On Mesenchymal Stem Cells and Regulatory T Cells in Organ Transplantation

Abstract

Cellular therapy presents itself as a prospective alternative to current drug-based immunosuppressive regimens in the field of organ transplantation. Therefore it becomes essential to investigate its influence on immunomodulatory mechanisms operating in the graft recipient and to evaluate the potential efficacy of this novel treatment for the suppression of alloreactivity. The aim of this thesis is to study the interaction between MSC and nTreg, the effect of MSC on other T cell subsets and the influence of immunosuppressive drugs on MSC-mediated processes. In chapter 2 the adipose-tissue derived MSC used for the research presented in this thesis are characterized and their immunomodulatory capacity on different lymphocyte subsets is described. Further, the functionality of MSC and nTreg upon interaction is evaluated and the involved cytokines are assessed. Chapter 3 focuses on the ability of MSC to induce de novo Treg. The newly formed Treg are characterized with respect to their suppressive function and immunophenotypical properties. In addition, the role of IL-2 in the generation of iTreg is explored by means of the anti-CD25 antibody basiliximab. The potential of another MSC-drug combination therapy for organ recipients is evaluated in vitro in chapter 4. As alloreactive CD8+CD28- T cells remain unaffected by the CD28-CD80/86 co-stimulation blocking fusion protein belatacept, the effect of MSC on these cells is examined. Chapter 5 describes a gene polymorphism association study to evaluate the effect of different FOXP3 gene variants on kidney graft survival. In chapter 6 the results obtained in the context of this thesis are summarized and appraised with respect to their translation to the clinical application of MSC therapy for organ transplantation.