Immune interventions in stroke

Abstract

Approaches for the effective management of acute stroke are sparse, and many measures for brain protection fail. However, our ability to modulate the immune system and modify the progression of multiple sclerosis is increasing. As a result, immune interventions are currently being explored as therapeutic interventions in acute stroke. In this Review, we compare the immunological features of acute stroke with those of multiple sclerosis, identify unique immunological features of stroke, and consider the evidence for immune interventions. In patients with acute stroke, microglial activation and cell death products trigger an inflammatory cascade that damages vessels and the parenchyma within minutes to hours of the ischaemia or haemorrhage. Immune interventions that restrict brain inflammation, vascular permeability and tissue oedema must be administered rapidly to reduce acute immune-mediated destruction and to avoid subsequent immunosuppression. Preliminary results suggest that the use of drugs that modify disease in multiple sclerosis might accomplish these goals in ischaemic and haemorrhagic stroke. Further elucidation of the immune mechanisms involved in stroke is likely to lead to successful immune interventions.

Figures

Figure 1. The effects of cross-talk between lymphocytes and ischaemic neurons on the time window for immune intervention

NK cells are used as an example of lymphocytes. In the early stages of stroke (less than ~24h after onset), fractalkine from ischaemic neurons recruits NK cells to the ischaemic areas. These NK cells affect ischaemic neurons in three ways. They directly kill neurons that have lost immunological identity through loss of MHC Ib (1). They release cytokines, mainly IFN-γ and TNF-α, that promote glutamate release and lead to neuronal hyperactivity and excitotoxicity (2). Finally, they secrete cytokines such as IFN-γ and GM-CSF that activate microglia and macrophages and condition astrocytes, which in turn release inflammatory mediators such as IL-1β, IL-6, and NO (3). At times more than ~24 h after stroke onset, signals from ischaemic neurons can turn off NK cells., , Peripheral NK cells are also downregulated by the effects of ischaemic brain injury on the sympathetic, parasympathetic and/or hypothalamic–pituitary–adrenal axis systems. Abbreviations: BDNF, brain-derived neurotrophic factor; CCL12, chemokine ligand 12; CXCL10, C–X–C motif chemokine 10; EGF, epidermal growth factor; GABA, γ-aminobutyric acid; GM-CSF, granulocyte macrophage colony-stimulating factor; NK, natural killer; NO, nitrogen oxide; TGF-β, transforming growth factor β; TNF, tumour necrosis factor. Whether this scenario applies to ICH is not known. It is presumed that some features, such as cell trafficking, and the impact of NK cells on neural structures, are shared by ICH.

Figure 2. The effect of fingolimod in patients with AIS and ICH

Red outlines indicate the sizes of lesions. a | Representative MRI images from patients with AIS who were treated with fingolimod or with standard management. Infarct locations and occlusion of arteries were similar at baseline in the patients shown (left). Fingolimod treatment led to a significant reduction in lesion size after 7 days (middle). CET1 imaging showed that the acute ischaemic lesion was smaller in patients who received fingolimod than in controls (right). b | Representative CT and MRI images from patients with ICH who were treated with fingolimod or with standard management. Both patients had basal ganglia region haemorrhage and haematoma volumes were similar at baseline. Fingolimod led to a marked resolution of oedema and no midline shift, whereas in control patients, oedema persisted during days 7–14 and was accompanied by a midline shift. Abbreviations: AIS, acute ischaemic stroke; CET, contrast-enhanced T1-weighted; DWI, diffusion-weighted imaging; ICH, intracerebral haemorrhage.