Monoclonal antibodies against CD20 are a highly effective therapy for multiple sclerosis (MS) currently in phase III clinical development. CD20 is commonly viewed as an archetypical B cell marker. However, a subset of human T lymphocytes (T cells) also expresses CD20. Presently, not much is known about the functional or pathological relevance of CD20-expressing T cells, but a possible involvement of this T cell subpopulation in autoimmune disorders has been suggested. CD20+ T cells can assume a pro-inflammatory Th17 phenotype in rheumatoid arthritis (RA) and MS, and increased numbers of CD3+CD20dim T cells can be found in peripheral blood (PB) of MS patients. Like CD20+ B cells, CD3+CD20dim T cells are effectively depleted from PB of MS and RA patients by the anti-CD20 antibody rituximab, which may, in part, be responsible for the effectiveness of anti-CD20 therapeutic strategies. Unpublished preliminary experiments suggest that CD3+CD20dim T cells in PB may be increased during MS relapses; CD20-expressing T cells are also present in CSF but an association with disease-activity has yet to be studied. Furthermore, next-generation deep T cell receptor -chain variable region (TCR-V) immune-repertoire sequencing suggests that identical CD20dim T cell clonotypes in peripheral blood and CSF may be involved in MS disease-activity. To our knowledge, no murine equivalent to human CD3+CD20dim T cells has been identified. However, treatment of mice with an antibody specific for MS4aB1, a murine CD20 homolog expressed on T cells, was found to ameliorate disease severity of experimental autoimmune encephalomyelitis (EAE), theoretically mimicking the therapeutic effect of rituximab-mediated CD3+CD20dim T cell depletion, in the absence of B cell depletion, in humans. The objective of this research program is to delineate the potential pathological involvement of CD3+CD20dim T cells in the immune pathology of MS. Methods: We will perform extensive phenotypic, transcriptional, and functional characterizations of CD20+ T cells in PB (Aim 1), to examine whether CD20+ T cells and/or other T cell subsets can provide an antigen-specific, immunologically active, and sustained connection between the periphery and CNS compartments (Aim 2), and to determine their prevalence in MS CSF during different stages of the disease (Aim 2) and compared to other neurological diseases (Aim 3).

Public Health Relevance

Therapeutic monoclonal antibodies against CD20 mainly target B lymphocytes for destruction and are highly effective therapies for multiple sclerosis (MS) that will likely become available in 2015. However, CD20 is also expressed on a previously mostly neglected, small but not negligible subpopulation of T lymphocytes. This project seeks to determine in how far CD20-expressing T cells are involved in the autoimmune attack against myelin of the central nervous system in MS, to understand whether targeted depletion of this lymphocyte subset may represent a viable novel therapeutic option for MS with a potentially superior safety profile.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS092835-02
Application #
9127811
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Utz, Ursula
Project Start
2015-08-15
Project End
2020-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Zamvil, Scott S; Spencer, Collin M; Baranzini, Sergio E et al. (2018) The Gut Microbiome in Neuromyelitis Optica. Neurotherapeutics 15:92-101
Greenfield, Ariele L; Hauser, Stephen L (2018) B-cell Therapy for Multiple Sclerosis: Entering an era. Ann Neurol 83:13-26
Ryu, Jae Kyu; Rafalski, Victoria A; Meyer-Franke, Anke et al. (2018) Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration. Nat Immunol 19:1212-1223
Cruz-Herranz, Andrés; Sagan, Sharon A; Sobel, Raymond A et al. (2017) T cells targeting neuromyelitis optica autoantigen aquaporin-4 cause paralysis and visual system injury. J Nat Sci 3:
Sagan, Sharon A; Cruz-Herranz, Andrés; Spencer, Collin M et al. (2017) Induction of Paralysis and Visual System Injury in Mice by T Cells Specific for Neuromyelitis Optica Autoantigen Aquaporin-4. J Vis Exp :
Eggers, Erica L; Michel, Brady A; Wu, Hao et al. (2017) Clonal relationships of CSF B cells in treatment-naive multiple sclerosis patients. JCI Insight 2:
Lehmann-Horn, Klaus; Wang, Sheng-Zhi; Sagan, Sharon A et al. (2016) B cell repertoire expansion occurs in meningeal ectopic lymphoid tissue. JCI Insight 1:e87234
Tremlett, Helen; Fadrosh, Douglas W; Faruqi, Ali A et al. (2016) Associations between the gut microbiota and host immune markers in pediatric multiple sclerosis and controls. BMC Neurol 16:182
Papinutto, Nico; Schlaeger, Regina; Panara, Valentina et al. (2015) 2D phase-sensitive inversion recovery imaging to measure in vivo spinal cord gray and white matter areas in clinically feasible acquisition times. J Magn Reson Imaging 42:698-708
Palanichamy, Arumugam; Apeltsin, Leonard; Kuo, Tracy C et al. (2014) Immunoglobulin class-switched B cells form an active immune axis between CNS and periphery in multiple sclerosis. Sci Transl Med 6:248ra106

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