Kidney transplantation is the best treatment option for patients with kidney failure. Unfortunately many patients lose their allograft due to (chronic) rejection. Rejection is caused by the immune... Show moreKidney transplantation is the best treatment option for patients with kidney failure. Unfortunately many patients lose their allograft due to (chronic) rejection. Rejection is caused by the immune reaction of the recipient against the donor’s human leukocyte antigens (HLA). While traditional kidney allocation is based on HLA matching on the antigen level, matching on the epitope level could be more feasible. Furthermore, epitope mismatch analysis could be used for post-transplant risk stratification, enabling the personalisation of immunosuppressive treatment for kidney transplant recipients. In this thesis, the basic science and clinical application of HLA epitopes in kidney transplantation are discussed. Show less
This thesis is about the role of stromal cells in inflammatory bowel disease (IBD) and to assess the therapeutic potential of local mesenchymal stromal cell (MSC)-therapy. First, we discuss the... Show moreThis thesis is about the role of stromal cells in inflammatory bowel disease (IBD) and to assess the therapeutic potential of local mesenchymal stromal cell (MSC)-therapy. First, we discuss the recent insights in the function of stromal cells in the healthy and inflamed gut and characterize fibroblasts in perianal fistulas from patients with IBD. Furthermore, we study the long-term effects of MSC-therapy for the treatment of perianal fistulas and the efficacy of locally injected MSCs in the inflamed intestines of in vivo IBD models. Lastly, we investigate the cytokine environment of inflamed tissue from IBD patients and how this could affect local MSC-therapy. Show less
The studies described in this thesis have provided novel insight into airway epithelial repair mechanisms and their modulation by cigarette smoke, and insight into mesenchymal stromal cell... Show moreThe studies described in this thesis have provided novel insight into airway epithelial repair mechanisms and their modulation by cigarette smoke, and insight into mesenchymal stromal cell treatment of COPD. We have shown that cigarette smoke delays wound repair in injured airway epithelial cells and that the inflammatory mediators present in the lungs of patients with COPD increase the regenerative potential of MSCs. We have furthermore demonstrated that MSCs from patients with severe COPD can be safely used as a cell-based therapy to treat these patients. Many questions remain regarding route of administration, dosage and timing of MSCs administration in COPD. Useful outcome parameters to assess MSC-mediated effects on lung tissue are largely undetermined, and we propose to include analysis of effects on endothelial and inflammatory cells in future clinical trials. The use of ALI-PBEC and alveolar epithelial cell cultures and ex vivo lung perfusion models will help to advance our understanding of the potential of MSCs in pulmonarydiseases. Parallel developments in other areas of regenerative medicine, including those related to induced pluripotent stem cells and ex vivo organ engineering, will synergistically advance the much awaited therapeutic arsenal that is needed to restore pulmonary function in COPD Show less
A frequent manifestation of Crohn's disease (CD) is the formation of perianal fistulas which can greatly affect patient's quality of life due to continuous pain, abscess formation and malodourous... Show moreA frequent manifestation of Crohn's disease (CD) is the formation of perianal fistulas which can greatly affect patient's quality of life due to continuous pain, abscess formation and malodourous discharge from the fistula causing skin irritation. Nowadays, a wide range of medical and surgical therapies for perianal fistulizing CD is available. However, achieving complete fistula healing is often a long process preceded by multiple relapses during the treatment. Currently, mesenchymal stromal cells (MSCs) have gained much interest as a potential therapeutic option for inflammatory disorders, including fistulizing CD, because they possess immunosuppressive and tissue regenerative properties. We performed a clinical trial evaluating MSCs as a treatment for perianal fistulas. Local administration of MSCs additional to a standardized surgical treatment was safe and feasible and resulted in a higher percentage of healed fistulas compared to placebo. In addition, several experimental studies were performed to unravel the mechanism of action of MSCs. The role of the time of MSC administration, disease severity, prestimulation of MSCs with inflammatory cytokines, migration of MSCs and the formation of spheroid-like structures are described in this thesis. Show less
Hematopoietic stem cell transplantation (HSCT) and mesenchymal stromal (MSC) cell therapy are currently under investigation as novel therapies for inflammatory bowel diseases (IBD). Hematopoietic... Show moreHematopoietic stem cell transplantation (HSCT) and mesenchymal stromal (MSC) cell therapy are currently under investigation as novel therapies for inflammatory bowel diseases (IBD). Hematopoietic stem cells are thought to repopulate the immune system and reset the immunological response to luminal antigens. MSCs have the capacity to differentiate into a wide variety of distinct cell lineages and to suppress immune responses in vitro and in vivo. The main goal of this thesis was to study the safety, feasibility, and applicability of stem cell therapy in IBD. Chapter 2 concludes that autologous HSCT appears to be safe and can be an alternative strategy for Crohn__s disease patients with severe and therapy resistant disease. Data from the phase I study described in Chapter 3 demonstrates that MSCs isolated from Crohn__s disease patients have similar characteristics compared to MSCs from healthy donors and that administration of autologous bone marrow derived MSCs appears to be safe and feasible in the treatment of refractory Crohn__s disease. Chapter 4 shows that MSC phenotype and function are not affected by therapeutic concentrations of drugs commonly used in the treatment of IBD. Chapter 5 demonstrates that IFN-_ activation of MSCs increases their immunosuppresive capacities and importantly, their therapeutic efficacy in vivo. Show less
