http://repub.eur.nl/res/aut/33735/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/37670/ 2012-09-15T00:00:00Z BACKGROUND: Innate immunity plays a role in controlling adaptive immune responses. METHODS: We investigated the clinical relevance of single nucleotide polymorphisms in 22 genes encoding innate, secreted, and signaling pattern recognition receptors in a total of 520 donor-recipient pairs of postmortem, human leukocyte antigen-DR-compatible kidney transplantations. Associations with rejection incidence were tested in an a priori randomized training set and validation set. RESULTS: Polymorphisms in TLR-3 (rs3775296) in the recipients and in Ficolin-2 (rs7851696; Ala258Ser) and C1qR1 (rs7492) in the donors showed the strongest association with severe rejection. In multivariate analysis, presence of the Ficolin-2 Ala258Ser variant in the donor predicted lower incidence of severe rejection (odds ratio=0.3; 95% confidence interval, 0.1-0.9; P=0.024) and of graft loss (hazard ratio=0.5; 95% confidence interval, 0.2-1.0; P=0.046) independently of clinical risk factors. Ficolin-2 messenger RNA expression was detected in pretransplantation biopsies from 69 donor grafts. Serum and tissue Ficolin-2 levels were unaffected by genotype. Ficolin-2 protein, which bound to dying cells, was detected in donor kidneys in a passenger leukocyte-like pattern. Indeed, monocytes, monocyte-derived macrophages, and peripheral blood mononuclear cells expressed Ficolin-2. Donor grafts with the Ficolin-2 Ala258Ser variant contained significantly elevated expression of interleukin 6, having ascribed cytoprotective effects. It has been described that Ala258Ser leads to increased binding capacity of Ficolin-2 to N-acetylglucosamine. CONCLUSIONS: Presence of the Ficolin-2 Ala258Ser polymorphism in the donor independently predicts improved graft outcome. Based on mechanistic data, we propose that this functional polymorphism leads to more efficient handling of injured cells by phagocytozing cells, resulting in decreased intragraft exposure to danger signals and dampened alloimmune responses. Copyright http://repub.eur.nl/res/pub/25110/ 2009-01-01T00:00:00Z Mesenchymal stem cells (MSC) are characterized by their multilineage differentiation capacity and immunosuppressive properties. They are resident in virtually all tissues and we have recently characterized MSC from the human heart. Clinical heart transplantation offers a model to study the fate of transplanted human MSC. In this study, we isolated and expanded MSC from heart tissue taken before, and 1 week up to 6 years after heart transplantation. MSC from posttransplantation tissue were all of donor origin, demonstrating the longevity of endogenous MSC and suggesting an absence of immigration of recipient MSC into the heart. MSC isolated from transplanted tissue showed an immunophenotype that was characteristic for MSC and maintained cardiomyogenic and osteogenic differentiation capacity. They furthermore preserved their ability to inhibit the proliferative response of donor-stimulated recipient peripheral blood mononuclear cells. In conclusion, functional MSC of donor origin remain present in the heart for several years after transplantation. http://repub.eur.nl/res/pub/35925/ 2007-08-01T00:00:00Z A fully major histocompatilbility complex (MHC) matched donor is not available for the majority of patients in need of a haematopoietic stem cell transplantation (SCT), which illustrates the need for a tool to define acceptable MHC disparities. Previously, we noticed that a variety of single MHC class I mismatched allogeneic donor-recipient pairs did not elicit an allogeneic cytotoxic-lymphocyte (CTL) response in vitro if the MHC amino-acid sequences had five or more differences in the α-helices plus five or more differences in the β-sheet (≥α5β) (7). To address the clinical relevance of this observation, we analysed CTL precursor (CTLp) assay outcome and SCT outcome in 53 Dutch recipients of a single MHC class I mismatched graft from an unrelated donor. Overall patient survival was 44% after 4 years. In multivariate analysis, recipients of a ≥5α5β mismatched graft with negative CTLp frequencies in vitro before transplantation demonstrated superior survival: survival at 4 years was 80% as compared to 47% in recipients of other mismatched grafts with negative CTLp frequencies (hazard ratio = 0.131; 95% CI = (0.03-0.61); P = 0.009). This option of acceptable mismatches may enlarge the pool of potentially acceptable stem cell donors.