Injury intensifies T cell mediated graft-versus-host disease in a humanized model of traumatic brain injury

Abstract

The immune system plays critical roles in promoting tissue repair during recovery from neurotrauma but is also responsible for unchecked inflammation that causes neuronal cell death, systemic stress, and lethal immunodepression. Understanding the immune response to neurotrauma is an urgent priority, yet current models of traumatic brain injury (TBI) inadequately recapitulate the human immune response. Here, we report the first description of a humanized model of TBI and show that TBI places significant stress on the bone marrow. Hematopoietic cells of the marrow are regionally decimated, with evidence pointing to exacerbation of underlying graft-versus-host disease (GVHD) linked to presence of human T cells in the marrow. Despite complexities of the humanized mouse, marrow aplasia caused by TBI could be alleviated by cell therapy with human bone marrow mesenchymal stromal cells (MSCs). We conclude that MSCs could be used to ameliorate syndromes triggered by hypercytokinemia in settings of secondary inflammatory stimulus that upset marrow homeostasis such as TBI. More broadly, this study highlights the importance of understanding how underlying immune disorders including immunodepression, autoimmunity, and GVHD might be intensified by injury. Traumatic brain injury (TBI) is a major contributor to long-term disability and mortality in children and adults, and, despite intensive efforts, there are no effective treatments for TBI 1,2. Sequelae of TBI and soft tissue injuries resulting from polytrauma include changes in cerebral metabolism, excitotoxicity, induction of emergency hematopoiesis, infiltration of fluid and inflammatory cells into the brain, systemic cytokine storm and localized cytokine release, and activation of microglia, the resident macrophage of the central nervous system 3-8. The immune system plays critical roles in promoting tissue repair and clearance of dying neurons during recovery from neurotrauma but is also responsible for the deleterious inflammation that kills healthy neurons. Systemic immunodepression and vulnerability to infection often follow the acute phase of TBI wherein hypercytokinemia and inflammation resolve, placing patients at increased risk of pneumonia and sepsis 9. Thus, understanding the contribution of the immune system to recovery is critical to development of efficacious therapies for neurotrauma 10,11 .

Tailored Therapeutic Doses of Dexmedetomidine in Evolving Neuroinflammation after Traumatic Brain Injury

“…Although the main cells are monocytes between days 3 and 5, in the following days, T lymphocytes, natural killers, and dendritic cells begin to appear in the damaged tissue [71,72]. Previous studies have reported that investigating T cells in the context of neuroinflammatory conditions in TBI is critical [20,67,72]. In this research, T cells infiltrating the damaged tissue were observed at posttraumatic days 1 and 3, but it was seen more obviously 72 h after TBI, as mentioned before.…”

“…In healthy brains, normally there are a few peripheral immune cells; nevertheless, these cells infiltrate and accumulate near the damaged area [67]. In response to TBI, firstly, local cytokines and chemokines are triggered, and then immune cells are activated.…”