Abstracts

Rationale: Post-traumatic epilepsy is one of numerous problematic outcomes to traumatic brain injury (TBI). Due to its refractory nature, better mechanistic understanding is needed to develop novel and effective treatments. The immune system responds to infection or injury, including TBI, via a well-orchestrated series of events that include an innate response in which cytokines and chemokines are released that recruit immune cells to the injury. An important pro-inflammatory cytokine released during the early response to injury is macrophage migration inhibitory factor (MIF). This fundamental component of the immune response may be involved in tissue repair, or tissue damage, and is part of the non-specific, innate immune response. If antigen is present following an injury, the innate immune response precedes antigen processing and presentation, and subsequent T cell recognition, the hallmarks of a transition from an innate to a specific, adaptive immune response. Our previous work demonstrated an early expansion and activation of splenocytes within 24 hrs of a TBI that was highly suggestive of an adaptive immune response. We subsequently demonstrated that the splenocyte expansion is dependent on invariant chain (CD74). The full-length CD74 molecule can exist as a cell surface receptor for macrophage inhibitory factor (MIF). MIF binding to full-length cell surface CD74 results in a signaling cascade that modulates cytokine and chemokine production. However, the proteolytic cleavage product of CD74, CLIP, has an additional function in antigen processing, the first step in the transition from an innate to an adaptive immune response. Depleting CD74 in our experiments resulted in a reduction in lesion size and neuroinflammation following fluid percussion injury (FPI). Several fundamental questions that remain to be answered are whether CD74 contributes to the neurodegenration of TBI via an innate response involving MIF or from its contribution to the transition between innate and adaptive immunity, or both and, importantly, how do these functions influence TBI-induced pathology? Methods: To address these questions, we administered ISO1, a MIF antagonist, at 30 minutes after an FPI. We then assessed splenocyte expansion and gamma delta T cell activation at 24 hrs after FPI. The 24 hour time point is when we have previously seen robust expansion of splenocytes, including gamma delta T cells. Results: The results show that treatment with ISO1 after FPI significantly reduces the expansion of CLIP-bearing B cells, but had no significant effect on the expansion of gamma delta T cells Conclusions: These results suggest that MIF might have a role in mediating specific, adaptive immune responses, in addition to its well-defined role in contributing to an innate immune response. Follow-up studies are currently underway to determine if ISO1 treatment will also be neuroprotective and prevent the development of post-traumatic epilepsy. Funding: Citizens United for Research in Epilepsy (CURE): Prevention of Acquired Epilepsies Awards to MKNR & LAS