Genome-wide association studies in kidney transplantation: Advantages and constraints

Since the discovery of the human leukocyte antigen (HLA) system, the role of HLA molecules in the field of transplantation has been appreciated: better matching leads to better graft function. Since then, the association of other genetic polymorphisms with clinical outcome has been investigated in many studies. Genome-wide association studies (GWAS) represent a powerful tool to identify causal genetic variants, by simultaneously analyzing millions of single nucleotide polymorphisms scattered across the genome. GWAS in transplantation may indeed be useful to reveal novel markers that may potentially be involved in the mechanism of allograft rejection and graft failure. However, the relevance of GWAS for risk stratification or donor selection for an individual patient is limited as is already reflected by the fact that many parameters, significant in one study,  cannot be confirmed in another one.   Stemcel biology/Regenerative medicine (incl. bloodtransfusion

Heterologous immunity of virus-specific T cells leading to alloreactivity: possible implications for solid organ transplantation

Exposure of the adaptive immune system to a pathogen can result in the activation and expansion of T cells capable of recognizing not only the specific antigen but also different unrelated antigens, a process which is commonly referred to as heterologous immunity. While such cross-reactivity is favourable in amplifying protective immune responses to pathogens, induction of T cell-mediated heterologous immune responses to allo-antigens in the setting of solid organ transplantation can potentially lead to allograft rejection. In this review, we provide an overview of murine and human studies investigating the incidence and functional properties of virus-specific memory T cells cross-reacting with allo-antigens and discuss their potential relevance in the context of solid organ transplantation.Transplantation and autoimmunit

HLA-C antibodies in women with recurrent miscarriage suggests that antibody mediated rejection is one of the mechanisms leading to recurrent miscarriage

AbstractHLA-C is the only polymorphic classical HLA I antigen expressed on trophoblast cells. It is known that higher incidence of C4d deposition on trophoblast cells is present in women with recurrent miscarriage. C4d is a footprint of antibody-mediated classical complement activation. Therefore, this study hypothesize that antibodies against HLA-C may play a role in the occurrence of unexplained consecutive recurrent miscarriage.Present case control study compared the incidence of HLA-C specific antibodies in 95 women with at least three consecutive miscarriages and 105 women with uneventful pregnancy. In the first trimester of the next pregnancy, presence and specificity of HLA antibodies were determined and their complement fixing ability. The incidence of HLA antibodies was compared with uni- and multivariate logistic regression models adjusting for possible confounders.Although in general a higher incidence of HLA antibodies was found in women with recurrent miscarriage 31.6% vs. in control subjects 9.5% (adjusted OR 4.3, 95% CI 2.0–9.5), the contribution of antibodies against HLA-C was significantly higher in women with recurrent miscarriage (9.5%) compared to women with uneventful pregnancy (1%) (adjusted OR 11.0, 95% CI 1.3–89.0). In contrast to the control group, HLA-C antibodies in the recurrent miscarriage group were more often able to bind complement.The higher incidence of antibodies specific for HLA-C in women with recurrent miscarriage suggests that HLA-C antibodies may be involved in the aetiology of unexplained consecutive recurrent miscarriage

Culture of graft-infiltrating cells from cryopreserved endomyocardial biopsies

Graft-infiltrating cells can be cultured from fresh endomyocardial biopsies (EMB) taken after heart transplantation to determine their growth patterns, phenotypic composition, and functional characteristics for clinical or scientific purposes. In this study we investigated whether graft-infiltrating cells can also be cultured successfully after cryopreservation of these EMB. Three different cryopreservation methods were used. One method gave successful growth in 100% of the cases (n = 6): The biopsy fragments were preincubated in 10% vol/vol dimethyl sulfoxide during 5 min at O°C, frozen to -70°C at approximately 1°C per minute, and subsequently immersed and stored in liquid nitrogen. Thawing was performed rapidly in water at 37°C. In addition, the effect of cryopreservation on cell surface phenotype and donor-specific cytotoxicity of these graft-infiltrating cells was analyzed. When compared to cultures of nonfrozen control biopsies, both qualities remained constant in most cases, although a variation in CD4+/CD8+ cell ratio was observed in 33% of these cultures. However, when nonfrozen fragments of size-matched biopsies were cultured separately, a similar variation in phenotype was noted, indicating that this phenomenon can be attributed to sampling variation and not to the cryopreservation procedure. The present findings suggest that it is no longer required to culture fresh (nonfrozen) post-transplant EMB to propagate graft-infiltrating cells: Culturing can be limited to cryopreserved EMB that are selected retrospectively, depending on actual clinical or scientific interests. Besides greatly facilitating the long-term monitoring of heart transplant recipients, this also means a substantial decrease in cost and work load for laboratories involved in heart transplantation

Unspecified donation in kidney exchange: when to end the chain

This paper studies participation of unspecified donors in kidney exchange through simultaneous domino paired donation (DPD) and non-simultaneous extended altruistic donor (NEAD) chains. It extends existing research by investigating the termination of chains, the possibility of transplantation across the blood type barrier, and the impact of incentives in multi-center exchanges. Furthermore, it looks into the effect of various configuration parameters such as the time interval between exchanges. Our analysis is based on a simulation study that uses data of all 438 patient-donor pairs and 109 unspecified donors who were screened at Dutch transplant centers between 2003 and 2011. Because multi-center coordination may raise incentive issues, special attention is paid to individually rational implementation. We find that chains are best terminated when no further segment is part of an optimal exchange within 3 months. Transplantation across the blood type barrier allows for longer continuation of chains, more transplants and more equity among patient groups. NEAD chains perform slightly better than DPD chains, provided that the renege rate is sufficiently low. Additional substantial gains are due to national individually rational coordination. Particularly highly sensitized and blood type O patients benefit. Appropriate timing of ex-changes can further improve these results

Comparison of different luminex single antigen bead kits for memory B cell-derived HLA antibody detection

Transplantation and autoimmunit

Peripheral monitoring of direct and indirect alloantigen presentation pathways in clinical heart transplant recipients

It has been reported that the response to alloantigens presented by the direct and indirect pathway may be of differential relevance after human kidney transplantation. Accordingly, we monitored these routes in peripheral blood mononuclear cells (PBMC) of heart transplant patients from before transplantation and up to 2 years thereafter in an attempt to find a correlation with the clinical status of the patients. Both before and after transplantation, comparable proportions of PBMC samples reacted in mixed lymphocyte culture to nondepleted donor spleen cells (direct route), but never to donor cells depleted for antigen-presenting cells (indirect route). In contrast, the latter route could easily be activated by a nominal antigen and persisted after transplantation, although the proportion of PBMC samples responding was significantly suppressed, irrespective of the occurrence of rejection. Consequently, complete removal of antigen-presenting cells from the stimulator population in a mixed lymphocyte culture with PBMC as responder is not a suitable tool for measuring indirect presentation of alloantigens, and therefore not relevant for monitoring the immunological status of heart transplant recipients

Infectious pathogens may trigger specific allo-HLA reactivity via multiple mechanisms

Nephrolog