Leukocyte interaction with immunological interfaces of the brain after stroke
Final Report Abstract
Stroke is a major health burden as a leading cause of morbidity and mortality worldwide. Blood flow restoration—through thrombolysis or endovascular thrombectomy—is the only effective treatment but restricted to a limited proportion of patients due to time window constraint and accessibility to technology. Over the past two decades, research has investigated the basic mechanisms that lead to neuronal death following cerebral ischemia. However, the use of neuroprotective paradigms in stroke has been marked by failure in translation from experimental research to clinical practice. In the past few years, much attention has focused on the immune response to acute cerebral ischemia as a major factor to the development of the brain lesions and neurological deficits. Key inflammatory processes after stroke include the activation of resident glial cells as well as invasion of circulating leukocytes. Recent research on anti-inflammatory strategies for stroke has focused on limiting the transendothelial migration of peripheral immune cells from the compromised vasculature into the brain parenchyma. However, recent trials testing blockage of cerebral leukocyte infiltration in patients obtained discrepant results. This emphasizes the need to better scrutinize how immune cells are regulated at the blood brain interface and enter the brain parenchyma and particularly consider also alternative cerebral infiltration routes for leukocytes. Therefore, the aim of this project was to test the choroid plexus as potential entry site for pro-inflammatory T cells to the ischemic brain. We were able specific accumulation of T cells in the peri-infarct cortex and detection of T cells as the predominant population in the ipsilateral ChP in mice as well as in human post-stroke autopsy samples. T-cell migration from the ChP to the peri-infarct cortex was confirmed by in vivo cell tracking of photoactivated T cells. In turn, significantly less T cells invaded the ischemic brain after hotothrombotic lesion of the ipsilateral ChP and in a stroke model encompassing ChP ischemia. As an add-on to this core project, we were able to initiate and sucessfully conduct the first international, preclinical multicenter trial with support from this project’s funding to validate a therapeutic approach targeting the migration of leukocytes to the postischemic brain. Thereby, studies realized by this project explored on one side a novel and clinically potentially relevant pathway of cerebral T cell migration and on the other side enabled a landmark preclinical validation study.
Publications
- „Results of a preclinical randomized controlled multicenter trial (pRCT): Anti-CD49d treatment for acute brain ischemia. “ Science Translational Medicine, 2015, 5;7(299):299ra121
Llovera G, [...] Dirnagl U, Planas AM, Plesnila N, Vivien D, Liesz A
(See online at https://doi.org/10.1126/scitranslmed.aaa9853) - Interfering with the Chronic Immune Response Rescues Chronic Degeneration After Traumatic Brain Injury. J Neurosci. 2016, 21;36(38):9962-75
Ertürk A, Mentz S, Stout EE, Hedehus M, Dominguez SL, Neumaier L, Krammer F, Llovera G, Srinivasan K, Hansen DV, Liesz A, Scearce-Levie KA, Sheng M
(See online at https://doi.org/10.1523/JNEUROSCI.1898-15.2016) - „The next step in translational research: lessons learned from the first preclinical randomized controlled trial.“ J Neurochem. 2016, Oct;139
Llovera G, Liesz A
(See online at https://doi.org/10.1111/jnc.13516) - The choroid plexus is a key cerebral invasion route for T cells after stroke. Acta Neuropathol. 2017, 134(6):851-868
Llovera G, Benakis C, Enzmann G, Cai R, Arzberger T, Ghasemigharagoz A, Mao X, Malik R, Lazarevic I, Liebscher S, Ertürk A, Meissner L, Vivien D, Haffner C, Plesnila N, Montaner J, Engelhardt B, Liesz A
(See online at https://doi.org/10.1007/s00401-017-1758-y)
