Contributions
Abstract: EP1614
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - 25 Biomarkers
Background: Interferon-beta (IFN-β) is one of the first-line therapies in relapsing-remitting multiple sclerosis (RRMS) and one-third of patients are poor responders to this therapy. We previously reported that a class IV semaphorin (Sema4A) is increased in the sera of MS patients, those with high Sema4A do not respond well to IFN-β therapy. Although Correlation between Sema4A and Mammalian target of rapamycin (mTOR) signaling in CD8+ T cells has been shown recently, the relationship in CD4+ T cells has not been unknown.
Goals: In this study, we confirmed reproducibility of our previous study in larger cohort and evaluate new outcome measure of MS. In addition, we tried to reveal the mechanism by which Sema4A inhibits the therapeutic effect of IFN-β.
Methods: This study examined 201 RRMS patients (58 facilities in Japan) who met the MacDonald criteria 2010. Serum Sema4A levels were examined using sandwich ELISA. We also evaluated clinical severity of 48 RRMS patients receiving IFN-β therapy. To analyze the effect of Sema4A in CD4+ T cell differentiation, we stimulated coculture of human CD4+ and CD14+ cells with recombinant Sema4A.
Results: MS patients with high serum Sema4A tended to have earlier age of onset, higher annual relapse ratio, and more severe EDSS score change than those with low Sema4A. No significant differences were found in positive ratio of oligoclonal immunoglobulin G bands and distribution of brain MRI lesions. A total of 9 of 28 (32.1%) patients with low Sema4A achieved remission status after 5 years from start IFN-β therapy, but only 1 of 12 (8.3%) patients with high Sema4A did. When we differentiated human CD4+ T cells, Sema4A promoted phosphorylation of mTOR (Ser2448) and ribosomal protein S6 kinase beta-1 (S6K1) which acts downstream of mTORC1 pathway. Moreover, Sema4A increased the proportion of both Th1 and Th17 cells, which was canceled by rapamycin, mTOR inhibitor.
Conclusion: Our results suggest that high serum Sema4A correlates with IFN-β resistance in RRMS patients by activation of mTOR signaling.
Disclosure:
Akiko Hosokawa Namba: nothing to disclose
Tatsusada Okuno: nothing to disclose
Toru Koda: nothing to disclose
Kazuya Yamashita: nothing to disclose
Mikito Shimizu: nothing to disclose
Makoto Kinoshita: nothing to disclose
Atsushi Kumanogoh: nothing to disclose
Yusei Miyazaki: nothing to disclose
Masaaki Niino: nothing to disclose
Katsuichi Miyamoto: nothing to disclose
Yuji Nakatsuji: nothing to disclose
Hideki Mochizuki: nothing to disclose
Abstract: EP1614
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - 25 Biomarkers
Background: Interferon-beta (IFN-β) is one of the first-line therapies in relapsing-remitting multiple sclerosis (RRMS) and one-third of patients are poor responders to this therapy. We previously reported that a class IV semaphorin (Sema4A) is increased in the sera of MS patients, those with high Sema4A do not respond well to IFN-β therapy. Although Correlation between Sema4A and Mammalian target of rapamycin (mTOR) signaling in CD8+ T cells has been shown recently, the relationship in CD4+ T cells has not been unknown.
Goals: In this study, we confirmed reproducibility of our previous study in larger cohort and evaluate new outcome measure of MS. In addition, we tried to reveal the mechanism by which Sema4A inhibits the therapeutic effect of IFN-β.
Methods: This study examined 201 RRMS patients (58 facilities in Japan) who met the MacDonald criteria 2010. Serum Sema4A levels were examined using sandwich ELISA. We also evaluated clinical severity of 48 RRMS patients receiving IFN-β therapy. To analyze the effect of Sema4A in CD4+ T cell differentiation, we stimulated coculture of human CD4+ and CD14+ cells with recombinant Sema4A.
Results: MS patients with high serum Sema4A tended to have earlier age of onset, higher annual relapse ratio, and more severe EDSS score change than those with low Sema4A. No significant differences were found in positive ratio of oligoclonal immunoglobulin G bands and distribution of brain MRI lesions. A total of 9 of 28 (32.1%) patients with low Sema4A achieved remission status after 5 years from start IFN-β therapy, but only 1 of 12 (8.3%) patients with high Sema4A did. When we differentiated human CD4+ T cells, Sema4A promoted phosphorylation of mTOR (Ser2448) and ribosomal protein S6 kinase beta-1 (S6K1) which acts downstream of mTORC1 pathway. Moreover, Sema4A increased the proportion of both Th1 and Th17 cells, which was canceled by rapamycin, mTOR inhibitor.
Conclusion: Our results suggest that high serum Sema4A correlates with IFN-β resistance in RRMS patients by activation of mTOR signaling.
Disclosure:
Akiko Hosokawa Namba: nothing to disclose
Tatsusada Okuno: nothing to disclose
Toru Koda: nothing to disclose
Kazuya Yamashita: nothing to disclose
Mikito Shimizu: nothing to disclose
Makoto Kinoshita: nothing to disclose
Atsushi Kumanogoh: nothing to disclose
Yusei Miyazaki: nothing to disclose
Masaaki Niino: nothing to disclose
Katsuichi Miyamoto: nothing to disclose
Yuji Nakatsuji: nothing to disclose
Hideki Mochizuki: nothing to disclose