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Research InterestsMultiple sclerosis (MS) is an autoimmune disease of central nervous system myelin affecting individuals in their prime. Experimental autoimmune encephalomyelitis (EAE) is the animal model for MS, it is used to understand the immune interactions in MS and many therapies that are used in MS are initially validated in EAE.
I. Studies in EAE: Studies in the animal model are directed towards investigating various approaches to induce tolerance and potential approaches that may lead to new therapies for MS.
II. Studies In MS Patients: In multiple sclerosis patients the research is focused on generating immunologic assays that reflect disease activity and that may be used to measure response to treatments. We found that the frequency of IL-12 (a cytokine produced by activated macrophages and dendritic cells) producing monocytes in untreated MS patients was higher than in controls. Furthermore, IL-12 expression segregated with the disease activity. Many of these studies are included as part of clinical trials in the Autoimmunity Centers of Excellence (Principal Investigator: Khoury)
- Investigating the role of Th1 versus Th.2 cells in the pathogenesis of EAE.
- Costimulatory pathways in EAE and how they can be manipulated to treat EAE.
- Mechanisms of axonal pathology in EAE 4. Role of stem/progenitor cells in recovery from disease.
- Mechanistic studies related to the ongoing clinical trials: treatment of MS patients with Copaxone/albuterol, oral interferon-tau, and CTLA4Ig
- Longitudinal studies of patients treated with immunomodulatory therapies
- Correlation of immunologic markers with MRI and clinical disease activity
Comabella M, Balashov K, Issazadeh S, Smith D, Weiner HL, and Khoury SJ. Elevated Interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy. J. Clin. Invest. 1998:102:671-678.
Chitnis T, Najafian N, Abdallah KA, Dong V, Yagita H, Sayegh MH, and Khoury SJ. CD28 independent induction of experimental autoimmune encephalomyelitis. J. Clin. Invest. 2001; 107: 575-583.
Chitnis, T., N. Najafian, C. Benou, A.D.G. Salama, M. J., M.H. Sayegh, and S.J. Khoury. Effect of targeted disruption of STAT4 and STAT6 genes on the induction of experimental autoimmune encephalomyelitis. J. Clin. Invest. 2001; 108:739-74.
De Jager PL, Rossin E, Pyne S, Tamayo P, Ottoboni L, Viglietta V, Weiner M, Soler D, Izmailova E, Faron-Yowe L, O'Brien C, Freeman S, Granados S, Parker A, Roubenoff R, Mesirov JP, Khoury SJ, Hafler DA, Weiner HL. Cytometric profiling in multiple sclerosis uncovers patient population structure and a reduction of CD8low cells. Brain. 2008 Jul;131(Pt 7):1701-11.
Elyaman W, Kivisäkk P, Reddy J, Chitnis T, Raddassi K, Imitola J, Bradshaw E, Kuchroo VK, Yagita H, Sayegh MH, Khoury SJ. Distinct functions of autoreactive memory and effector CD4+ T cells in experimental autoimmune encephalomyelitis. Am J Pathol. 2008 Aug;173(2):411-22. PMC2475778
Villoslada P, Moreno B, Melero I, Pablos JL, Martino G, Uccelli A, Montalban X, Avila J, Rivest S, Acarin L, Appel S, Khoury SJ, McGeer P, Ferrer I, Delgado M, Obeso J, Schwartz M. Immunotherapy for neurological diseases. Clin Immunol. 2008 Sep;128(3):294-305.
Liptak Z, Berger AM, Sampat MP, Charil A, Felsovalyi O, Healy BC, Hildenbrand P, Khoury SJ, Weiner HL, Bakshi R, Guttmann CR. Medulla oblongata volume: a biomarker of spinal cord damage and disability in multiple sclerosis. AJNR Am J Neuroradiol. 2008 Sep;29(8):1465-70.
Viglietta V, Bourcier K, Buckle GJ, Healy B, Weiner HL, Hafler DA, Egorova S, Guttmann CR, Rusche JR, Khoury SJ. CTLA4Ig treatment in patients with multiple sclerosis: an open-label, phase 1 clinical trial. Neurology. 2008 Sep 16;71(12):917-24.
Pluchino S, Muzio L, Imitola J, Deleidi M, Alfaro-Cervello C, Salani G, Porcheri C, Brambilla E, Cavasinni F, Bergamaschi A, Garcia-Verdugo JM, Comi G, Khoury SJ, Martino G. Persistent inflammation alters the function of the endogenous brain stem cell compartment. Brain. 2008 Oct;131(Pt 10):2564-78. PMC2570715
Wang Y, Imitola J, Rasmussen S, O'Connor KC, Khoury SJ. Paradoxical dysregulation of the neural stem cell pathway sonic hedgehog-Gli1 in autoimmune encephalomyelitis and multiple sclerosis. Ann Neurol. 2008 Oct;64(4):417-27.
Bakshi R, Neema M, Healy BC, Liptak Z, Betensky RA, Buckle GJ, Gauthier SA, Stankiewicz J, Meier D, Egorova S, Arora A, Guss ZD, Glanz B, Khoury SJ, Guttmann CR, Weiner HL. Predicting clinical progression in multiple sclerosis with the magnetic resonance disease severity scale. Arch Neurol. 2008 Nov;65(11):1449-53.
Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel RA, Mitsdoerffer M, Strom TB, Elyaman W, Ho IC, Khoury SJ, 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.
Quintana FJ, Farez MF, Viglietta V, Iglesias AH, Merbl Y, Izquierdo G, Lucas M, Basso AS, Khoury SJ, Lucchinetti CF, Cohen IR, Weiner HL. Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis. Proc Natl Acad Sci USA. 2008 Dec 2;105(48):18889-94. PMC2596207