Long‐term peripheral immune cell profiling reveals further targets of oral cladribine in MS

Abstract

Objectives: To expand the knowledge about the immunological consequences of cladribine (CLAD), a pulsed immune reconstitution therapy approved for active multiple sclerosis (MS), beyond the known short-term effects on peripheral immune cell subsets. Methods: In this study, we characterized depletion and restitution kinetics as well as cytokine profiles of peripheral immune cell subsets in 18 patients with MS following treatment with oral CLAD. The methods involved blood collection prior to CLAD and every three months over a period of 24 months, and extensive characterization of various immune cells subsets by multiparametric flow cytometry. Results: We found a selectivity of CLAD towards central memory T cells and memory B cells and detected a hyper-repopulation of maturing B cells. Counts of classical (À65%) and various nonclassical TH17 cells (À84% to À87%) were markedly reduced 24 months after treatment start, and were comparable with depletion rates of classswitched memory B-cell phenotypes (À87% to À95%). The nadir of TH cells was more pronounced in the second treatment year. We observed a proportional surge of CD20 T-cell subsets and an expansion of regulatory T, B and NK cells. Natural killer T cells (NKT) were only depleted in year two and did not recover. Interpretation: Peripheral immune cell profiling revealed more differentiated insights into the immunological effects of CLAD. While some immune cell subsets expanded, we also observed additive depleting effects after the second treatment course. Further studies are required to elucidate whether these changes are paramount for the consistent and prolonged disease-modifying effect of CLAD.

The CD8 T Cell-Epstein-Barr Virus-B Cell Trialogue: A Central Issue in Multiple Sclerosis Pathogenesis

“…Cladribine is a synthetic purine nucleoside analogue that predominantly targets lymphocytes, disrupting DNA synthesis and repair and leading to cell death. In MS patients cladribine induces modest CD4 and CD8 T cell depletion and a more marked and persistent reduction in circulating B cells, mainly memory B cells, which could be the main mechanism underlying its efficacy ( 301 , 302 ). A preliminary study showing disappearance of CSF oligoclonal Ig bands in about half of MS patients 10 years after cladribine treatment suggests that cladribine also depletes B-cells within the CNS ( 300 ).…”

Multiple Sclerosis and SARS-CoV-2 Vaccination: Considerations for Immune-Depleting Therapies

“…These observations were made for a total dose of cladribine of 3.5 mg/kg vs. 5.25 mg/kg. In addition, cladribine treatment led to changes in the absolute cell count, relative distribution of many lymphocyte subsets and lowering of TH17 subsets [ 32 ]. The relationship of these observations to clinical effects remains to be elucidated.…”

MS and COVID-19 challenge: asymptomatic COVID-19 infection during treatment with cladribine

“…Cladribine is a DMT that has a long-term efficacy due to its mode of action. It shows a selectivity towards proinflammatory immune cell subsets, resulting in transient depletion of memory B cell and TH17 cell populations, while leaving the innate immune system intact [5]. The modest depletion induced by cladribine in T and NK cells and a more marked depletion of B cells are seen most significantly between the first and third months [5].…”