Periodic Reporting for period 2 - RecoverInFlame (T cell-driven inflammatory mechanisms promote recovery after acute brain injury)
Reporting period: 2020-05-01 to 2021-10-31
Acute brain injuries due to ischemic stroke and traumatic brain injuries (TBI) impose a leading medical and socioeconomic burden. Aside from the acute mortality and morbidity from these diseases, brain injuries are associated with a substantial long-term disability. Therapies for patients with acute brain injuries are limited, the only approved specific therapies for ischemic stroke patients are pharmacological or mechanical recanalization approaches while no specific therapy is available for TBI patients. Moreover, even these limited therapies for recanalization in ischemic stroke patients are available only in the hyperacute phase of vascular occlusion due to contraindications and inefficiency at delayed time points. Thereby, we currently face the situation that less than 20% of all stroke patients and none of the TBI patients receive a specific therapy. On the other side, strategies to improve neurological recovery after acute brain injury are restricted to rehabilitative training. Hence, novel and innovative therapies to support regenerative capacities after brain injury are desperately needed.
Over the past decade, inflammation of the injured brain has come into the focus of preclinical stroke research. Invasion of immune cells from the blood to the brain has been described as a key mechanism, which aggravates the initial infarct volume and exacerbates stroke outcome. On the other side we have observed that some immune cell subpopulations can also have a protective function and promote the recovery during the chronic phase after a stroke.
Therefore, the overall goal of this project is to harness the beneficial functions of the immune response to stroke and modify this immune response so that it supports recovery of stroke patients. We want to specifically utilize in this project the immune cell population of T cells, and exploit the therapeutic potential of these T cells as “Trojan horses” secreting immunoactive and pro-regenerative factors to promote recovery after brain injury (Figure 1).
Over the past decade, inflammation of the injured brain has come into the focus of preclinical stroke research. Invasion of immune cells from the blood to the brain has been described as a key mechanism, which aggravates the initial infarct volume and exacerbates stroke outcome. On the other side we have observed that some immune cell subpopulations can also have a protective function and promote the recovery during the chronic phase after a stroke.
Therefore, the overall goal of this project is to harness the beneficial functions of the immune response to stroke and modify this immune response so that it supports recovery of stroke patients. We want to specifically utilize in this project the immune cell population of T cells, and exploit the therapeutic potential of these T cells as “Trojan horses” secreting immunoactive and pro-regenerative factors to promote recovery after brain injury (Figure 1).
We achieved already several milestones of the proposed project and have published our results in a number of scientific, peer-reviewed manuscript.
Specifically,we were able to characterize the function of T cells on chronic recovery after experimental stroke and describe a previously unrecognized phenomenon of the chronic accumulation and local proliferation of T cells in the injured brain for very long time periods after stroke. This finding has been published and is of great relevance for ongoing translational stroke research (Figure 2). Moreover, we have characterized in great detail the influence that this cell population of T cells has on other resident immune cells (microglia) and non-immunological cells of the brain. We have shown that microbial metabolites, fermentation products of the gut flora, were able to modulate the inflamatory response to stroke and Alzheimer's disease utilizing such bacterially-derived metabolites after stroke improved the long-term functional recovery (behavior) of the experimental animals by modulating the immunological response. FIndings for both experimental disease models (stroke and AD) has already been published.
Besides the published work, many of the ongoing, unpublished findings have been presented and discussed at the First International Stroke-Immunology Conference which I have organized in 2020 and is a dedicated platform to discuss novel findings in this research field.
Specifically,we were able to characterize the function of T cells on chronic recovery after experimental stroke and describe a previously unrecognized phenomenon of the chronic accumulation and local proliferation of T cells in the injured brain for very long time periods after stroke. This finding has been published and is of great relevance for ongoing translational stroke research (Figure 2). Moreover, we have characterized in great detail the influence that this cell population of T cells has on other resident immune cells (microglia) and non-immunological cells of the brain. We have shown that microbial metabolites, fermentation products of the gut flora, were able to modulate the inflamatory response to stroke and Alzheimer's disease utilizing such bacterially-derived metabolites after stroke improved the long-term functional recovery (behavior) of the experimental animals by modulating the immunological response. FIndings for both experimental disease models (stroke and AD) has already been published.
Besides the published work, many of the ongoing, unpublished findings have been presented and discussed at the First International Stroke-Immunology Conference which I have organized in 2020 and is a dedicated platform to discuss novel findings in this research field.
We have established in this project already several novel methodologies that have previously not been used in stroke research or neuroscience at all. We are currently utilizing these methodologies for ongoing experiments and aim to make the methods openly available to the research community. In line with my lab's philiosphy on open and reproducible science we have recently pubslihed two video manuscript, describing in great detail and with hands-on views the execution of the most commonly used experimental stroke models according to a consensus meeting across a network of stroke scientists that I have organized in Munich in 2020.
Until end of the project's funding period, I expect that we will reach all major milestones of this project despite the considerable delays due to the Coronavirus pandemic that has affected the lab's efficacy in 2020. Specifically, we will be able to finalize and publish the work on T cell-microglia interaction in polarizing the immune milieu in the brain after stroke, characterize the specific secretome of T cells in the chronic phase after stroke and evaluate the efficacy of using a probiotic therapy to modulate the microbiota composition, and thereby the impact of shifting the peripheral immune compartment towards a pro-regenerative response.
After finalizing these specific work packages, addressing specific scientific questions and mechanisms of brain-immune interaction, we will test the internal validity and generalizability of our findings in a work package specifically dedicated for validation of exploratory findings before further translation. In work package we will address three key elements to improve reproducibility and translational robustness from bench to bedside in three independent tasks. First, we will perform a fully powered validation of key findings from the exploratory work packages. Second, we will test treatment efficacy under conditions of comorbidities and comedications common in patients with acute brain injuries. Finally, we will analyze the generalizability of findings from the paradigmatic photothrombosis model in other translationally relevant acute brain injury models.
Until end of the project's funding period, I expect that we will reach all major milestones of this project despite the considerable delays due to the Coronavirus pandemic that has affected the lab's efficacy in 2020. Specifically, we will be able to finalize and publish the work on T cell-microglia interaction in polarizing the immune milieu in the brain after stroke, characterize the specific secretome of T cells in the chronic phase after stroke and evaluate the efficacy of using a probiotic therapy to modulate the microbiota composition, and thereby the impact of shifting the peripheral immune compartment towards a pro-regenerative response.
After finalizing these specific work packages, addressing specific scientific questions and mechanisms of brain-immune interaction, we will test the internal validity and generalizability of our findings in a work package specifically dedicated for validation of exploratory findings before further translation. In work package we will address three key elements to improve reproducibility and translational robustness from bench to bedside in three independent tasks. First, we will perform a fully powered validation of key findings from the exploratory work packages. Second, we will test treatment efficacy under conditions of comorbidities and comedications common in patients with acute brain injuries. Finally, we will analyze the generalizability of findings from the paradigmatic photothrombosis model in other translationally relevant acute brain injury models.