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Understanding the role of antigen presenting cells in MS patients and the impact of the different treatments over the innate immunity

Grant number: 13/11959-7
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): December 01, 2013
Effective date (End): November 30, 2014
Field of knowledge:Health Sciences - Medicine
Principal researcher:LEONILDA MARIA BARBOSA DOS SANTOS
Grantee:Felipe von Glehn Silva
Supervisor abroad: Howard L. Weiner
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Research place: Harvard University, Boston, United States  
Associated to the scholarship:13/00550-0 - Impact of Cerebrospinal Fluid Oligoclonal Bands Disappearance in Patients with Multiple Sclerosis treated with Natalizumab: evaluation of clinical, radiological and immunological aspects associated with JC virus infection stratification., BP.PD

Abstract

In the last years, several effective medications were introduced on the market, called disease modifying therapies, e.g. recombinant interferon beta (INF-²) and glatiramer acetate (GA), but they have a partial control on multiple sclerosis (MS). In 2006, a monoclonal humanized antibody (Natalizumab) that binds to alpha-4 subunit of integrins expressed on activated T cells surface showed a superior efficacy compared to the existing therapies. However, this treatment is associated with a serious side effect, which is the risk of development of progressive multifocal leukoencephalopathy (PML) caused by the JC virus. Natalizumab hinders the migration of T auto-reactive cells across the blood brain barrier to CNS, reducing inflammatory response. Recently, we described the disappearance of cerebrospinal fluid IgG oligoclonal bands (CSF OCB) of natalizumab treated patients. This is interesting because CSF OCB persists during disease clinical course and no existing treatment demonstrated to interfere with its production. We do not know yet the clinical implication of this BOC disappearance, but it may be linked to a down regulation of the inflammatory response, inactivating the antigen presenting cells (e.g. B cells and dendritic cells) or to an increased risk to CNS JC virus infection. Besides producing autoantibodies, B cells can function as professional antigen-presenting cells, able to activate CD4+ T-cell-specific responses through MHC class II, which contribute to the inflammatory response in MS. Moreover, B cells also influence the T-cell response through cytokine and chemokine production. Recent necropsies studies have shown a linkage of the adjacent cortical atrophy and demyelination lesions to B cells pseudo follicular structures that rise at pia-mater during disease course. This study aim to determine the function of pDCs, mDCs and B cells as antigen presenting cells, driving the inflammatory autoimmune disease. These cells will be compared between health controls, untreated and treated MS patients. Special interest will be given to natalizumab treated patients to determine the possible mechanisms involved in B and T cells interaction leading to CSF OCB disappearance. (AU)

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