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Age-Associated T Cells Cause Differential Long-Term Neuropathology and Functional Outcomes After Traumatic Brain Injury in Mice
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Age-Associated T Cells Cause Differential Long-Term Neuropathology and Functional Outcomes After Traumatic Brain Injury in Mice
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Dissertation
Age-Associated T Cells Cause Differential Long-Term Neuropathology and Functional Outcomes After Traumatic Brain Injury in Mice
2024
Overview
Traumatic brain injury (TBI) afflicts about 69 million people worldwide yearly. Patients aged 65 years and older account for an increasing proportion of those who suffer from TBI. Aged TBI patients experience increased morbidity and mortality compared to young TBI patients. Understanding the disparate response between older and young patients after TBI is still in its infancy. Using a well-established mouse model of TBI, I have uncovered potential cellular culprits for worse TBI outcomes in aged mice – the disproportionate number of CD8 T-cells within aged brains after TBI. These T-cells come from the peripheral blood and infiltrate the brain as the blood-brain barrier (BBB) is damaged after TBI. Inhibiting the infiltration of these CD8 T-cells via an FDA-approved drug called Natalizumab (a monoclonal antibody against the adhesion molecule integrin α4), also known as anti-CD49d antibody (aCD49d Ab), significantly reduces mortality in the aged mice but not young mice post-TBI. This treatment also improves long-term neurocognition and motor outcomes in aged mice post-TBI. At the molecular level, mice incur age-associated toxic and heightened cytokine responses, as shown in numerous upregulated pro-inflammatory cytokines, long-term post-TBI. aCD49d Ab attenuates this response along with augmentation of a neuroprotective Th2 response. Furthermore, aged mouse brains post-TBI comprise two pools of CD8+ T cells on the basis of their effector function: a dysfunctional population, which co-expresses inhibitory receptors and markers for effector function, and a functional population, which exhibits markers for effector function. Attenuating the functional population, aCD49d Ab remediates the cytotoxicity of CD8+ T cells, improving post-TBI outcomes in aged mice. Together, aCD49d Ab is a promising therapeutic strategy for treating TBI in aged individuals.
Publisher
ProQuest Dissertations & Theses
Subject
ISBN
9798382763057
