Dr. Shea-Donohue’s research is focused on immune-based alterations in gastrointestinal function. A major goal of the work is to determine the contribution of non-immune cells to cytokine-induced alterations in gut function, particularly, the interaction between non-hematopoeitic cells and immune cells in mediating both transient and long term changes induced by upregulation of specific profiles of cytokines. The balance of immune-derived cytokines in vivo is critical to the control of infectious diseases, but polarization of the cytokine balance towards the Th1 or Th2 can have consequences that are inappropriate to host defense against agents that have different requirements for elimination. The mechanisms responsible for the Th1 and Th2-mediated immune response are of interest for several reasons. First, intestinal parasites continue to be a major worldwide health issue; second, the low incidence of parasite infection in industrial nations is cited as a factor in the increased prevalence of proinflammatory-based pathologies such as inflammatory bowel disease (IBD); and third, there is a seemingly paradoxical protection against Th2-mediated allergic reactions, both in the lung and gut, afforded by enteric infection.
We are currently exploring the mechanisms that regulate Th2 cytokine and cytokine receptor expression and the genes activated downstream receptor linked STAT signaling pathways. The focus is on genes that are mediate the immune-induced alterations in epithelial cell and smooth muscle function. The goal is to better understand the fate of these pathways in diseases such as IBD which are characterized by an immune balance and are associated with diarrhea. Although a current therapeutic target in IBD is reduction of Th1 cytokine activity, an alternate approach is to rectify the Th1/Th2 cytokine imbalance by increasing Th2 cytokines. The recent clinical success of therapies directed at targeting Th 2 cytokines provides a more specific therapeutic approach to the treatment of IBD than that offered by the standard anti-inflammatory and anti-immune regimens.
Dawson HD, Beshah E, Nishi S, Solano-Aguilar G, Zhao, A, Madden K, Dubey JP, Shea-Donohue T, Lunney JK, Urban JF Jr. Localized multi-gene expression patterns support an evolving Th1/Th2-like paradigm in response to infection with Toxoplasma gondii and Ascaris suum. Infection and Immunity. 2005, 73:1116-1128.
Au Yeung K, Smith A, Zhao A, Madden KB, Elfrey J, Sullivan C, Levander O, Urban JF, and Shea-Donohue T. Impact of vitamin E or selenium deficiency on helminth-induced alterations in murine intestinal function. J. Exp. Parasitology. 2005, 109: 201-208
Smith A, Madden KB, Au Yeung K, Zhao A, Elfrey J, Finkelman FD, Levander O, Shea-Donohue T, Urban JF Jr. Effect of selenium and/or vitamin E deficiencies on Heligmosomoides polygyrus infections in mice. J. Nutrition. 2005, 135: 830-836.
Zhao A, Morimoto A, Dawson H, Elfrey J, Madden KB, Gause WC, Min B, Finkelman FD, Urban JF, Shea-Donohue T. Immune regulation of protease-activated receptor-1 expression in murine small intestine during Nippostrongylus brasiliensis infection. Journal of Immunology. 2005, 175(4):2563-2639.
Shea-Donohue T, Cook IJ, de Giorgio R, Tonini M, Dent J, Costa M, Grundy D, Sanders KM, Schemann M, Smith TK, Brookes SJ; the varenna group. A teaching module on irritable bowel syndrome. Neurogastroenterol Motil. 2005 Oct;17 Suppl 3:20-40.
Costa M, Sanders KM, Schemann M, Smith TK, Cook IJ, de Giorgio R, Dent J, Grundy D, Tonini M, Shea-Donohue T, Brookes SJ; the varenna group. A teaching module on cellular control of small intestinal motility. Neurogastroenterol Motil. 2005 Oct;17 Suppl 3:4-19.
Brookes SJ, Cook IJ, Costa M, de Giorgio R, Dent J, Grundy D, Sanders KM, Schemann M, Shea-Donohue T, Smith TK, Tonini M; the varenna group. Education project for pathophysiology of gastrointestinal motility. Neurogastroenterol Motil. 2005 Oct;17 Suppl 3:2-3.
Fasano A, Shea-Donohue T. The role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nature Clinical Practice: Gastroenterology and Hepatology, 2005 2(9):416-22.
Morimoto M, Morimoto M, Zhao A, Madden KB, Dawson H, Finkelman FD, Mentink-Kane M, Urban JF, Wynn T, Shea-Donohue T. Functional importance of regional differences in localized gene expression of receptors for IL-13 in murine gut. Journal of Immunology. 2006 176(1):491-495.
Zhao A, Urban JF Jr., Morimoto M, Elfrey JE, Madden KB, Finkelman FD, Shea-Donohue T. Contribution of 5-HT(2A) receptor in nematode infection-induced murine intestinal smooth muscle hypercontractility. Gastroenterology. 2006 Aug;131(2):568-78.
Antalis T, Shea-Donohue T, Vogel S, Sears C, Fasano A. Protease functions in intestinal mucosal pathobiology. Nature Clinical Practice Gastroenterology and Hepatology. 2007, 393-402.
Urban JF, Steenhard N, Solano-Aguilar G, Dawson H, Iweala O, Nagler CR, Noland G, Kumar N, Anthony RM, Shea-Donohue T, Gause WC. Infection with parasitic nematodes confounds vaccination efficacy. Veterinary Parasitology. 2007,148(1): 14-20.
Scanlan B, Tuft B, Elfrey JE, Smith A, Zhao A, Morimoto M, Chmielinska J, Tejero-Taldo MI, Mak IT, Weglicki WB, Shea-Donohue T. Intestinal Inflammation Caused by Magnesium Deficiency Alters Basal and Oxidative Stress-Induced Intestinal Function. Molecular and Cellular Biochemistry 2007, 306(1-2): 59.
Shea-Donohue T, Thomas KE, Cody MJ, Zhao A, DeTolla LJ, Kopydlowski KM, Fukata M, Lira SA, and Vogel SN. Mice deficient in the CXCR2 ligand CXCL1 (KC/GRO-alpha) exhibit increased susceptibility to dextran sodium sulfate (DSS)-induced colitis. Innate Immunity 2008, 14 (2):117-124.
Zhao A, Urban JF, Anthony AM, Sun R, Stiltz J, van Rooijen N, Wynn T, Gause WC, and Shea-Donohue T. Th2 cytokine-Induced Alterations in Intestinal Smooth Muscle Function are Dependent on Alternatively Activated Macrophages. Gastroenterology. 2008, 135(1):217-225.
Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, Rallabhandi P, Shea-Donohue T, Tamiz A, Alkan S, Netzel-Arnett S, Antalis T, Vogel SN, Fasano A. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology. 2008, 135(1):194-204
Sutton TL, Zhao A, Madden KB, Elfrey JE, Tuft BA, Sullivan CA, Urban, JF, and Shea-Donohue T. Anti-inflammatory Mechanisms of Enteric Heligmosomoides polygyrus Infection on TNBS-Induced Colitis in a Murine Model. Infect Immun. (Epub July 21, 2008)