Assessment of Immunological Potential of Glial Restricted Progenitor Graft In Vivo-Is Immunosuppression Mandatory?

Urszula Kozlowska,Eytan R Barnea,Tomasz Zalewski,Maciej K Kurpisz,Aleksandra Klimczak,Karolina Anna Bednarowicz,Stefan Jurga,Katarzyna Chojnacka,Natalia Rozwadowska

doi:10.3390/cells10071804

Abstract

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease, causing motor neuron and skeletal muscle loss and death. One of the promising therapeutic approaches is stem cell graft application into the brain; however, an immune reaction against it creates serious limitations. This study aimed to research the efficiency of glial restricted progenitors (GRPs) grafted into murine CNS (central nervous system) in healthy models and the SOD1G93A ALS disease model. The cellular grafts were administered in semiallogenic and allogeneic settings. To investigate the models of immune reaction against grafted GRPs, we applied three immunosuppressive/immunomodulatory regimens: preimplantation factor (PiF); Tacrolimus; and CTLA-4, MR1 co-stimulatory blockade. We tracked the cells with bioluminescence imaging (BLI) in vivo to study their survival. The immune response character was evaluated with brain tissue assays and multiplex ELISA in serum and cerebrospinal fluid (CSF). The application of immunosuppressive drugs is disputable when considering cellular transplants into the immune-privileged site/brain. However, our data revealed that semiallogenic GRP graft might survive inside murine CNS without the necessity to apply any immunomodulation or immunosuppression, whereas, in the situation of allogeneic mouse setting, the combination of CTLA-4, MR1 blockade can be considered as the best immunosuppressive option.

Highlights

Amyotrophic lateral sclerosis (ALS) is a civilization neurodegenerative disease that affects upper and lower motor neurons (UMN and LMN, respectively) in various proportions.It is known as Lou Gehrig disease or less commonly as motor neuron disease
The immunological characteristics of the mouse glial restricted progenitors (GRPs) were thoroughly described in our previous study [18]; to better understand prospective cellular interactions, expression of TLR-4 was repeatedly performed
On day 1+ after transplantation, a signal was revealed by Magnetic Resonance Imaging (MRI) scan indicating proper localization of the cells, not touching the brain tissues as its damage could elicit an immune response

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a civilization neurodegenerative disease that affects upper and lower motor neurons (UMN and LMN, respectively) in various proportions. It is known as Lou Gehrig disease or less commonly as motor neuron disease. Progressive dysfunction of the motor neurons leads to skeletal muscle weakness and atrophy. In the last phase of the disease, there is a loss of intercostal muscles, leading to respiratory failure and death-most commonly within 2–3 years after diagnosis [3]. ALS is considered a motor neuron disease, there are cases of frontotemporal dementia (FTD) most possibly associated with the abnormalities within the

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