Human cord blood-derived regulatory T-cell therapy modulates the central and peripheral immune response after traumatic brain injury.

Henry W Caplan,Cecilia Martin,Naama E Toledano-Furman,Andrea S Bordt,Karthik S Prabhakara,Nicolas F Moreno,Louis Carrillo,Charles S Cox,Akshita Kumar,Scott D Olson

doi:10.1002/sctm.19-0444

Abstract

Traumatic brain injury (TBI) causes a profound inflammatory response within the central nervous system and peripheral immune system, which contributes to secondary brain injury and further morbidity and mortality. Preclinical investigations have demonstrated that treatments that downregulate microglia activation and polarize them toward a reparative/anti‐inflammatory phenotype have improved outcomes in preclinical models. However, no therapy to date has translated into proven benefits in human patients. Regulatory T cells (Treg) have been shown to downregulate pathologic immune responses of the innate and adaptive immune system across a variety of pathologies. Furthermore, cellular therapy has been shown to augment host Treg responses in preclinical models; yet, studies investigating the use of Treg as a therapeutic for TBI are lacking. In a rodent TBI model, we demonstrate that human umbilical cord blood Treg modulate the central and peripheral immune response after injury in vitro and in vivo.

Highlights

Based on previous work with progenitor cells, such as mesenchymal stem cells (MSC) and multipotent adult progenitor cells (MAPC), we evaluated to the ability of human umbilical cord blood (UCB)-derived Treg to attenuate proinflammatory cytokine production by stimulated human and rodent immune cells, as this has been predicative of successful translation of cell therapies into animal models.[7,9,12,13,14]
This study demonstrates that human regulatory T cells (Treg) expanded from umbilical cord blood can reduce neuroinflammation associated with traumatic brain injury
Given the critical role we believe the spleen and splenocytes play in regulating the immune response after Traumatic brain injury (TBI), we further examined the effect of Treg on immune responses of rat splenocytes, both naïve (Naïve Sp) and 24 hours post-CCI (CCI Sp), in order to better understand the role of peripheral immune cells after TBI

Summary

Introduction

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality.[1,2] TBI causes a profound inflammatory response within the central nervous system (CNS) and peripheral immune system, which contributes to secondary brain injury and further morbidity and mortality.[3,4] Microglia, the resident myeloid cells in CNS, are key mediators of the inflammatory response within the brain after TBI.[3,5] Previously, we have demonstrated that cell therapy including mesenchymal stem cells (MSC) and multipotent adult progenitor cells (MAPC) downregulate microglia activation and polarize them toward a reparative/anti-inflammatory phenotype and have improved outcomes in preclinical models.[6,7,8] The mechanism of action of cell therapy likely involves interaction with and modulation of the endogenous immune system, regulatory T cells (Treg).[9] Treg maintain self-tolerance and regulate immune responses, and Treg dysfunction is involved in many immunologicrelated pathologies from graft vs host disease to multiple sclerosis.[10,11] Several clinical trials using Treg therapy are under way in several disease processes. Investigations into the use of Treg therapy for TBI are lacking. We evaluated the ability of human Treg to STEM CELLS Transl Med. 2020;9:903–916

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Conclusion