Abstract
There is a growing optimism about the potential of new disease-modifying therapies (DMTs) in the management of relapsing-remitting multiple sclerosis (RRMS) patients. However, this initial enthusiasm has been tempered by evidence indicating that multiple sclerosis (MS) patients undergoing DMT may be at higher risk of developing infections through incompletely understood mechanisms. As neutrophils provide the first line of defense against pathogens, here we have compared the effects of some of the commonly used MS DMTs (i.e., moderate-efficacy injective, first-line: interferonβ-1b (IFNβ-1b), glatiramer acetate (GA); and high-efficacy, second-line: fingolimod (FTY) and natalizumab (NAT)) on the in vitro viability and functions of neutrophils isolated from healthy subjects. All the DMTs tested impaired the ability of neutrophils to kill Klebsiella pneumoniae, whereas none of them affected the rate of neutrophil apoptosis or CD11b and CD62L cell surface expression. Intriguingly, only FTY exposure negatively affected K. pneumoniae-induced production of reactive oxygen species (ROS) in polymorphonuclear leukocytes (PMNs). Furthermore, neutrophils exposed to K. pneumoniae secreted enhanced amounts of CXCL8, IL-1β and TNF-α, which were differentially regulated following DMT pretreatment. Altogether, these findings suggest that DMTs may increase the susceptibility of MS patients to microbial infections, in part, through inhibition of neutrophil functions. In light of these data, we recommend that the design of personalized therapies for RRMS patients should take into account not just the mechanism of action of the chosen DMT but also the potential risk of infection associated with the administration of such therapeutic compounds to this highly vulnerable population.
Highlights
Over the past decade, an increasing number of disease-modifying therapies (DMTs) have been successfully launched on the market for the treatment of relapsing-remitting multiple sclerosis (RRMS) patients [1,2,3,4]
As we have previously shown that polymorphonuclear leukocytes (PMNs) isolated from RRMS patients display reduced intracellular killing activity [20], here we sought to determine whether treatment with first-line DMTs, such as IFNβ-1b (Extavia®) and glatiramer acetate (GA) (Copaxone®), or second-line DMTs, such as FTY (Gilenya®) and NAT (Tysabri®), would affect neutrophil functions in vitro
Our primary objective was to evaluate the direct effect of DMTs on the intracellular killing activity of PMNs isolated from healthy subjects (HSs), hereinafter referred to as PMNs
Summary
An increasing number of disease-modifying therapies (DMTs) have been successfully launched on the market for the treatment of relapsing-remitting multiple sclerosis (RRMS) patients [1,2,3,4]. Despite the effectiveness of DMTs in treating RRMS patients, it has become increasingly clear that their use, in particular second-line DMTs, may be associated with increased risk of microbial infections, both opportunistic and community-acquired [1,2,3,11,12,13,14], representing one of the main issues to be dealt with when choosing the most appropriate therapeutic course of action [13]. Our results indicate that DMTs impair the ability of PMNs from healthy subjects (HSs) to kill Klebsiella pneumoniae and to secrete pro-inflammatory cytokines, suggesting that a direct effect of these agents on neutrophil functions may weaken the immune response against pathogens in MS patients
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