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Expansion of Tregs mediates Murine (m) aCD52 mAb suppression of experimental autoimmune encephalomyelitis (EAE)
Author(s): ,
N. Kiapoor
Affiliations:
University of North Carolina at Chapel Hill, Chapel Hill, NC
,
B. Wu
Affiliations:
University of North Carolina at Chapel Hill, Chapel Hill, NC
,
S. Kapoor
Affiliations:
University of North Carolina at Chapel Hill, Chapel Hill, NC
,
X. Zhang
Affiliations:
University of North Carolina at Chapel Hill, Chapel Hill, NC
,
M. Thamilarasan
Affiliations:
University of North Carolina at Chapel Hill, Chapel Hill, NC
,
Y. Wan
Affiliations:
University of North Carolina at Chapel Hill, Chapel Hill, NC
S. Markovic-Plese
Affiliations:
University of North Carolina at Chapel Hill, Chapel Hill, NC; Neurology, Thomas Jefferson University, Philadelphia, PA, United States
ECTRIMS Online Library. Kiapoor N. Oct 12, 2018; 228168; P1790
Nazanin Kiapoor
Nazanin Kiapoor
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Abstract: P1790

Type: Poster Sessions

Abstract Category: N/A

Objective: To examine the therapeutic mechanisms of action (MOAs) of anti (aCD52 mAb in relapsing remitting multiple sclerosis (RRMS).
Background: Lemtrada (aCD52 mAb) is an approved therapy for RRMS, however it's MOAs are not elucidated. Our reported studies in RRMS patients revealed a four-fold increase in the percentage of T-regulatory (Treg) cells and a subsequent inhibition of the IFN-g+ and IL-17A+CD4+ cells.
Methods: SJL/PLP139-151, Bl6/MOG35-55 and FoxP3-Diphteria Toxin Receptor (DTR) transgenic mice (DT-inducible Foxp3 depletion) models were used. On day 12 post-immunization (p.i.), mice received áCD52 aCD52 mAb or isotype control for 5 days. When indicated, DT was administered to DTR mice to induce Treg depletion. On days 21, 32 and 60 mice were sacrificed, and cells derived from peripheral blood mononuclear cells (PBMC), draining lymph nodes (dLN), spleen, brain and spinal cord infiltrates were examined by flow cytometry.
Results: aCD52 mAb treatment significantly decreased clinical scores in the acute disease (Bl6/MOG and SJL/PLP ) and second clinical flare-up (SJL/PLP) in comparison to the control group. Flow cytometry results revealed that Tregs (CD4+CD25+FOXP3+) had expanded within the PBMC, brain, dLN and spinal cord infiltrates. The percentages of CD4+IL17A+CD4+ cells were reduced in the brain, spinal cord, dLN and spleen, and the percentage of CD4+IFN-g+CD4+ cells was decreased in the brain following treatment. Treg depletion following aCD52 mAb treatment abrogated its therapeutic effect.
Conclusion: aCD52 mAb treatment decreased EAE disease activity, and was associated with the expansion of Treg cells in multiple organs and Th17/Th1 suppression. Depletion of Tregs abrogated the therapeutic effect, suggesting that Treg expansion and subsequent Th1/Th17 suppression mediate the therapeutic effect.
This study is was funded by Genzyme Corp.
Disclosure: Nazanin Kiapour: nothing to disclose
Bing Wu: nothing to disclose
Sahil Kapoor: nothing to disclose
Madhan Thamilarasan: nothing to disclose
Yisong Wan: nothing to disclose
Silva Markovic-Plese: research grant support from Genzyme Corp., Chugai Pharmaceutical, Genentec Inc., Novartis, advisory board member for EMD Serono

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