Leukocyte repopulation following alemtuzumab treatment in relapsing-remitting MS contains multiple regulatory immune cell types
ECTRIMS Online Library. Gilmore W. 10/27/17; 200634; P979
Dr. Wendy Gilmore
Dr. Wendy Gilmore
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Abstract

Abstract: P979

Type: Poster

Abstract Category: Pathology and pathogenesis of MS - 15 Immunology

Background: Alemtuzumab is a humanized antibody against CD52 that causes rapid leukopenia, followed by leukocyte repopulation in a specific sequence over time. In patients with relapsing-remitting MS (RRMS), a bias in favor of CD4+ regulatory T cells (Tregs) occurs in the early stages of repopulation that is believed to contribute to mechanisms of clinical efficacy. Because immune regulation is not restricted to the T cell compartment, we hypothesized that additional regulatory cell types are represented in the repopulating lymphoid pool, involving B and NK cell compartments.
Goals: To analyze changes over time in lymphoid cell types, including Tregs, regulatory B cells (Bregs) and regulatory natural killer (NKregs) cells following alemtuzumab treatment in patients with RRMS.
Methods: Blood samples were collected from RRMS patients enrolled in CARE-MS II at the University of Southern California and Stanford University and in patients enrolled in an investigator-initiated study at the University of British Columbia and University of Chicago. Patients were treated with two annual cycles of alemtuzumab, with blood sampling timepoints at baseline (M0) and at months 5, 11, 17, 23, 36 and 48. Changes in the percentage of Tregs, Breg and NKregs in PBMC were assessed by FACS, comparing baseline values with those from remaining timepoints. Treg function was also assessed.
Results: In CD4+ T cells, the percentage of CD4+CD25hiCD127negfoxP3+ Tregs increased modestly, but significantly, at M5 compared with baseline values, accompanied by an increase in Treg function and a trend for reduction in CD4+CD25+CD127+foxP3neg effector T cells over time. In B cells, a marked and significant increase in the percentage of CD19+CD20+CD27negCD38hi Bregs was observed at M5 and remained elevated at M11, 17 and 23. CD20+CD27+ memory B cells dropped to minimal levels by M5 and remained reduced. Finally, as previously reported, the percentage of CD3negCD56hi NK cells in PBMC increased significantly at M5 and was sustained through M36.
Conclusions: In addition to a significant increase in the percentage of regulatory T cells and NK cells during leukocyte repopulation after alemtuzumab treatment, a marked and sustained increased in the percentage of Bregs in PBMC was also observed. These data indicate that the clinical efficacy of alemtuzumab reflects changes in multiple regulatory immune cell types, and is not restricted to the T cell compartment.
Disclosure: Funded by Sanofi Genzyme
WG: Research support from Sanofi Genzyme. BTL: Research support from Teva Pharmaceuticals and Novartis. AT: Research support from Sanofi Genzyme, Biogen, Chugai, CIHR, Roche, Michael Smith Foundation and the MS Society of Canada. Consulting fees from Biogen, Roche, EMD Serono and Teva Pharmaceuticals. AJ: Honoraria and consulting fees from Bayer, Biogen, Teva Pharmaceuticals, Novartis and Sanofi Genzyme. JD: Grant support for clinical trial research from Actelion and Roche-Genentech. Honoraria and consulting fees from Biogen-Idec and Sanofi Genzyme. LPW: Research support from Teva Pharmaceuticals. PL: nothing to disclose. EEK: Research support from Novartis and Teva Pharmaceuticals. AML: nothing to disclose.

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