Abstract
Background: Blockade of the cytokine interleukin-1 (IL-1) with IL-1 receptor antagonist (IL-1Ra) is a candidate treatment for stroke entering phase II/III trials, which acts by inhibiting harmful inflammatory responses. Infection is a common complication after stroke that significantly worsens outcome and is related to stroke-induced deficits in systemic immune function thought to be mediated by the sympathetic nervous system. Therefore, immunomodulatory treatments for stroke, such as IL-1Ra, carry a risk of aggravating stroke-associated infection. Our primary objective was to determine if factors associated with antibody-mediated antibacterial defences were further compromised in patients treated with IL-1Ra after stroke. Methods: We assessed plasma concentrations of immunoglobulin isotypes and complement components in stroke patients treated with IL-1Ra or placebo and untreated non-stroke controls using multiplex protein assays. Activation of the sympathetic nervous system (SNS) was determinedby measuring noradrenaline, a major SNS mediator. Results: There were significantly lower plasma concentrations of IgM, IgA, IgG1 and IgG4 in stroke-patients compared to non-stroke controls, however there were no differences between stroke patients treated with placebo or IL-1Ra. Concentrations of complement components associated with the classical pathway were increased and those associated with the alternative pathways decreased in stroke patients, neither being affected by treatment with IL-1Ra. Noradrenaline concentrations were increased after stroke in both placebo and IL-1Ra-treated stroke patients compared to non-stroke controls. Conclusion: These data show treatment with IL-1Ra after stroke does not alter circulating immunoglobulin and complement concentrations and is therefore unlikely to further aggravate stroke-associated infection susceptibility through reduced availability of these key anti-microbialmediators.
Highlights
Blocking the actions of the inflammatory cytokine interleukin-1 (IL-1) using a highly selective IL-1 receptor antagonist (IL-1Ra) reduced injury and improved outcome in multiple experimental animal models of cerebral ischemia and is in ongoing clinical stroke trials1–4
Concentrations of complement components are differentially affected by stroke and not affected by treatment with IL-1Ra As complement components are directly associated with the antibacterial functions of immunoglobulins, we investigated stroke-induced changes in circulating complement components and if any changes observed were further influenced by treatment with IL-1Ra
Plasma IgM concentration is reduced after stroke and is not affected by treatment with IL-1Ra Immunoglobulin M (IgM) is the predominant immunoglobulin isotype associated with early B cell antibody responses to infection by innate-like B cells, which we have previously shown to be depleted after experimental stroke in mice6,10,11
Summary
Blocking the actions of the inflammatory cytokine interleukin-1 (IL-1) using a highly selective IL-1 receptor antagonist (IL-1Ra) reduced injury and improved outcome in multiple experimental animal models of cerebral ischemia and is in ongoing clinical stroke trials. The inflammatory-modifying properties of IL-1Ra may confer protective effects to the brain after stroke; due to its potential for immunosuppression, it may compromise systemic immune responses important for defence against infection. Systemic immune dysregulation is important to consider in the context of stroke as patients are highly susceptible to infection, which likely involves roles for stroke-induced impairments in some immune functions. We have previously shown deficits in early antibody responses, IgM, associated with innate-like B cells in both experimental animals and stroke patients, which may contribute to post-stroke infection susceptibility. Infection is a common complication after stroke that significantly worsens outcome and is related to stroke-induced deficits in systemic immune function thought to be mediated by the sympathetic nervous system. Our primary objective was to determine if factors associated with antibody-mediated antibacterial defences were further compromised in patients treated with IL-1Ra after stroke. Conclusion: These data show treatment with IL-1Ra after stroke does not version 2 (revision)
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