PI: Dr. Mohamed Oukka
Location: Seattle Children’s Research Institute, UW Immunology
Website: https://www.seattlechildrens.org/medical-staff/Mohamed-Oukka/

Engineering protein mimics to treat autoimmune diseases

Multiple sclerosis is an autoimmune disease, which results from the autoimmune attack of myelin-reactive T cells and recruitment of other immune cells in the central nervous system (CNS) and progressive demyelination.Tysabri and Fingolimod are two leading drugs that are currently approved for the treatment of Multiple Sclerosis (MS). Both of these drugs mediate their effects by blocking the migration of immune cells to the CNS. Whereas Tysabri, a monoclonal antibody specific to alpha integrin alpha 4 (one of the subunits of tVLa4) blocks the entry of cells to the CNS, the oral agent Fingolimod (Gilenya), a Sphingosine-1-phosphate (S1P) analogue approved for relapsing Multiple Sclerosis, inhibits the egress of immune cells from the lymphoid organs. While both therapies are effective, they have life-threatening side effects. Tysabri has been associated with the development of progressive multifocal leukoencephalopathy (PML), a rare infection of the CNS by the JC virus. MS patients treated with Fingolimod are at risk of developing cardiovascular diseases and a subset of patients develop severe relapses and even lesions that resemble brain tumors.Multiple sclerosis (MS), and its mouse model (experimental autoimmune encephalomyelitis; EAE) are autoimmune diseases of the central nervous system initiated and propagated by auto-reactive CD4+ T cells. Th17 T cells, a subset of CD4 T cells that produce the cytokine IL-17, are potent inducers of autoimmune diseases and are strongly implicated in the pathogenicity of multiple sclerosis. Murine studies where this population is lost demonstrate a protective effect and Th17 cells increase in frequency in MS patients with active disease. However, precise mechanisms by which Th17 cells fulfill their pathogenic functions remain elusive. We have found that Th17 cells migrate quickly and accumulate in the CNS in mice immunized with myelin antigen prior to the onset of EAE.  This suggests that Th17 cells might be necessary for initiating the inflammatory processes that occur in the brain of MS patients. IL-23 is another cytokine critically involved in the generation of Th17 cells. IL-23 is a heterodimer composed of IL12/23p40 and IL-23p19. IL-23 is a key mediator of CNS autoimmune disease and functions by promoting survival and expansion of Th17 cells. Based upon these combined findings, we predict that agents capable of specifically blocking the function or the migration of Th17 may offer a new avenue to treat and limit inflammation that occurs in MS. We propose to use protein engineering to generate novel therapeutics for MS that will specifically antagonize the function of IL-17 and IL-23.