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Abstract Details

Cladribine Decreases CD95-expressing CD4+ and CD8+ Cells in Lymphoid Organs in Naïve Marmosets (Callithrix Jacchus)
Multiple Sclerosis
P13 - Poster Session 13 (5:30 PM-6:30 PM)
9-001
To assess lymphocyte subtype reduction in blood and lymphoid organs of marmosets after cladribine treatment using pharmacodynamic (PD) analysis.
Treatment of multiple sclerosis (MS) with cladribine tablets is based on reducing active lymphocytes, for which cladribine has high selectivity. CD95/FAS cell surface receptors, apoptotic signaling pathway regulators, are impaired in active lymphocytes of MS patients. Previously, only MS patient blood has been analyzed and immune cell reduction in lymphoid organs is unknown. Marmosets have been used for PD studies in naïve or experimental autoimmune encephalomyelitis models to test peripheral lymphocyte-targeting MS drugs with no rodent species cross-reactivity.
Twin marmosets were randomized to four groups (n=2 each). Three doses of subcutaneous cladribine (0.2, 0.4 and 0.8 mg/kg/day for 5 consecutive days in 2 weekly periods) were assessed; control group received 0.9% NaCl. Blood samples were taken weekly starting 2 weeks before, and up to 12 weeks after the first dose of cladribine for analysis of serum chemistry and immune monitoring. Animals were sacrificed in week 12; blood and lymphoid organs were sampled and immunophenotyped using flow cytometry and immunohistochemistry.

No differences in serum chemistry were observed between animals at different cladribine doses, with no profound reduction of total T- or B-lymphocytes or their subsets over time following cladribine treatment. In lymphoid organs, the percentage of CD95-expressing CD4+ or CD8+ T-cells in the CD3+ population was lower in cladribine-treated animals than in controls. This difference was statistically significant when cladribine-treated animals were pooled.
No profound reduction of lymphocyte subsets was observed following cladribine exposure. The reduction of lymphoid T-cell subsets suggests a novel mechanism for cladribine involving the CD95/FAS pathway. The limited effect on other immune cells is consistent with observations in normal lymphoid organs that the CD95/CD95L pathway is only expressed in scattered lymphocytes.
Authors/Disclosures

PRESENTER 		No disclosure on file
Ursula Boschert Shafaatian (C/o Serono) Ursula Boschert has nothing to disclose.
No disclosure on file