TY - JOUR
T1 - Differential reconstitution of T cell subsets following immunodepleting treatment with alemtuzumab (anti-CD52 monoclonal antibody) in patients with relapsing-remitting multiple sclerosis
AU - Zhang, Xin
AU - Tao, Yazhong
AU - Chopra, Manisha
AU - Ahn, Mihye
AU - Marcus, Karen L.
AU - Choudhary, Neelima
AU - Zhu, Hongtu
AU - Markovic-Plese, Silva
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2013/12/15
Y1 - 2013/12/15
N2 - Alemtuzumab (anti-CD52 mAb) provides long-lasting disease activity suppression in relapsing-remitting multiple sclerosis (RRMS). The objective of this study was to characterize the immunological reconstitution of T cell subsets and its contribution to the prolonged RRMS suppression following alemtuzumab-induced lymphocyte depletion. The study was performed on blood samples from RRMS patients enrolled in the CARE-MS II clinical trial, which was recently completed and led to the submission of alemtuzumab for U.S. Food and Drug Administration approval as a treatment for RRMS. Alemtuzumab-treated patients exhibited a nearly complete depletion of circulating CD4+ lymphocytes at day 7. During the immunological reconstitution, CD4 +CD25+CD127low regulatory T cells preferentially expanded within the CD4+ lymphocytes, reaching their peak expansion at month 1. The increase in the percentage of TGF-β1-, IL-10-, and IL-4-producing CD4+ cells reached a maximum at month 3, whereas a significant decrease in the percentages of Th1 and Th17 cells was detected at months 12 and 24 in comparison with the baseline. A gradual increase in serum IL-7 and IL-4 and a decrease in IL-17A, IL-17F, IL-21, IL-22, and IFN-γ levels were detected following treatment. In vitro studies have demonstrated that IL-7 induced an expansion of CD4+CD25 +CD127low regulatory T cells and a decrease in the percentages of Th17 and Th1 cells. In conclusion, our results indicate that differential reconstitution of T cell subsets and selectively delayed CD4 + T cell repopulation following alemtuzumab-induced lymphopenia may contribute to its long-lasting suppression of disease activity.
AB - Alemtuzumab (anti-CD52 mAb) provides long-lasting disease activity suppression in relapsing-remitting multiple sclerosis (RRMS). The objective of this study was to characterize the immunological reconstitution of T cell subsets and its contribution to the prolonged RRMS suppression following alemtuzumab-induced lymphocyte depletion. The study was performed on blood samples from RRMS patients enrolled in the CARE-MS II clinical trial, which was recently completed and led to the submission of alemtuzumab for U.S. Food and Drug Administration approval as a treatment for RRMS. Alemtuzumab-treated patients exhibited a nearly complete depletion of circulating CD4+ lymphocytes at day 7. During the immunological reconstitution, CD4 +CD25+CD127low regulatory T cells preferentially expanded within the CD4+ lymphocytes, reaching their peak expansion at month 1. The increase in the percentage of TGF-β1-, IL-10-, and IL-4-producing CD4+ cells reached a maximum at month 3, whereas a significant decrease in the percentages of Th1 and Th17 cells was detected at months 12 and 24 in comparison with the baseline. A gradual increase in serum IL-7 and IL-4 and a decrease in IL-17A, IL-17F, IL-21, IL-22, and IFN-γ levels were detected following treatment. In vitro studies have demonstrated that IL-7 induced an expansion of CD4+CD25 +CD127low regulatory T cells and a decrease in the percentages of Th17 and Th1 cells. In conclusion, our results indicate that differential reconstitution of T cell subsets and selectively delayed CD4 + T cell repopulation following alemtuzumab-induced lymphopenia may contribute to its long-lasting suppression of disease activity.
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U2 - 10.4049/jimmunol.1301926
DO - 10.4049/jimmunol.1301926
M3 - Article
C2 - 24198283
AN - SCOPUS:84890400796
SN - 0022-1767
VL - 191
SP - 5867
EP - 5874
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -