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Sema4A expressed on hematopoietic cells determines interferon-beta response in Th17 autoimmunity
Author(s): ,
M. Kinoshita
Affiliations:
Department of Neurology
,
T. Okuno
Affiliations:
Department of Neurology
,
A. Namba
Affiliations:
Department of Neurology
,
T. Koda
Affiliations:
Department of Neurology
,
M. Shimizu
Affiliations:
Department of Neurology
,
A. Kumanogoh
Affiliations:
Department of Respiratory Medicine and Clinical Immunology, Osaka University, Suita
,
Y. Nakatsuji
Affiliations:
Toyama University, Toyama, Japan
H. Mochizuki
Affiliations:
Department of Neurology
ECTRIMS Online Library. Kinoshita M. Oct 12, 2018; 228920
Makoto Kinoshita
Makoto Kinoshita
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Abstract: P1079

Type: Poster Sessions

Abstract Category: Pathology and pathogenesis of MS - Immunology

Background: In the context of CNS-targeted autoimmunity, Th1- and Th17-mediated immune responses are implicated in the pathogenesis. Importantly, interferon-beta treatment is postulated to exacerbate Th17-mediated CNS inflammation. However, the precise mechanism as to how Th17 cells accelerate the disease condition under interferon-beta treatment remains elusive.
Objective: Sema4A, the Class IV semaphorin, has previously been reported to be elevated in the serum of patients with multiple sclerosis (MS) resistant to interferon-beta treatment. Thus, in this study we aimed to clarify the pathogenic implication of Sema4A in CNS inflammation under interferon-beta treatment.
Methods: Detailed clinical analysis was performed among 201 patients with MS in correlation to serum Sema4A levels. Serum cytokine and T cell characterization was also conducted in the subgroup. To clarify the exact role of Sema4A in vivo, adoptive transfer of either Th1- or Th17-skewed cells were performed into either wild-type or Sema4A knock-out mice. Bone marrow (BM) chimera mice were also generated to clarify the role of CNS derived Sema4A in the adoptively transferred EAE model. Interferon-beta response was further analyzed in either wild-type or Sema4A knock-out mice.
Results: Serum IL-17A level was significantly higher in patients with MS with high Sema4A levels. Quantitative PCR analysis revealed elevation of ROR gamma t in CD4+ T cells isolated from high Sema4A MS patients. In contrast to Th1-skewed condition, Sema4A knock-out mice transferred with Th17-skewed cells showed amelioration of the clinical score. BM chimera study revealed lack of Sema4A expression in hematopoietic cells showing less severe disease course. Finally, Sema4A knock-out mice showed resistance to Th17-mediated exacerbation under interferon treatment.
Conclusion: Sema4A expressed on hematopoietic cells plays a critical role in Th17-mediated interferon resistance.
Disclosure: Makoto Kinoshita received research grant from Japan Agency for Medical Research and Development, and Grant-in-Aid for Scientific Research.
Tatsusada Okuno received speaker honoraria from Novartis Pharma, Biogen Idec, Takeda Pharmaceuticals, NIHON Pharmaceutical, Japan Blood Products Organization, research grant from Mitsubishi Tanabe Pharma, Novartis Pharma, Takeda science foundation, Japan Agency for Medical Research and Development, and Grant-in-Aid for Scientific Research.
Akiko Namba has nothing to disclose.
Toru Koda has nothing to disclose.
Mikito Shimizu received research grant from Grant-in-Aid for Scientific Research.
Atsushi Kumanogoh received research grant from Japan Agency for Medical Research and Development, Japan Science and Technology Agency, and Grant-in-Aid for Scientific Research.
Yuji Nakatsuji received speaker honoraria from Novartis Pharma, Biogen Idec, Mitsubishi Tanabe Pharma, research grant from Novartis Pharma, Health and Labour Sciences Research Grant, and Japan Agency for Medical Research and Development.
Hideki Mochizuki received speaker honoraria from AbbVie, FP Pharmaceutical, KyowaHakko Kirin, Otsuka Pharmaceutical, GlaxoSmithKline, Sumitomo Dainippon Pharma, NIHON PHARMACEUTICAL, Boehringer Ingelheim, Novartis Pharma, research grant from Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research, and Health and Labour Sciences Research Grant.

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