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Repopulation of T, B, and NK cells following alemtuzumab treatment in relapsing-remitting multiple sclerosis.
J Neuroinflammation. 2020 Jun 15; 17(1):189.JN

Abstract

OBJECTIVE

To characterize long-term repopulation of peripheral immune cells following alemtuzumab-induced lymphopenia in relapsing-remitting MS (RRMS), with a focus on regulatory cell types, and to explore associations with clinical outcome measures.

METHODS

The project was designed as a multicenter add-on longitudinal mechanistic study for RRMS patients enrolled in CARE-MS II, CARE-MS II extension at the University of Southern California and Stanford University, and an investigator-initiated study conducted at the Universities of British Columbia and Chicago. Methods involved collection of blood at baseline, prior to alemtuzumab administration, and at months 5, 11, 17, 23, 36, and 48 post-treatment. T cell, B cell, and natural killer (NK) cell subsets, chemokine receptor expression in T cells, in vitro cytokine secretion patterns, and regulatory T cell (Treg) function were assessed. Clinical outcomes, including expanded disability status score (EDSS), relapses, conventional magnetic resonance imaging (MRI) measures, and incidents of secondary autoimmunity were tracked.

RESULTS

Variable shifts in lymphocyte populations occurred over time in favor of CD4+ T cells, B cells, and NK cells with surface phenotypes characteristic of regulatory subsets, accompanied by reduced ratios of effector to regulatory cell types. Evidence of increased Treg competence was observed after each treatment course. CD4+ and CD8+ T cells that express CXCR3 and CCR5 and CD8+ T cells that express CDR3 and CCR4 were also enriched after treatment, indicating heightened trafficking potential in activated T cells. Patterns of repopulation were not associated with measures of clinical efficacy or secondary autoimmunity, but exploratory analyses using a random generalized estimating equation (GEE) Poisson model provide preliminary evidence of associations between pro-inflammatory cell types and increased risk for gadolinium (Gd+) enhancing lesions, while regulatory subsets were associated with reduced risk. In addition, the risk for T2 lesions correlated with increases in CD3+CD8+CXCR3+ cells.

CONCLUSIONS

Lymphocyte repopulation after alemtuzumab treatment favors regulatory subsets in the T cell, B cell, and NK cell compartments. Clinical efficacy may reflect the sum of interactions among them, leading to control of potentially pathogenic effector cell types. Several immune measures were identified as possible biomarkers of lesion activity. Future studies are necessary to more precisely define regulatory and effector subsets and their contributions to clinical efficacy and risk for secondary autoimmunity in alemtuzumab-treated patients, and to reveal new insights into mechanisms of immunopathogenesis in MS.

TRIAL REGISTRATION

Parent trials for this study are registered with ClinicalTrials.gov: CARE-MS II: NCT00548405, CARE-MS II extension: NCT00930553 and ISS: NCT01307332.

Authors+Show Affiliations

Department of Neurology, Keck School of Medicine, University of Southern California, 1333 San Pablo Street McKibben Hall Room 245A, Los Angeles, CA, 90033, USA. wgilmore@usc.edu.Department of Neurology, Keck School of Medicine, University of Southern California, 1333 San Pablo Street McKibben Hall Room 245A, Los Angeles, CA, 90033, USA.Department of Neurology, Keck School of Medicine, University of Southern California, 1333 San Pablo Street McKibben Hall Room 245A, Los Angeles, CA, 90033, USA.Department of Neurology, Keck School of Medicine, University of Southern California, 1333 San Pablo Street McKibben Hall Room 245A, Los Angeles, CA, 90033, USA.Department of Neurology, Keck School of Medicine, University of Southern California, 1333 San Pablo Street McKibben Hall Room 245A, Los Angeles, CA, 90033, USA.Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.Department of Neurology, Keck School of Medicine, University of Southern California, 1333 San Pablo Street McKibben Hall Room 245A, Los Angeles, CA, 90033, USA. Department of Radiology, University of Southern California, Los Angeles, CA, USA.Department of Neurology, Keck School of Medicine, University of Southern California, 1333 San Pablo Street McKibben Hall Room 245A, Los Angeles, CA, 90033, USA.Department of Neurology, Keck School of Medicine, University of Southern California, 1333 San Pablo Street McKibben Hall Room 245A, Los Angeles, CA, 90033, USA.Department of Neurology, University of Chicago School of Medicine, Chicago, IL, USA.Department of Neurology, Stanford University, Palo Alto, CA, USA.Department of Neurology, University of British Columbia, Vancouver, CA, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32539719

Citation

Gilmore, Wendy, et al. "Repopulation of T, B, and NK Cells Following Alemtuzumab Treatment in Relapsing-remitting Multiple Sclerosis." Journal of Neuroinflammation, vol. 17, no. 1, 2020, p. 189.
Gilmore W, Lund BT, Li P, et al. Repopulation of T, B, and NK cells following alemtuzumab treatment in relapsing-remitting multiple sclerosis. J Neuroinflammation. 2020;17(1):189.
Gilmore, W., Lund, B. T., Li, P., Levy, A. M., Kelland, E. E., Akbari, O., Groshen, S., Cen, S. Y., Pelletier, D., Weiner, L. P., Javed, A., Dunn, J. E., & Traboulsee, A. L. (2020). Repopulation of T, B, and NK cells following alemtuzumab treatment in relapsing-remitting multiple sclerosis. Journal of Neuroinflammation, 17(1), 189. https://doi.org/10.1186/s12974-020-01847-9
Gilmore W, et al. Repopulation of T, B, and NK Cells Following Alemtuzumab Treatment in Relapsing-remitting Multiple Sclerosis. J Neuroinflammation. 2020 Jun 15;17(1):189. PubMed PMID: 32539719.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Repopulation of T, B, and NK cells following alemtuzumab treatment in relapsing-remitting multiple sclerosis. AU - Gilmore,Wendy, AU - Lund,Brett T, AU - Li,Peili, AU - Levy,Alex M, AU - Kelland,Eve E, AU - Akbari,Omid, AU - Groshen,Susan, AU - Cen,Steven Yong, AU - Pelletier,Daniel, AU - Weiner,Leslie P, AU - Javed,Adil, AU - Dunn,Jeffrey E, AU - Traboulsee,Anthony L, Y1 - 2020/06/15/ PY - 2019/05/23/received PY - 2020/05/19/accepted PY - 2020/6/17/entrez PY - 2020/6/17/pubmed PY - 2020/6/17/medline KW - Alemtuzumab KW - B cell subsets KW - Drug mechanisms KW - Immune regulation KW - Lymphocyte repopulation KW - Lymphopenia KW - Multiple sclerosis KW - Natural killer cell subsets KW - T cell subsets KW - Tolerance SP - 189 EP - 189 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 17 IS - 1 N2 - OBJECTIVE: To characterize long-term repopulation of peripheral immune cells following alemtuzumab-induced lymphopenia in relapsing-remitting MS (RRMS), with a focus on regulatory cell types, and to explore associations with clinical outcome measures. METHODS: The project was designed as a multicenter add-on longitudinal mechanistic study for RRMS patients enrolled in CARE-MS II, CARE-MS II extension at the University of Southern California and Stanford University, and an investigator-initiated study conducted at the Universities of British Columbia and Chicago. Methods involved collection of blood at baseline, prior to alemtuzumab administration, and at months 5, 11, 17, 23, 36, and 48 post-treatment. T cell, B cell, and natural killer (NK) cell subsets, chemokine receptor expression in T cells, in vitro cytokine secretion patterns, and regulatory T cell (Treg) function were assessed. Clinical outcomes, including expanded disability status score (EDSS), relapses, conventional magnetic resonance imaging (MRI) measures, and incidents of secondary autoimmunity were tracked. RESULTS: Variable shifts in lymphocyte populations occurred over time in favor of CD4+ T cells, B cells, and NK cells with surface phenotypes characteristic of regulatory subsets, accompanied by reduced ratios of effector to regulatory cell types. Evidence of increased Treg competence was observed after each treatment course. CD4+ and CD8+ T cells that express CXCR3 and CCR5 and CD8+ T cells that express CDR3 and CCR4 were also enriched after treatment, indicating heightened trafficking potential in activated T cells. Patterns of repopulation were not associated with measures of clinical efficacy or secondary autoimmunity, but exploratory analyses using a random generalized estimating equation (GEE) Poisson model provide preliminary evidence of associations between pro-inflammatory cell types and increased risk for gadolinium (Gd+) enhancing lesions, while regulatory subsets were associated with reduced risk. In addition, the risk for T2 lesions correlated with increases in CD3+CD8+CXCR3+ cells. CONCLUSIONS: Lymphocyte repopulation after alemtuzumab treatment favors regulatory subsets in the T cell, B cell, and NK cell compartments. Clinical efficacy may reflect the sum of interactions among them, leading to control of potentially pathogenic effector cell types. Several immune measures were identified as possible biomarkers of lesion activity. Future studies are necessary to more precisely define regulatory and effector subsets and their contributions to clinical efficacy and risk for secondary autoimmunity in alemtuzumab-treated patients, and to reveal new insights into mechanisms of immunopathogenesis in MS. TRIAL REGISTRATION: Parent trials for this study are registered with ClinicalTrials.gov: CARE-MS II: NCT00548405, CARE-MS II extension: NCT00930553 and ISS: NCT01307332. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/32539719/Repopulation_of_T,_B,_and_NK_cells_following_alemtuzumab_treatment_in_relapsing-remitting_multiple_sclerosis L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-020-01847-9 DB - PRIME DP - Unbound Medicine ER -
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