Human-derived Treg and MSC combination therapy may augment immunosuppressive potency in vitro, but did not improve blood brain barrier integrity in an experimental rat traumatic brain injury model.

Henry W Caplan,Soheil Zorofchian,Scott D Olson,Karthik S Prabhakara,Naama E Toledano Furman,Cecilia Martin,Hasen Xue,Charles S Cox

doi:10.1371/journal.pone.0251601

Henry W Caplan, Soheil Zorofchian + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0251601

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Journal: PloS one	Publication Date: May 26, 2021
Citations: 3	License type: CC BY 4.0

Affiliation: The University of Texas Health Science Center

Abstract

Traumatic brain injury (TBI) causes both physical disruption of the blood brain barrier (BBB) and altered immune responses that can lead to significant secondary brain injury and chronic inflammation within the central nervous system (CNS). Cell therapies, including mesenchymal stromal cells (MSC), have been shown to restore BBB integrity and augment endogenous splenic regulatory T cells (Treg), a subset of CD4+ T cells that function to regulate immune responses and prevent autoimmunity. We have recently shown that infusion of human cord blood-derived Treg decreased neuroinflammation after TBI in vivo and in vitro. However, while both cells have demonstrated anti-inflammatory and regenerative potential, they likely utilize differing, although potentially overlapping, mechanisms. Furthermore, studies investigating these two cell types together, as a combination therapy, are lacking. In this study, we compared the ability of Treg+MSC combination therapy, as well as MSC and Treg monotherapies, to improve BBB permeability in vivo and suppress inflammation in vitro. While Treg+MSC combination did not significantly augment potency in vivo, our in vitro data demonstrates that combination therapy may augment therapeutic potency and immunosuppressive potential compared to Treg or MSC monotherapy.

Highlights

In the United States alone, there are over 2 million cases of traumatic brain injury (TBI) each year, leading to approximately 50,000 deaths, as well as significant long-term morbidity for survivors [1, 2]
We examined the ability of cell therapy to restore the blood brain barrier (BBB), as disruption leads to increased edema and decreased effectiveness of osmotherapies to reduce pathologic increases in intracranial pressure
We sought to determine whether Treg+mesenchymal stromal cells (MSC) combination therapy would augment or inhibit BBB repair after CCI in comparison to MSC and Treg monotherapy

Summary

Introduction

In the United States alone, there are over 2 million cases of traumatic brain injury (TBI) each year, leading to approximately 50,000 deaths, as well as significant long-term morbidity for survivors [1, 2]. There are two broad phases of TBI: 1) the primary injury itself, which causes immediate tissue damage and neuronal cell death and 2) a hyperexcitatory and inflammatorymediated secondary brain injury in the subsequent hours to days and beyond [3]. The prevention or mitigation of secondary brain injury has been studied extensively over the preceding. Effects of Treg and MSC combination therapy on blood brain barrier repair and inflammation

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