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- Title
(DXT34) Revealing the Immune Cell Subtype Reconstitution Profile in Cladribine-Treated Patients at the 96-Week Timepoint (CLARITY) Using Deconvolution Algorithms.
- Authors
Kalatskaya, Irina; Giovannoni, Gavin; Leist, Thomas P.; Soelberg-Sorensen, Per; Boschert, Ursula; DeMartino, Julie; Rolfe, Alex
- Abstract
Background: Cladribine tablets (CTs) cumulative licensed dose of 3.5 mg/kg (CT3.5), administered as 2 short oral courses over 2 years, transiently reduces total lymphocyte counts, with median values returning to normal range within 11 months and median B cells by 6 months. Clinical efficacy of CTs is sustained beyond lymphocyte recovery. Flow cytometric observations suggest long-lasting reductions in memory B cells. Objectives: Characterize immune cell transcriptomic signatures in peripheral blood from patients with relapsing-remitting multiple sclerosis during immune repopulation at 96 weeks in the CLARITY study using advanced computational algorithms and correlate these signatures with corresponding flow cytometry data of main lymphocyte subtypes. Methods: Gene expression data (U133 Plus 2.0 array) in whole blood samples at 96 weeks were available from patients randomized to placebo (n = 57), CT3.5 (n = 62), or CT 5.25 mg/kg (CT5.25, n = 70). These were analyzed with the CIBERSORT deconvolution algorithm (to estimate absolute fractions of 22 immune cell subtypes) and the xCell signature-based method (cell type enrichment analysis for 43 immune cell subtypes). Wilcoxon rank sum tests compared between treatment arms. Spearman rank correlation coefficient was used to measure the relationship between signatures and cell counts. P values < .05 were considered nominally significant. Results: At 96 weeks, the relative abundance of naive B cells in CT3.5- and CT5.25-treated patients was significantly higher vs placebo. Plasma cells and class-switched memory B cells were signifi- cantly reduced with CTs vs placebo. The M2 macrophage signature was significantly enhanced with CTs vs placebo. Cell abundance of both naive and memory CD4+ and CD8+ was significantly reduced with CTs vs placebo. Deconvolution signature scores were positively and significantly correlated with corresponding flow cytometry data (r: 0.68-0.72 CD19+ B cells, 0.71 CD4+ T cells, 0.67-0.69 CD8+ T cells). Conclusions: At 96 weeks following CT treatment in year 2, changes in leukocytes suggestive of a shift towards an anti-inflammatory phenotype were detected.
- Subjects
ADENOSINES; ALGORITHMS; CONFERENCES &; conventions; IMMUNE system; TIME
- Publication
International Journal of MS Care, 2020, Vol 22, Issue S2, p27
- ISSN
1537-2073
- Publication type
Article