Long term immunologic consequences of experimental stroke and mucosal tolerance

J Michael Gee,Anna Savos,Jessica Hadwin,Angela Kalil,Matthew Thullbery,Kyra J Becker,Dannielle Zierath

doi:10.1186/2040-7378-1-3

J Michael Gee, Anna Savos + Show 5 more

Open Access

https://doi.org/10.1186/2040-7378-1-3

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Abstract

BackgroundAn inflammatory insult following middle cerebral artery occlusion (MCAO) is associated with a predisposition to develop a deleterious autoimmune response to the brain antigen myelin basic protein (MBP). Induction of immunologic tolerance to brain antigens prior to MCAO prevents this deleterious autoimmune response and is associated with better functional outcome early after stroke. In this study, we sought to determine the long term immunologic consequences of experimental stroke and induction of mucosal tolerance.MethodsMale Lewis rats were tolerized to MBP or ovalbumin (OVA) by intranasal administration prior to MCAO and administration of lipopolysaccharide (LPS). Neurological outcome was assessed at set points after MCAO and animals sacrificed at 3 months; the immune response to MBP in brain and spleen was determined using ELISPOT assay and degree of cellular inflammatory brain infiltrate assessed by immunocytochemistry.ResultsAnimals that developed a pro-inflammatory (TH1) response to MBP experienced worse outcome, while those that developed a regulatory response (TREG) experienced better outcome. A TREG response in spleen was also associated with decreased inflammation and an increase in the number of FoxP3 positive cells in brain. In this study, tolerization to MBP prior to MCAO was associated with a tendency to develop a TH1 response to MBP by 3 months after MCAO.ConclusionThese data show that induction of immunological tolerance to MBP is associated with improved outcome after stroke. This study, however, raises concern about the potential for inadvertent induction of detrimental autoimmunity through mucosal administration of antigen.

Highlights

There is a complex interplay between the central nervous system (CNS) and the systemic immune system; the immune response appears to contribute to ischemic brain injury and cerebral ischemia affects the systemic immune response
By inducing systemic inflammation in the peri-infarct period, there appears to be a fundamental change in how the immune system responds to the CNS antigens exposed in injured brain; a detrimental autoimmune response emerges, and this autoimmune response is associated with worse functional outcome 1 month after middle cerebral artery occlusion (MCAO) [5,6]
Using the paradigm of mucosal tolerance, we demonstrated that induction of a that of a regulatory response (TREG) response to the brain antigen myelin basic protein (MBP) prior to cerebral ischemia could prevent development of the deleterious autoimmune response to this antigen and improve outcome[6] There are, documented concerns about the long term consequences of mucosal tolerance/immune deviation therapy [7,8,9]

Summary

Introduction

There is a complex interplay between the central nervous system (CNS) and the systemic immune system; the immune response appears to contribute to ischemic brain injury and cerebral ischemia affects the systemic immune response. By inducing systemic inflammation in the peri-infarct period, there appears to be a fundamental change in how the immune system responds to the CNS antigens exposed in injured brain; a detrimental autoimmune response emerges, and this autoimmune response is associated with worse functional outcome 1 month after middle cerebral artery occlusion (MCAO) [5,6]. This observation may help explain why patients who experience infection in the immediate post-stroke period have increased morbidity and mortality. We sought to determine the long term immunologic consequences of experimental stroke and induction of mucosal tolerance

Methods

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Conclusion