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Mohamed Oukka, PhD

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Mohamed Oukka, PhD

Children's Title: Principal Investigator

Academic Title: Assistant Professor of Pediatrics / Adjunct Assistant Professor of Immunology, UW School of Medicine

Research Center: Center for Immunity and Immunotherapies

"While training at Harvard, I listened to a young mother, a multiple sclerosis (MS) patient, describe her daily struggle with this terrible disease. I was moved by her words and found myself driven to find a cure for MS. Since then, I have dedicated my scientific career to finding cures for autoimmune diseases and have used my training to develop research on possible treatments and eventual cures for MS. I firmly believe that my work in this field will be crucial for designing better therapies to treat autoimmune diseases. The best reward for my research would be making a positive difference in people’s lives."

Making a Difference

Overview

Clinical Interests

Multiple Sclerosis, Lupus, Crohn's Disease, Cancer

Research Description

Professional History:
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 Seattle Children's Research Institute in 2009, he held positions at Brigham and Women's Hospital and Harvard medical School in Boston.

Research Description:
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. Our novel research model has considerably enhanced our understanding of how Tregs are generated in vivo and how they inhibit myelin damage. 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 naive 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.

Early on in my carreer as molecular immunologist I was struck by people with MS and how their immune systems were attacking their own cells and organs. MS is so striking in young adults and such a debilitating disease. When a young mother has MS and is disabled, taking care of her own kids can be a challenge. MS really affects the whole family. I am interested in applied-science that leads to drug discoveries to help patients. If my research can make a difference in people's lives, for me that's the best reward.

Research Focus Area

Autoimmune Disorders, Immunology

Awards and Honors

Award NameAward DescriptionAwarded ByAward Date
Award RG3882-A1 (PI) - Multiple Sclerosis SocietyNational Multiple Sclerosis SocietyJan. 1, 2009

Publications

γδ T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism.
Immunity , 2010 Sep 24: 351-63
Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice.
Journal of immunology (Baltimore, Md. : 1950) , 2010 May 1: 4605-9
FoxP3+RORgammat+ T helper intermediates display suppressive function against autoimmune diabetes.
Journal of immunology (Baltimore, Md. : 1950) , 2010 Apr 1: 3377-85
Adaptive autoimmunity and Foxp3-based immunoregulation in zebrafish.
PloS one , 2010 Mar 5: e9478
IL-23 receptor regulates unconventional IL-17-producing T cells that control bacterial infections.
Journal of immunology (Baltimore, Md. : 1950) , 2010 Feb 15: 1710-20
Genetic evidence that the differential expression of the ligand-independent isoform of CTLA-4 is the molecular basis of the Idd5.1 type 1 diabetes region in nonobese diabetic mice.
Journal of immunology (Baltimore, Md. : 1950) , 2009 Oct 15: 5146-57
Regulatory T cells in mouse periapical lesions.
Journal of endodontics , 2009 Sep: 1229-33
IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells.
Proceedings of the National Academy of Sciences of the United States of America , 2009 Aug 4: 12885-90
Cutting edge: IL-23 receptor gfp reporter mice reveal distinct populations of IL-17-producing cells.
Journal of immunology (Baltimore, Md. : 1950) , 2009 May 15: 5904-8
TH17 cells and regulatory T cells in primary immunodeficiency diseases.
The Journal of allergy and clinical immunology , 2009 May: 977-83; quiz 984-5
IL-17 producing CD4+ T cells mediate accelerated ischemia/reperfusion-induced injury in autoimmunity-prone mice.
Clinical immunology (Orlando, Fla.) , 2009 Mar: 313-21
IL-17 and Th17 Cells.
Annual review of immunology , 2009: 485-517
Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys.
Journal of immunology (Baltimore, Md. : 1950) , 2008 Dec 15: 8761-6
IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells.
Nature immunology , 2008 Dec: 1347-55
IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells.
Proceedings of the National Academy of Sciences of the United States of America , 2008 Nov 25: 18460-5
Exogenous IFN-gamma ex vivo shapes the alloreactive T-cell repertoire by inhibition of Th17 responses and generation of functional Foxp3+ regulatory T cells.
European journal of immunology , 2008 Sep: 2512-27
Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression.
Journal of immunology (Baltimore, Md. : 1950) , 2008 Aug 15: 2277-84
IL-21 and TGF-beta are required for differentiation of human T(H)17 cells.
Nature , 2008 Jul 17: 350-2
Induction and effector functions of T(H)17 cells.
Nature , 2008 Jun 19: 1051-7
Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor.
Nature , 2008 May 1: 65-71
Th17 cells: effector T cells with inflammatory properties.
Seminars in immunology , 2007 Dec: 362-71
A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells.
Nature immunology , 2007 Dec: 1380-9
Ets-1 is a negative regulator of Th17 differentiation.
The Journal of experimental medicine , 2007 Nov 26: 2825-35
Interplay between pathogenic Th17 and regulatory T cells.
Annals of the rheumatic diseases , 2007 Nov: iii87-90
JAGGED1 and delta1 differentially regulate the outcome of experimental autoimmune encephalomyelitis.
Journal of immunology (Baltimore, Md. : 1950) , 2007 Nov 1: 5990-8
The dynamics of effector T cells and Foxp3+ regulatory T cells in the promotion and regulation of autoimmune encephalomyelitis.
Journal of neuroimmunology , 2007 Nov: 51-60
Reciprocal generation of Th1/Th17 and T(reg) cells by B1 and B2 B cells.
European journal of immunology , 2007 Sep: 2400-4
Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid.
The Journal of experimental medicine , 2007 Aug 6: 1775-85
Anti-thymocyte globulin (ATG) prevents autoimmune encephalomyelitis by expanding myelin antigen-specific Foxp3+ regulatory T cells.
International immunology , 2007 Aug: 1003-10
Dynamics of antigen-specific regulatory T-cells in the context of autoimmunity.
Seminars in immunology , 2007 Aug: 272-8
IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells.
Nature , 2007 Jul 26: 484-7
Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression.
The Journal of experimental medicine , 2007 Jun 11: 1257-65
Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation.
Nature medicine , 2007 Apr: 423-31
T(H)-17 cells in the circle of immunity and autoimmunity.
Nature immunology , 2007 Apr: 345-50

Presentations

Presentations TitleEventLocationDate
Role of Th17 Cells in Autoimmunity15. Department of Rheumatology, University of WashingtonSeattle, WANov. 16, 2009
Interplay Between Th17 and Regulatory T Cells in AutoimmunityForsythe InstituteBoston, MassachusettsJune 4, 2009
Regulatory T Cells and IL-17 Producing Cells in Immunity and Autoimmunity13. Center of Research CHUM-Notre DameMontreal, CanadaMay 21, 2009
Regulatory T Cells and IL-17 Producing Cells in Immunity and Autoimmunity16. Department of Immunology, University of WashingtonSeattle, WAJan. 23, 2009

Primary Office

Seattle Children's Research Institute
JMB - 7 - Immunology
1900 - 9th Ave
Seattle, WA 98101
206-987-7450

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