Research Focus: Neuroinflammation in damage and repair relevant to multiple sclerosis and other nervous system disorders.
Multiple Sclerosis (MS) is the most common neurological disease of young adults in Canada, and second only to trauma as the most debilitating. Affecting more than 75,000 Canadians, symptoms include altered sensation, loss of balance, disturbances of vision or speech, extreme fatigue, muscle weakness or paralysis as well as depression and cognitive dysfunction. MS is a central nervous system (CNS) chronic inflammatory and demyelinating neurodegenerative disorder, characterized by microvascular alterations, inflammatory infiltrates, demyelination, glial scarring, oligodendrocyte loss, and ultimately disability secondary to axonal damage and loss. Current disease modifying therapies for MS target inflammatory processes and fall into two groups: those well tolerated with only partial efficacy, or those with greater efficacy but increased risk profiles.
Therapies with immunomodulatory as well as neuroprotective capabilities have the greatest promise in treating and preventing the disability attributed to inflammatory demyelination and neurodegeneration. Current projects apply molecular and cellular techniques in cell based and disease models to study the relative contributions of inflammatory cells and mediators to disease development, with particular emphasis on the following:
Quandt JA, Huh J, Baig M, Yao K, Ito N, Bryant M, Kawamura K, Pinilla C, McFarland HF, Martin R, Ito K. Humanized models support the etiologic role of DRB5*0101 in multiple sclerosis. J Immunol In Press
Li X, Johnson K, Bryant M, Elkahloun AG, Amar M, Remaley AT, De Silva R, Hallenbeck JM, Quandt JA. Intranasal Delivery of E-selectin Reduces Atherosclerosis in ApoE-/-Mice. PLOS one. 2011 6(6):e20620
Kawamura K, Yao K, Quandt JA, Huh J, Baig M, Quigley L, Ito N, Necker A, McFarland HF, Muraro PA, Martin R, Ito K. Different development of myelin basic protein agonist- and antagonist-specific human TCR transgenic T cells in the thymus and periphery. J Immunol. 2008 Oct 15;181(8):5462-72.
Cassiani-Ingoni R, Muraro PA, Magnus T, Reichert-Scrivner S, Schmidt J, Huh J, Quandt JA, Bratincsak A, Shahar T, Eusebi F, Sherman LS, Mattson MP, Martin R, Rao MS. Disease progression after bone marrow transplantation in a model of multiple sclerosis is associated with chronic microglial and glial progenitor response. J Neuropathol Exp Neurol. 2007 Jul;66(7):637-49.
Gelderblom H, Londoņo D, Bai Y, Cabral ES, Quandt J, Hornung R, Martin R, Marques A, Cadavid D. High production of CXCL13 in blood and brain during persistent infection with the relapsing fever spirochete Borrelia turicatae. J Neuropathol Exp Neurol. 2007 Mar;66(3):208-17.
Gelderblom H, Schmidt J, Londoņo D, Bai Y, Quandt J, Hornung R, Marques A, Martin R, Cadavid D. Role of interleukin 10 during persistent infection with the relapsing fever Spirochete Borrelia turicatae. Am J Pathol. 2007 Jan;170(1):251-62.
Lünemann JD, Gelderblom H, Sospedra M, Quandt JA, Pinilla C, Marques A, Martin R. Cerebrospinal fluid-infiltrating CD4+ T cells recognize Borrelia burgdorferi lysine-enriched protein domains and central nervous system autoantigens in early lyme encephalitis. Infect Immun. 2007 Jan;75(1):243-51.
Li Y, Huang Y, Lue J, Quandt JA, Martin R, Mariuzza RA. Structure of a human autoimmune TCR bound to a myelin basic protein self-peptide and a multiple sclerosis-associated MHC class II molecule. EMBO J. 2005 Sep 7;24(17):2968-79.
Quandt JA, Baig M, Yao K, Kawamura K, Huh J, Ludwin SK, Bian HJ, Bryant M, Quigley L, Nagy ZA, McFarland HF, Muraro PA, Martin R, Ito K. Unique clinical and pathological features in HLA-DRB1*0401-restricted MBP 111-129-specific humanized TCR transgenic mice. J Exp Med. 2004 Jul 19;200(2):223-34.
Anderson SA, Shukaliak-Quandt J, Jordan EK, Arbab AS, Martin R, McFarland H, Frank JA. Magnetic resonance imaging of labeled T-cells in a mouse model of multiple sclerosis. Ann Neurol. 2004 May;55(5):654-9.
Shukaliak-Quandt J, Borras E, Prat E, Gelderblom H, Houghten RA, Kashani A, Pinilla C, Stuerzebecher CS, Martin R. Peptidic complex mixtures as therapeutic agents in CNS autoimmunity. Mol Immunol. 2004 Feb;40(14-15):1075-87.
Shukaliak-Quandt JA, Dorovini-Zis K, Wu V, Prameya R. The beta chemokines CCL4 and CCL5 enhance adhesion of specific CD4+ T cell subsets to human brain endothelial cells (HBMEC) in vitro. J Neuropath Exp Neurol 2004 63:350-362.