Bone Marrow Transfer in Relapsing-Remitting EAE Ameliorates Disease at First Remission, with No Synergistic Effect upon Co-Transplantation with Mesenchymal Stem Cells.

Giovanni Ferrara,Nicole Kerlero De Rosbo,Gianluigi Mancardi,Antonio Uccelli,Federico Ivaldi

doi:10.3390/vaccines9070736

Abstract

Multiple sclerosis (MS) is a neurological disorder characterized by an autoimmune response, demyelinating plaques and axonal damage. Intense immunosuppression (II) followed by autologous hematopoietic stem cell transplantation has been proposed as a treatment in severe forms of MS. We have used murine relapsing-remitting (RR) experimental autoimmune encephalomyelitis (RR-EAE) to evaluate the transplantation of syngeneic bone marrow cells (BMC) after II, in combination with mesenchymal stem cells (MSCs) as a new therapeutic adjunct capable of improving immune reconstitution. In EAE-affected mice treated with BMC alone, we observed a drastic reduction in the clinical course only during the early RR phase of the disease. There was no difference in the RR-EAE clinical course between mice treated with BMC alone and co-transplanted mice. To analyze the immune reconstitution, we quantified the circulating immune cells in naïve and RR-EAE-affected mice after II, with BMC alone or in combination with MSC. Although II resulted in reduced numbers of circulating immune cells, reconstitution did not differ in co-transplanted mice. During the early phase of the disease, IL-4 was significantly elevated in co-transplanted mice, as compared to those treated with BMC alone. These data suggest that BMC transplantation after II transiently ameliorates the clinical symptoms of RR-EAE, but that co-transplantation with MSC has no synergistic effect.

Highlights

Multiple sclerosis (MS) is an autoimmune disorder driven by autoreactive T-cell and Bcells, resulting in focal inflammatory infiltrates in the central nervous system (CNS), demyelinating areas and axonal loss [1,2]
We studied the effect of the intravenous administration of bone marrow cells (BMC) after a lethal dose of γ radiation on the course
Our hypothesis was that co-transplantation with BMC and mesenchymal stem cells (MSCs) would synthe therapeutic effecteffect of each treatment observed in thisinand studies, we did ergize the therapeutic of each treatment observed thisprevious and previous studies, wenot observe any enhancement of engraftment or increased rapidity of reconstitution upon did not observe any enhancement of engraftment or increased rapidity of reconstitution co-transplantation, nor nor did co-transplantation lead lead to antoamelioration of theofdisease course, upon co-transplantation, did co-transplantation an amelioration the disease as compared to treatment with BMC alone

Summary

Introduction

Multiple sclerosis (MS) is an autoimmune disorder driven by autoreactive T-cell and Bcells, resulting in focal inflammatory infiltrates in the central nervous system (CNS), demyelinating areas and axonal loss [1,2]. It is generally believed that both genetic and environmental factors contribute to the development and progression of the disease. The peripheral autoimmune response plays a critical role in the development of the disease, especially during its early phases [2] and is the target of the currently available disease modifying treatments (DMTs). In aggressive forms of MS that are not responsive to currently available DMTs, intense immunosuppression, followed by the infusion of autologous hematopoietic stem cells (HSCs), is highly effective in stopping disease activity and progression [3]. Experimental autoimmune encephalomyelitis (EAE) is the purported animal model for MS, which is induced by T-cell and B-cell autoreactivity to myelin components [5]. Depending on the mouse strain and myelin antigen used, murine EAE can present with different clinical courses, including relapsing-remitting EAE (RR-EAE) induced in SJL/J mice with proteolipid protein (PLP)

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Conclusion