (i.e., when they are “doubly cytotoxic deficient”), they remain capable of inducing many GVHD symptoms and death in recipients. Dr. Levy and his colleagues have recently found that highly purified populations of CD8 + or CD4 + T cells lacking these killing functions also induce lethal GVHD posttransplant. Researchers in this laboratory also investigate the process of engraftment following BMT. These studies examine the presence of defined donor progenitor cell populations (lineage committed and more primitive multi-lineage stem cells) and peripheral chimerism in recipients post-transplant. They are interested in understanding the mechanisms used by: 1) donor lymphoid cells for their facilitation and support of progenitor cells and engraftment after transplant, and 2) barrier cells in the host, which inhibit progenitor cells 112 and engraftment. Their recent findings have surprisingly demonstrated that total body irradiated BMT recipients lacking both perforin- and CD95L-dependent mechanisms maintain strong barrier function. Thus, efforts directed at diminishing the host’s ability to affect cytotoxicity through these pathways are unlikely to facilitate the engraftment process. Transplant of progenitor cells with defined cytokine receptor deficiencies will be used to further investigate the molecules involved. Recent studies also have documented that during the first month following BMT, there are two defined stages of engraftment, i.e., an early period when progenitor cells from the donor are present in the recipient followed by a later period during which time such cells may be eliminated. These findings show that cytotoxic function via perforin and FasL is not necessary to establish early progenitor presence but is required for the establishment of long-term chimerism in the recipient. SELECTED PUBLICATIONS 2002 Jiang, Z, Adams, GB, Hanash, AM, Scadden, DT, and Levy, RB. The contribution of cytotoxic and noncytotoxic function by donor T-cells that support engraftment after allogeneic bone marrow transplantation. Biology of Blood and Marrow Transplantation 8:588-96, 2002. Chill, JH, Nivasch, R, Levy, RB, Albeck, S, Schreiber, G, and Anglister, J. The human interferon receptor: NMR-based modeling, mapping of the IFN-alpha 2 binding site, and observed ligand-induced tightening. Biochemistry 41:3575-85, 2002. Levy, RB and Aoki, C. Alpha7 nicotinic acetylcholine receptors occur at postsynaptic densities of AMPA receptor-positive and -negative excitatory synapses in rat sensory cortex. The Journal of Neuroscience 22:5001-15, 2002. UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
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SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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