Mohamed Oukka , Ph.D.
Assistant Professor, Pediatrics
Adjunct Assistant Professor, Immunology

Department of Pediatrics, University of Washington
Center for Immunity and Immunotherapies
Seattle Children's Research Institute, C9S-7 Immunology
1900 9th Avenue
Box 359300-C9S-6
Seattle, WA 98101
Tel: 206.987-7450
Email: moukka@u.washington.edu

Clinical Interests: Multiple Sclerosis, Lupus, Crohn's Disease, Cancer, Infectious Diseases

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.

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.

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 function 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 suggest that in order for Tregs to effectively control autoimmune reactions in the target organ, it may also be necessary to control tissue inflammation.

Now we have ongoing studies focused on elucidating the specific mechanisms by which Tregs fulfill their suppressive function and identifying mechanisms by IL-6 produced during inflammation that inhibit Treg functions.  The mechanisms that enhance and those that inhibit functions of Treg cells will have direct impact on developing potential immunomodulatory therapies for autoimmunity. 

Selected Publications:

Oukka M, Cohen-Tannoudji M, Tanaka Y, Babinet C, Kosmatopoulos K. Medullary thymic epithelial cells induce tolerance to intracellular proteins. J Immunol. 1996; 156: 968-975.

Oukka M, Colucci-Guyon E, Tran PL, Cohen-Tannoudji M, Babinet C, Lotteau V, Kosmatopoulos K. CD4 T cell tolerance to nuclear proteins induced by medullary thymic epithelium. Immunity. 1996; 4:545-553.

Oukka M, Ho IC, de la Brousse FC, Hoey T, Grusby MJ, Glimcher LH. The transcription factor NFAT4 is involved in the generation and survival of T cells. Immunity. 1998; 9:295-304.

Oukka M, Kim ST, Lugo G, Sun J, Wu LC, Glimcher LH. A mammalian homolog of Drosophila schnurri, KRC, regulates TNF receptor-driven responses and interacts with TRAF2. Mol Cell. 2002; 9:121-131.

Oukka M, Wein MN, Glimcher LH. Schnurri-3 (KRC) interacts with c-Jun to regulate the IL-2 gene in T cells. J Exp Med. 2004; 199:15-24.

Bettelli E, Dastrange M, Oukka M.  Foxp3 interacts with nuclear factor of activated T cells and NF-kB to repress cytokine gene expression and effector functions of T helper cells.  Proc Natl Acad Sci USA. 2005; 102:5138-5143.

Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK. Reciprocal developmental pathways for the generation of pathogenic effector T(H)17 and regulatory T cells.  Nature. 2006; 441:235-238.

Korn T, Reddy J, Gao W, Bettelli E, Awasthi A, Petersen TR, Backstrom BT, Sobel RA, Wucherpfennig KW, Strom TB, Oukka M*, Kuchroo VK*. Nat Med. 2007 Apr;13(4):423-31. Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat Med. 2007 Apr;13 (4):423-431. Mohamed Oukka and Vijay Kuchroo share the last authorship. . (* Corresponding authors)

Korn T, Bettelli E, Gao W, Awasthi A, Jaeger A, Strom TB, Oukka M*, Kuchroo VK*.  Il-21 initiates an alternate pathway to induce proinflammatory Th17 cells. Nature, 2007 Jul 26 448(7152): 484-487.  (* Corresponding authors)

Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, Belkaid Y. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T-reg cells via retinoic acid.  J Exp Med. 2007 Aug 6; 204(8): 1775-1785.

Moisan J, Grenninloh R, Bettelli E, Oukka M, I-Cheng Ho. ETS1 is negative regulator of Th17 differentiation, J Exp Med 2007, Nov 26 (12): 2825-2835.

Awasthi A, Carrier Y, Peron JP, Bettelli E, Kamanaka M, Flavell R, Kuchroo VK, Oukka M*, Weiner HL*. A dominant role of Interleukin 27 in generating Interleukin 10 producing anti-inflammatory T cells. Nature Immunol. 2007, Dec 08 (12), 1380-1389. Mohamed Oukka and Howard Weiner share the last authorship. (* Corresponding authors)

Quintana F, Basso1 A,  Iglesias A, Korn T, Farez M,  Bettelli E,  Caccamo M,  Oukka M Weiner H.L. Control of Treg and Th17 cells by AHR. Nature. 2008 May1; 453: 65-71.

 Yang L, Anderson DE, Baecher Allan C, Hastings W Bettelli E, Oukka M, Kuchroo VK, Hafler DA. IL-21 and TGF-β are required for differentiation of Human Th17. Nature July 17, 454 (7202): 350-352.

Korn T, Oukka M. Dynamics of antigen-specific regulatory T-cells in the context of autoimmunity. Semin Immunol. 2007 Aug;19(4):272-8. Epub 2007 Apr 16.

Oukka M. TH17 cells and Regulatory T cells in autoimmunity. Ann Rheum Dis. 2008 Dec;67 Suppl 3:iii26-29.

 Korn T, Mitsdoerffer M, Croxford AL, Awasthi A, Dardalhon VA, Galileos G, Vollmar P, Stritesky GL, Kaplan MH, Waisman A, Kuchroo VK, Oukka M. IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells.Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18460-5. Epub 2008 Nov 17.

Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel RA, Mitsdoerffer M, Strom TB, Elyaman W, Ho IC, Khoury S, Oukka M*, Kuchroo VK*. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat Immunol. 2008 Dec;9(12):1347-55. Epub 2008 Nov 9. (* Corresponding authors).

Awasthi A, Riol-Blanco L, Jäger A, Korn T, Pot C, Galileos G, Bettelli E, Kuchroo VK, Oukka M. IL-23 receptor gfp reporter mice reveal distinct populations of IL-17 producing cells. Cutting edge J.Immunol. 2009 May 15 (10): 5904-5908.

Riol-Blanco L, Lazarevic V, Awasthi A, Mitsdoerffer M, Wilson BS, Croxford A, Waisman A, Kuchroo VK, Glimcher LH, Oukka M.  IL-23 receptor regulates unconventional IL-17-producing T cells that control bacterial infections.  J. Immunol. 2010 Feb 15;184(4):1710-20.  Epub 2010 Jan 18.

Posted 2/9/10