Effect of Ocrelizumab on B- and T-Cell Receptor Repertoire Diversity in Patients With Relapsing Multiple Sclerosis From the Randomized Phase III OPERA Trial.

Autor:	Laurent SA; From the Department of Neurology (S.A.L., E.L.E., H.W., B.M., S.D., A.P., M.R.W., B.A.C.C., H.-C.B.), Weill Institute for Neurosciences; Biomedical Sciences Graduate Program (N.B.S.); Bakar Computational Health Sciences Institute and Department of Pediatrics (M.S.); Department of Bioengineering and Therapeutic Sciences (R.D.H.), University of California, San Francisco, CA; Department of Human Genetics (R.D.H.), McGill University, Montreal, QC, Canada; and OMNI Biomarker Development (A.E.H.), Genentech, Inc., South San Francisco, CA., Strauli NB; From the Department of Neurology (S.A.L., E.L.E., H.W., B.M., S.D., A.P., M.R.W., B.A.C.C., H.-C.B.), Weill Institute for Neurosciences; Biomedical Sciences Graduate Program (N.B.S.); Bakar Computational Health Sciences Institute and Department of Pediatrics (M.S.); Department of Bioengineering and Therapeutic Sciences (R.D.H.), University of California, San Francisco, CA; Department of Human Genetics (R.D.H.), McGill University, Montreal, QC, Canada; and OMNI Biomarker Development (A.E.H.), Genentech, Inc., South San Francisco, CA., Eggers EL; From the Department of Neurology (S.A.L., E.L.E., H.W., B.M., S.D., A.P., M.R.W., B.A.C.C., H.-C.B.), Weill Institute for Neurosciences; Biomedical Sciences Graduate Program (N.B.S.); Bakar Computational Health Sciences Institute and Department of Pediatrics (M.S.); Department of Bioengineering and Therapeutic Sciences (R.D.H.), University of California, San Francisco, CA; Department of Human Genetics (R.D.H.), McGill University, Montreal, QC, Canada; and OMNI Biomarker Development (A.E.H.), Genentech, Inc., South San Francisco, CA., Wu H; From the Department of Neurology (S.A.L., E.L.E., H.W., B.M., S.D., A.P., M.R.W., B.A.C.C., H.-C.B.), Weill Institute for Neurosciences; Biomedical Sciences Graduate Program (N.B.S.); Bakar Computational Health Sciences Institute and Department of Pediatrics (M.S.); Department of Bioengineering and Therapeutic Sciences (R.D.H.), University of California, San Francisco, CA; Department of Human Genetics (R.D.H.), McGill University, Montreal, QC, Canada; and OMNI Biomarker Development (A.E.H.), Genentech, Inc., South San Francisco, CA., Michel B; From the Department of Neurology (S.A.L., E.L.E., H.W., B.M., S.D., A.P., M.R.W., B.A.C.C., H.-C.B.), Weill Institute for Neurosciences; Biomedical Sciences Graduate Program (N.B.S.); Bakar Computational Health Sciences Institute and Department of Pediatrics (M.S.); Department of Bioengineering and Therapeutic Sciences (R.D.H.), University of California, San Francisco, CA; Department of Human Genetics (R.D.H.), McGill University, Montreal, QC, Canada; and OMNI Biomarker Development (A.E.H.), Genentech, Inc., South San Francisco, CA., Demuth S; From the Department of Neurology (S.A.L., E.L.E., H.W., B.M., S.D., A.P., M.R.W., B.A.C.C., H.-C.B.), Weill Institute for Neurosciences; Biomedical Sciences Graduate Program (N.B.S.); Bakar Computational Health Sciences Institute and Department of Pediatrics (M.S.); Department of Bioengineering and Therapeutic Sciences (R.D.H.), University of California, San Francisco, CA; Department of Human Genetics (R.D.H.), McGill University, Montreal, QC, Canada; and OMNI Biomarker Development (A.E.H.), Genentech, Inc., South San Francisco, CA., Palanichamy A; From the Department of Neurology (S.A.L., E.L.E., H.W., B.M., S.D., A.P., M.R.W., B.A.C.C., H.-C.B.), Weill Institute for Neurosciences; Biomedical Sciences Graduate Program (N.B.S.); Bakar Computational Health Sciences Institute and Department of Pediatrics (M.S.); Department of Bioengineering and Therapeutic Sciences (R.D.H.), University of California, San Francisco, CA; Department of Human Genetics (R.D.H.), McGill University, Montreal, QC, Canada; and OMNI Biomarker Development (A.E.H.), Genentech, Inc., South San Francisco, CA., Wilson MR; From the Department of Neurology (S.A.L., E.L.E., H.W., B.M., S.D., A.P., M.R.W., B.A.C.C., H.-C.B.), Weill Institute for Neurosciences; Biomedical Sciences Graduate Program (N.B.S.); Bakar Computational Health Sciences Institute and Department of Pediatrics (M.S.); Department of Bioengineering and Therapeutic Sciences (R.D.H.), University of California, San Francisco, CA; Department of Human Genetics (R.D.H.), McGill University, Montreal, QC, Canada; and OMNI Biomarker Development (A.E.H.), Genentech, Inc., South San Francisco, CA., Sirota M; From the Department of Neurology (S.A.L., E.L.E., H.W., B.M., S.D., A.P., M.R.W., B.A.C.C., H.-C.B.), Weill Institute for Neurosciences; Biomedical Sciences Graduate Program (N.B.S.); Bakar Computational Health Sciences Institute and Department of Pediatrics (M.S.); Department of Bioengineering and Therapeutic Sciences (R.D.H.), University of California, San Francisco, CA; Department of Human Genetics (R.D.H.), McGill University, Montreal, QC, Canada; and OMNI Biomarker Development (A.E.H.), Genentech, Inc., South San Francisco, CA., Hernandez RD; From the Department of Neurology (S.A.L., E.L.E., H.W., B.M., S.D., A.P., M.R.W., B.A.C.C., H.-C.B.), Weill Institute for Neurosciences; Biomedical Sciences Graduate Program (N.B.S.); Bakar Computational Health Sciences Institute and Department of Pediatrics (M.S.); Department of Bioengineering and Therapeutic Sciences (R.D.H.), University of California, San Francisco, CA; Department of Human Genetics (R.D.H.), McGill University, Montreal, QC, Canada; and OMNI Biomarker Development (A.E.H.), Genentech, Inc., South San Francisco, CA., Cree BAC; From the Department of Neurology (S.A.L., E.L.E., H.W., B.M., S.D., A.P., M.R.W., B.A.C.C., H.-C.B.), Weill Institute for Neurosciences; Biomedical Sciences Graduate Program (N.B.S.); Bakar Computational Health Sciences Institute and Department of Pediatrics (M.S.); Department of Bioengineering and Therapeutic Sciences (R.D.H.), University of California, San Francisco, CA; Department of Human Genetics (R.D.H.), McGill University, Montreal, QC, Canada; and OMNI Biomarker Development (A.E.H.), Genentech, Inc., South San Francisco, CA., Herman AE; From the Department of Neurology (S.A.L., E.L.E., H.W., B.M., S.D., A.P., M.R.W., B.A.C.C., H.-C.B.), Weill Institute for Neurosciences; Biomedical Sciences Graduate Program (N.B.S.); Bakar Computational Health Sciences Institute and Department of Pediatrics (M.S.); Department of Bioengineering and Therapeutic Sciences (R.D.H.), University of California, San Francisco, CA; Department of Human Genetics (R.D.H.), McGill University, Montreal, QC, Canada; and OMNI Biomarker Development (A.E.H.), Genentech, Inc., South San Francisco, CA., von Büdingen HC; From the Department of Neurology (S.A.L., E.L.E., H.W., B.M., S.D., A.P., M.R.W., B.A.C.C., H.-C.B.), Weill Institute for Neurosciences; Biomedical Sciences Graduate Program (N.B.S.); Bakar Computational Health Sciences Institute and Department of Pediatrics (M.S.); Department of Bioengineering and Therapeutic Sciences (R.D.H.), University of California, San Francisco, CA; Department of Human Genetics (R.D.H.), McGill University, Montreal, QC, Canada; and OMNI Biomarker Development (A.E.H.), Genentech, Inc., South San Francisco, CA. h-christian.von_buedingen@roche.com.
Jazyk:	angličtina
Zdroj:	Neurology(R) neuroimmunology & neuroinflammation [Neurol Neuroimmunol Neuroinflamm] 2023 Apr 24; Vol. 10 (4). Date of Electronic Publication: 2023 Apr 24 (Print Publication: 2023).
DOI:	10.1212/NXI.0000000000200118
Abstrakt:	Background and Objectives: The B cell-depleting anti-CD20 antibody ocrelizumab (OCR) effectively reduces MS disease activity and slows disability progression. Given the role of B cells as antigen-presenting cells, the primary goal of this study was to evaluate the effect of OCR on the T-cell receptor repertoire diversity. Methods: To examine whether OCR substantially alters the molecular diversity of the T-cell receptor repertoire, deep immune repertoire sequencing (RepSeq) of CD4 + and CD8 + T-cell receptor β-chain variable regions was performed on longitudinal blood samples. The IgM and IgG heavy chain variable region repertoire was also analyzed to characterize the residual B-cell repertoire under OCR treatment. Results: Peripheral blood samples for RepSeq were obtained from 8 patients with relapsing MS enrolled in the OPERA I trial over a period of up to 39 months. Four patients each were treated with OCR or interferon β1-a during the double-blind period of OPERA I. All patients received OCR during the open-label extension. The diversity of the CD4 + /CD8 + T-cell repertoires remained unaffected in OCR-treated patients. The expected OCR-associated B-cell depletion was mirrored by reduced B-cell receptor diversity in peripheral blood and a shift in immunoglobulin gene usage. Despite deep B-cell depletion, longitudinal persistence of clonally related B-cells was observed. Discussion: Our data illustrate that the diversity of CD4 + /CD8 + T-cell receptor repertoires remained unaltered in OCR-treated patients with relapsing MS. Persistence of a highly diverse T-cell repertoire suggests that aspects of adaptive immunity remain intact despite extended anti-CD20 therapy. Trial Registration Information: This is a substudy (BE29353) of the OPERA I (WA21092; NCT01247324) trial. Date of registration, November 23, 2010; first patient enrollment, August 31, 2011. (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
Databáze:	MEDLINE
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