Interleukin (IL)-21 supports induction and expansion of CD8(+) T cells, and can also regulate the differentiation of B cells into antibody-producing plasma cells. We questioned whether the number... Show moreInterleukin (IL)-21 supports induction and expansion of CD8(+) T cells, and can also regulate the differentiation of B cells into antibody-producing plasma cells. We questioned whether the number of circulating donor-specific IL-21 producing cells (pc) can predict kidney transplant rejection, and evaluated this in two different patient cohorts. The first analysis was done on pre-transplantation samples of 35 kidney transplant recipients of whom 15 patients developed an early acute rejection. The second study concerned peripheral blood mononuclear cell (PBMC) samples from 46 patients obtained at 6 months after kidney transplantation of whom 13 developed late rejection. Significantly higher frequencies of donor-specific IL-21 pc were found by Elispot assay in both patients who developed early and late rejection compared to those without rejection. In addition, low frequencies of donor-specific IL-21 pc were associated with higher rejection-free survival. Moreover, low pre-transplant donor-specific IL-21 pc numbers were associated with the absence of anti-HLA antibodies. Donor-reactive IL-21 was mainly produced by CD4(+) T cells, including CD4(+) follicular T helper cells. In conclusion, the number of donor-specific IL-21 pc is associated with an increased risk of both early and late rejection, giving it the potential to be a new biomarker in kidney transplantation. Show less
Background. Identification of specific HLA alleles and T-cell epitopes that influence the course of BK polyomavirus (BKPyV) infection after kidney transplantation (KTx), including development of... Show moreBackground. Identification of specific HLA alleles and T-cell epitopes that influence the course of BK polyomavirus (BKPyV) infection after kidney transplantation (KTx), including development of BKPyV-associated nephropathy (BKPyVAN), can be useful for patient risk stratification and possibly vaccine development. Methods. In a retrospective cohort of 407 living kidney donor-recipient pairs, donor and recipient HLA class I and II status were correlated with the occurrence of recipient BKPyV viremia and BKPyVAN in the first year after KTx. Relevant HLA alleles were systematically analyzed for candidate peptide epitopes in silico. Results. Although none of the 78 HLA alleles analyzed increased the risk of BKPyV viremia and BKPyVAN, a considerable reduction of BKPyV viremia and BKPyVAN cases was observed in HLA-B51-positive KTx recipients. Multivariate analysis showed that HLA-B51 positivity, found in 36 (9%) recipients, reduced the risk of viremia approximately fivefold (hazard ratio, 0.18; 95% confidence interval, 0.04-0.73; P = 0.017). Four HLA-B51-restricted putative cytotoxic T lymphocyte epitopes were identified, including a previously described HLA-B super-motif-containing peptide (LPLMRKAYL), encoded by 2 relevant T-antigens (small T and large T) and previously shown to be highly immunogenic. Conclusions. In conclusion, HLA-B51-positive kidney transplant recipients were less susceptible to BKPyV infection, which might be explained by efficient presentation of a particular BKPyV-derived immunogenic peptide. Show less
Schonewille, H.; Rood, J.J. van; Verduin, E.P.; Watering, L.M.G. van de; Haasnoot, G.W.; Claas, F.H.J.; ... ; Brand, A. 2019
Virus-specific T cells have been shown to cross-react with allogeneic HLA (allo-HLA) at a clonal level. However, the impact of a single virus on the allorepertoire has never been investigated at... Show moreVirus-specific T cells have been shown to cross-react with allogeneic HLA (allo-HLA) at a clonal level. However, the impact of a single virus on the allorepertoire has never been investigated at the polyclonal level.We made an inventory of the incidence and specificity of allo-HLA-cross-reactive-virus-specific CD8(+) T cells in 24 healthy individuals. T cells were stained for 25 virus-specific tetramers, and mixed-lymphocyte reactions were performed against a panel of HLA-typed allostimulators. Allospecificity was confirmed by IFN gamma-ELISA using T-cell clones against a panel of HLA-typed cell-lines.The polyclonal immune repertoire directed against CMV alone was associated with a memory response against six allo-HLA molecules. Besides, a single allostimulator activated memory T-cell responses with multiple viral specificities.Concluding, a single virus can substantially broaden the allo-HLA memory T-cell repertoire. This study only looked at CMV- and EBV-specific T cells, whereas the immune repertoire consists of T cells directed against many different viruses. Hence, transplant patients receiving an HLA-mismatched graft may already express a poly clonal repertoire of anti-donor-memory T cells before transplantation. Show less
Craenmehr, M.H.C.; Nederlof, I.; Cao, M.; Drabbels, J.J.M.; Spruyt-Gerritse, M.J.; Anholts, J.D.H.; ... ; Eikmans, M. 2019
Luminex single antigen bead assays revolutionized human leukocyte antigen (HLA) antibody detection owing to their superior sensitivity compared to conventional methods. Nevertheless, the advent of... Show moreLuminex single antigen bead assays revolutionized human leukocyte antigen (HLA) antibody detection owing to their superior sensitivity compared to conventional methods. Nevertheless, the advent of higher sensitivity came at the expense of difficulty in clinical decision-making, since not all luminex detectable antibodies are clinically relevant. Therefore, new tools such as C1q/C3d assays and IgG subclass analysis emerged with the aim to discriminate the inert antibodies from the deleterious ones. Here, we provide an overview on the technical challenges related to these different HLA antibody detection systems and briefly refer to the recent literature regarding the clinical relevance of these assays, mainly in the field of kidney transplantation. Show less
Johnsen, G.M.; Storvold, G.L.; Drabbels, J.J.M.; Haasnoot, G.W.; Eikmans, M.; Spruyt-Gerritse, M.J.; ... ; Stafr, A.C. 2018
Acute atherosis is an arterial lesion most often occurring in pregnancies complicated by preeclampsia, a hypertensive pregnancy disorder. Acute atherosis predominates in the maternal spiral... Show moreAcute atherosis is an arterial lesion most often occurring in pregnancies complicated by preeclampsia, a hypertensive pregnancy disorder. Acute atherosis predominates in the maternal spiral arteries in the decidua basalis layer of the pregnant uterus. This layer forms the fetal-maternal immunological interface, where fetal extravillous trophoblasts interact with maternal immune cells to promote decidual spiral artery remodeling and maternal immune tolerance towards the fetus. Of the classical polymorphic class I HLAs, extravillous trophoblasts express only HLA-C. HLA-C is a ligand for killer immunoglobulin-like receptors (KIR) on NK- and T-cells. Genetic combinations of fetal HLA-C and maternal KIRs affect pregnancy outcome. However, the role of HLA and KIR genes in acute atherosis is unknown.We hypothesized that specific genetic combinations of fetal HLA and maternal KIR are associated with the presence of acute atherosis lesions in the decidua basalis. We genotyped HLA class-I and II loci in paired fetal and maternal DNA samples from 166 pregnancies (83 preeclamptics, 83 controls). Acute atherosis was identified in 38 of these. Maternal KIR-loci were also genotyped.We found that the combination of maternal KIR-B haplotype and fetal HLA-C2 was significantly associated with acute atherosis in preeclampsia. In preeclamptic pregnancies with acute atherosis, 60% had this combination, compared to 24.5% in those without acute atherosis (p = 0.001). We suggest that interactions between fetal HLA-C2 and activating KIRs on maternal decidual NK-cells or T-cells may contribute to the formation of acute atherosis by promoting local decidual vascular inflammation. Show less
