Contributions
Abstract: P693
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: The B cell depleting anti-CD20 antibody ocrelizumab (OCR) effectively ameliorates multiple sclerosis (MS) disease activity. However, to date little is known about the effects of OCR on the adaptive immune system beyond B cell depletion.
Objective: To evaluate the effect of OCR on B and T cell repertoires in patients treated with OCR.
Methods: Longitudinal blood samples were collected from 8 patients enrolled in the OPERA I trial. We studied 4 RMS patients: 2 treated with OCR for the whole period and 2 treated with IFNβ1a followed by OCR in the open label extension. PBMCs were isolated and B- and T-cells analyzed by flow cytometry. Unsorted longitudinal PBMC samples (1x107) were subjected to deep immune repertoire sequencing (RepSeq) of the immunoglobulin (IgM and IgG) heavy chain variable (VH) region. TCR-Vβ repertoires were generated from sorted CD4+ and CD8+ T cells.
Results: We observed the expected B-cell depletion under OCR treatment, while no significant depletion was found in the overall CD3+ T cell compartment. Very low numbers of B cells remained detectable even in OCR treated patients. B cell depletion was mirrored by reduced diversity of B cell receptors (BCR). Clonal relatedness between IgM and IgG suggestive of active B cell receptor class-switch recombination was found throughout the study in residual B cells from OCR-treated patients. The diversity of the CD4+/CD8+-T-cell repertoires remained unaffected.
Conclusion: Presence of a diverse B cell repertoire with clonal relatedness between IgM and IgG-expressing B cells suggests persistence of a functional residual B cell compartment under active OCR treatment. Persistence of a highly diverse T cell repertoire suggests the adaptive character of the T cell compartment is maintained despite B cell depletion. Our pilot suggests that important functions of the adaptive immune system may remain intact under long-term OCR treatment.
Disclosure:
S. Laurent has nothing to disclose
B. Michel has nothing to disclose
H. Wu has nothing to disclose
E. Eggers has nothing to disclose.
S. Demuth has nothing to disclose.
N. Strauli has nothing to disclose
M.R. Wilson has received grant support from F. Hoffman-La Roche Ltd and Genentech, Inc.
M. Sirota was previsouly employed by Pfizer, and is currnetly a consultant for NGMBio, RevMed and Novartis and an advisor to twoXAR.
A. Herman is an employee of Genentech, Inc., and shareholder of F. Hoffmann-La Roche Ltd.
H.-C. von Buedingen is an employee of F. Hoffmann-La Roche Ltd.
Abstract: P693
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: The B cell depleting anti-CD20 antibody ocrelizumab (OCR) effectively ameliorates multiple sclerosis (MS) disease activity. However, to date little is known about the effects of OCR on the adaptive immune system beyond B cell depletion.
Objective: To evaluate the effect of OCR on B and T cell repertoires in patients treated with OCR.
Methods: Longitudinal blood samples were collected from 8 patients enrolled in the OPERA I trial. We studied 4 RMS patients: 2 treated with OCR for the whole period and 2 treated with IFNβ1a followed by OCR in the open label extension. PBMCs were isolated and B- and T-cells analyzed by flow cytometry. Unsorted longitudinal PBMC samples (1x107) were subjected to deep immune repertoire sequencing (RepSeq) of the immunoglobulin (IgM and IgG) heavy chain variable (VH) region. TCR-Vβ repertoires were generated from sorted CD4+ and CD8+ T cells.
Results: We observed the expected B-cell depletion under OCR treatment, while no significant depletion was found in the overall CD3+ T cell compartment. Very low numbers of B cells remained detectable even in OCR treated patients. B cell depletion was mirrored by reduced diversity of B cell receptors (BCR). Clonal relatedness between IgM and IgG suggestive of active B cell receptor class-switch recombination was found throughout the study in residual B cells from OCR-treated patients. The diversity of the CD4+/CD8+-T-cell repertoires remained unaffected.
Conclusion: Presence of a diverse B cell repertoire with clonal relatedness between IgM and IgG-expressing B cells suggests persistence of a functional residual B cell compartment under active OCR treatment. Persistence of a highly diverse T cell repertoire suggests the adaptive character of the T cell compartment is maintained despite B cell depletion. Our pilot suggests that important functions of the adaptive immune system may remain intact under long-term OCR treatment.
Disclosure:
S. Laurent has nothing to disclose
B. Michel has nothing to disclose
H. Wu has nothing to disclose
E. Eggers has nothing to disclose.
S. Demuth has nothing to disclose.
N. Strauli has nothing to disclose
M.R. Wilson has received grant support from F. Hoffman-La Roche Ltd and Genentech, Inc.
M. Sirota was previsouly employed by Pfizer, and is currnetly a consultant for NGMBio, RevMed and Novartis and an advisor to twoXAR.
A. Herman is an employee of Genentech, Inc., and shareholder of F. Hoffmann-La Roche Ltd.
H.-C. von Buedingen is an employee of F. Hoffmann-La Roche Ltd.