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Office: (859) 323-5131
Fax: (859) 257-8994
Lab: (859) 323-5914
Email: dcohen@uky.edu
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Donald A. Cohen, Ph.D.
Professor
Doctoral Studies: University of Cincinnati.
Postdoctoral: Medical College of Virginia.
Research Statement:
Inflammation in various organs can be caused by a variety of factors, including infectious agents, autoimmunity, environmental pollutants and therapeutic modalities. Regardless of the cause, the failure to adequately regulate the inflammatory response can lead to persistent inflammation and the development of structural changes in tissue architecture that can affect normal function in the inflamed tissue. Research in this laboratory is focused on understanding immunological mechanisms which regulate the onset and persistence of inflammation in acute and chronic disease settings.
I. Contribution of Innate Immune Cells to the Development of Experimental Colitis. Inflammatory bowel disease (IBD) is a severe chronic inflammation of the intestinal tract that affects over 1.4 million people in the U.S. The precise roles of individual types of immune cells in the development of IBD remain unresolved, including the role of macrophages and dendritic cells. Macrophages play multiple roles during an inflammatory response. First, macrophages present in the tissue are involved in initiating an inflammatory response by engulfing inflammatory stimuli and then releasing factors which call in additional immune cells to the tissue site. Secondly, additional macrophages arrive at the tissue site from the blood, thus amplifying inflammation. Finally, when the inflammatory stimulus is removed, macrophages then release a variety of factors that aid in the healing process in the injured tissue. Dendritic cells are critical for initiating specific immune responses against foreign antigens and their functional state determines the most appropriate type of immune response to efficiently eliminate infecting microorganisms. Under normal conditions in the intestinal tract, both macrophages and dendritic cells inhibit inflammation and immune responses to prevent reactions against ingested food antigens and normal intestinal microbes. However, this control is lost during IBD leading to chronic intestinal inflammation. We have demonstrated that both macrophages and dendritic cells play a protective role in preventing colitis and are identifying genes which control these protective functions. Understanding the mechanisms by which these innate immune cells regulate intestinal inflammation will allow identification of new potential therapeutic target in patients with inflammatory bowel disease.
II. Deviation of Anti_Tumor Immunity via IL-10 Production in Non_Small Cell Carcinoma . A number of studies on non-small cell lung carcinoma (NSCLC) have correlated survival outcome and therapeutic response rates with expression of the immunosuppressive cytokine, interleukin-10 (IL-10). In spite of clinical data which strongly correlate IL-10 expression with poor prognosis in NSCLC, virtually nothing is known about the mechanisms by which IL-10 decreases the survival rate in NSCLC patients. We are evaluating the hypothesis that the synthesis of IL-10 in vivo by NSCLC cells reduces the immune response toward tumor associated antigens, enabling enhanced primary tumor growth and metastatic potential. We are addressing this hypothesis using a mouse primary tumor model and a mouse lung metastatic tumor model in which murine lung carcinoma cells constitutively release high or low amounts of IL-10. The following specific questions are being investigated: 1. Does expression of IL-10 by Lewis lung cells suppress the generation of cellular immune responses against tumor associated antigens? 2. Does expression of IL-10 by Lewis lung cells suppress the generation of humoral immune responses against tumor associated antigens? 3. Does IL-10 expression increase the rate of primary tumor growth and spontaneous and experimental metastasis in the lung? 4. Does IL-10 increase angiogenesis at the tumor site? These studies will provide a framework from which we can determine if the poorer prognosis of NSCLC patients with elevated circulating IL-10 levels is due to IL-10 synthesis by the tumor cells and whether tumor derived IL-10 affects tumor development via alterations in the immune response against tumor associated antigens.
Selected Recent Publications:
Qualls J, , Tuna H, Kaplan AM, and Cohen DA. Dendritic Cell-Mediated Suppression of Dextran Sodium Sulfate Induced Colitis in Mice. Inflamm Bowel Dis. 15(2):236-47, 2009.
Jose P, Kaplan AM, and DA Cohen. Inhibition of IL-10 signaling in lung dendritic cells by TLR4 ligands. Exp Lung Res. 35(1):1-28, 2009.
Qualls J, Kaplan AM, and Cohen DA. Qualls J, Kaplan AM, and Cohen DA. Suppression of Experimental Colitis by Intestinal Mononuclear Phagocytes. J Leukoc Biol 80: 802-815, 2006.
Hongo, D, Bryson J.S., Kaplan A.M. and D.A. Cohen. Endogenous nitric oxide protects against T cell-dependent lethality during graft-vs-host disease and idiopathic pneumonia syndrome. J. Immunol. 173: 1744-1756, 2004 [Abstract]
Fernandez, S., A.M. Kaplan, and D.A. Cohen. Inhibition of IL-10 receptor function in the lung by toll-like receptor agonists. J. Immunol. 172: 2613 - 2620, 2004 [Abstract]
Burnett, S, Kerschen, EJ, Zhang J., Zeng, L., Straley, SC, A. M. Kaplan and D. A. Cohen. Conditional macrophage ablation in transgenic mice expressing a Fas-based suicide gene. J. Leuk. Biol., 75: 612-623, 2004 [Abstract]
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