Intracerebral hemorrhage (ICH) is a devastating type of stroke with high mortality and morbidity. Preclinical models have identified key roles for immune responses in both acute brain injury and in functional recovery. However, studies in human patients have been more challenging. Linking the pathophysiology seen in rodent models to that seen in patients is critical to the successful development of immunomodulatory therapies for the treatment of ICH. MISTIE III is a NINDS-funded, phase-3 randomized clinical trial testing the efficacy of minimally invasive hematoma evacuation on functional outcomes at 6 and 12 months after ICH. The trial design provides ICH drainage samples over days 2-5 after ICH onset, precisely the time points that local inflammatory responses contribute to injury and modulate responses that aid in repair in rodent models. This provides an unparalleled opportunity to answer fundamental biological questions about the pathophysiology of ICH in living patients over time. The overall hypothesis is that blood-derived macrophages transition to alternative activation over time and this transition is critical to resolution of inflammation via reduced cytokine signaling, enhanced phagocytosis, and inhibition of T effector responses. Ultimately, we predict that the timing of this transition directly impacts patient outcome.
Aim 1 will determine the cellular immune responses in the brain and peripheral blood of patients over time. CD16+ monocytes, CD4+CD127+CD25- effector T cells, CD4+CD127-CD25+ regulatory T cells, and CD8+ cytotoxic T cells will be sorted for in depth transcriptional profiling using RNA-seq. Complementary studies will utilize mass cytometry to comprehensively define and phenotype the leukocyte populations and track cell populations over time. Changes in the immune responses will be integrated using systems biology approaches and associations with patient outcome will be identified.
Aim 2 will determine how changing leukocyte phenotypes determine the effector functions of macrophages and T cells. Using ex vivo assays using macrophages and T cells harvested from patients blood and brain at various time points, the molecular mechanisms of phagocytosis and inhibition of effector T cell responses will be identified.
Intracerebral hemorrhage is a type of stroke with 50% mortality and no effective treatments. This project will determine the dynamics of the immune response in patients with intracerebral hemorrhage in order to identify which immune responses aid in clinical recovery. Ultimately, the goal is to identify new treatment targets for this devastating disease.
|Murphy, Meredith P; Kuramatsu, Joji B; Leasure, Audrey et al. (2018) Cardioembolic Stroke Risk and Recovery After Anticoagulation-Related Intracerebral Hemorrhage. Stroke 49:2652-2658|
|Goods, Brittany A; Vahey, Jacqueline M; Steinschneider, Arthur F et al. (2018) Blood handling and leukocyte isolation methods impact the global transcriptome of immune cells. BMC Immunol 19:30|