Ph.D Thesis

Ph.D StudentBen-Ami Eyal
SubjectMesenchymal Stem Cells as Immunomodulators for Therapy
in Autoimmune Myasthenia Gravis and Multiple
DepartmentDepartment of Medicine
Supervisors DR. Sonia Berrih
PROF. Ariel Miller
Full Thesis textFull thesis text - English Version


Mesenchymal stem cells (MSCs) are multipotent progenitor cells with broad immunoregulatory capabilities, making them a promising tool to treat autoimmune diseases (AID). Nevertheless, as in recent years T cells from patients with various AID have been found to resist suppression by functional regulatory T cells, the question of whether they could be regulated by MSCs arises. In this research we investigated the ability of allogenic adipose tissue-derived MSCs to regulate the activation of T cells from two different AID: Myasthenia Gravis (MG) and Multiple Sclerosis (MS). Our obtained results show that MSCs significantly inhibit T cell proliferation in a dose-dependent manner by inducing cell cycle arrest; leaving the latter anergic. Addressing the autoimmune patients, we show that the MSCs' ability to suppress proliferation of T cells of both diseases is significantly weaker compared to their ability to affect T cells of healthy individuals. While we found that this inhibition is based on a mechanism mediated through monocytes, the faulty cellular component was shown to be the patients’ T lymphocytes. MSC-treated MS and MG lymphocytes were found to produce significantly more Interleukin-2 (IL-2) than healthy subjects while coupling of the MSC treatment with neutralizing IL-2 antibodies resulted in inhibition levels similar to those of the healthy controls. MSCs were also found to down-regulate lymphocyte surface expression of the IL-2 receptor through both transcription inhibition and induction of receptor shedding. Addition of IL-2 to MSC-inhibited lymphocytes restored proliferation thus suggesting a key role played by this cytokine in the inhibitory mechanism. In addition, we demonstrated that MSCs significantly inhibit interferon-γ production and CD3, CD4 and CD28 receptors surface expression by activated lymphocytes and these effects are detected at similar levels in both patients and controls.

Addressing the MSC-monocyte interactions, we show through whole-genome expression analysis that the interaction between MSCs and monocytes induces extensive changes in gene expression patterns in both cellular populations. Finally, investigating the question of whether MSCs derived from autoimmune patients retain their immunomodulatory characteristics, we show that stem cells isolated from the thymus of MG patients are similar to healthy controls’ cells in both their phenotypic surface expression pattern and their ability to inhibit T cell proliferation. Taken together, the results obtained in this PhD research demonstrate the potential of a MSC-based cellular therapy for MG, MS and possibly other AID but also emphasize the need for better understanding of the underlying cellular and molecular mechanisms.