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Mohamed Oukka, Ph.D.
Mohamed Oukka, Ph.D.
Associate Professor, Pediatrics; Adjunct Associate Professor, Immunology
Dr. Oukka received his Ph.D. in Immunology at the University of Paris and Pasteur Institute (France) in 1997. Prior to joining the University of Washington and Children’s Research Institute in 2009, he held positions at Brigham and Women’s Hospital and Harvard Medical School in Boston.
Department of Pediatrics
University of Washington
Center for Immunity and Immunotherapies
Seattle Children's Research Institute Box 359300 C9S-6
1900 9th Avenue
Seattle WA 98101
Immunology Research Focus: The adaptive immune system is required to clear pathogens. However, under specific conditions, T cells from the adaptive immune system are dysregulated and attack the body's own tissues, leading to the development of autoimmune and graft versus host diseases. Autoimmune diseases represent a major threat to public health with >10 million Americans suffering from autoimmune disorders. Understanding how these diseases can be initiated and regulated is critical to the design of new therapeutics to treat autoimmune diseases.
Inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis represent aberrant or dys-regulated immune responses of the gastrointestinal tract, which lead to a state of chronic inflammation. These diseases, which affect more than 1.4 million Americans, are now known to involve variants of a number of different genes. Previous genetic studies uncovered a link between Crohn's and variants of the gene CARD15 (also known as NOD2), but this gene plays a role in only some Crohn's patients, and does not affect the risk for colitis. Recent discovery has linked the gene encoding for interleukin-23 (IL-23) receptor with the development of Crohn’s, and it is believed that IL-23 has a much larger effect on these inflammatory diseases, and affects risk for both Crohn's and colitis. However, how IL-23 initiates intestinal inflammation remains unclear. What are the IL-23 producing cells involved in the development of colitis? And more importantly, what signaling pathways regulate the expression of IL-23 in the intestine? Addressing these questions will certainly help us better understand the immune mechanisms that lead to IBD. To understand the role of IL-23 in colitis, we have generated a new mouse model in which the gene encoding for the Green Fluorescent Protein has been knocked-in in the endogenous IL-23R gene locus, using the method of homologous recombination in ES cells. We believe that this mouse will help us dissect precisely the immune mechanisms involved in CD and identify subsets of cells involved in this disease. The IL-23R GFP reporter model will still be useful, since we can track IL-23 expressing cells by using in vivo imaging and study where these cells are recruited in the intestine during the development of colitis. We could also use this reporter mouse to screen for drugs and treatments that turn off IL-23R expression in the intestine in the near future. The results from this study could lead to the design of drugs more appropriate for the treatment of inflammatory diseases than those currently available.
Multiple Sclerosis is an autoimmune disease in which myelin is the target of an immune attack. It is believed that a subset of cells called regulatory T cells (Tregs) have a major function in preventing the auto-aggressive cells from attacking the self-myelin. What are these protective cells? How are they generated? How do they protect self-myelin from damage? These questions are the focus of my research. These Treg cells do not seem to work effectively in patients with MS. Treatment with ex vivo-generated Tregs has been regarded as a potentially attractive therapeutic approach for autoimmune diseases. However, the dynamics and functions of Treg in autoimmunity are not well understood. We have generated novel genetically engineered mice in which we can visualize and track these Tregs during an ongoing disease in vivo. This novel model has considerably enhanced our understanding of how Tregs are generated in vivo and how they inhibit myelin damage in a mouse model of human MS. We have found that Tregs expand in the peripheral lymphoid compartment and readily accumulate in the central nervous system (CNS), but do not prevent the onset of disease. Tregs isolated from the CNS are effective in suppressing naïve T cells, but fail to control CNS-derived encephalitogenic T cells that secrete IL-6 and TNF. Our data suggests that in order for Tregs to effectively control autoimmune reactions in the target organ, it may also be necessary to control tissue inflammation. These studies are needed before we can envision targeting these innate signaling components for therapeutic benefits.
1. Lazarevic V, Chen X, Shim JH, Hwang ES, Jang E, Bolm AN, Oukka M, Kuchroo VK, Glimcher LH. T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt. Nat Immunol. 2011 Jan;12(1):96-104. Epub 2010 Dec 12.
2. Petermann F, Rothhammer V, Claussen MC, Haas JD, Blanco LR, Heink S, Prinz I, Hemmer B, Kuchroo VK, Oukka M, Korn T. γδ T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism. Immunity. 2010 Sep 24;33(3):351-63. Epub 2010 Sep 9.
3. Kyttaris VC, Zhang Z, Kuchroo VK, Oukka M, Tsokos GC. Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice. J Immunol. 2010 May 1;184(9):4605-9. Epub 2010 Mar 22.
4. Tartar DM, VanMorlan AM, Wan X, Guloglu FB, Jain R, Haymaker CL, Ellis JS, Hoeman CM, Cascio JA, Dhakal M, Oukka M, Zaghouani H. FoxP3+RORgammat+ T helper intermediates display suppressive function against autoimmune diabetes. J Immunol. 2010 Apr 1;184(7):3377-85. Epub 2010 Feb 24.
M.S., Biotechnology, Universite of Paris VI
Ph.D., Immunology, Pasteur Institute, Universite of Paris VI