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Abstract: There are concerns in the community that immune activation after vaccination could lead to (subclinical) rejection. Our aim was to define if pneumococcal vaccination induced HLA antibodies using highly sensitive methods. Forty-nine kidney transplant recipients were immunized with Pneumovax 23. The median interval between transplantation and vaccination was 6.5years, the median serum creatinine concentration 1.3, 1.3 and 1.4mg/dL pre-vaccination, at month 1 and 15 post-vaccination, respectively. In none of the patients biopsy-proven acute rejection was diagnosed within three years post-vaccination. Pneumococcal, HLA class I and II and major histocompatibility class I-related chain A (MICA) antibodies were determined by Luminex™ technology (xMAP™ Pneumococcal Immunity Panel and LABScreen™ Mixed beads, respectively) and HLA antibodies also by ELISA (Lambda Antigen Tray™). While pneumococcal antibodies were significantly higher at month 1 and 15 post- vs. pre-vaccination (p <0.0001 each), HLA/MICA antibodies remained unchanged as determined by Luminex™ and ELISA. Positive Luminex™ reactions were present in 63%, 67% and 63% (HLA class I), 47%, 47% and 55% (HLA class II) and 29%, 29% and 29% (MICA) pre-vaccination, at month 1 and 15, respectively. In clinically stable kidney transplant recipients there is no evidence for an increase in HLA antibodies after pneumococcal vaccination. [Copyright &y& Elsevier]

Background: Fetuin-A is a negative acute-phase protein, which acts as a potent calcification inhibitor and an antagonist of transforming growth factor-β. Thus, fetuin-A levels are influenced by chronic inflammation and actively affect fibrosis and calcification processes, respectively. Graft rejection, interstitial fibrosis and tubular atrophy, chronic inflammation and calcification are common causes for kidney allograft loss. This study evaluated whether pretransplant fetuin-A levels predict long-term graft survival and rejection episodes in patients after kidney transplantation. Methods: In 206 renal transplant recipients pretransplant fetuin-A levels were measured in serum by ELISA. During the 36 months' active follow-up (median 1,249 days) 13 patients died (94% patient survival) and renal allograft failure was reported in 18 patients (91% graft survival). Results: Pretransplant fetuin-A levels did not differ among patients with incident graft failures as compared to patients with functional graft after long-term follow-up or rejection episodes (fetuin-A: 393.6 ± 46 vs. 384.4 ± 69 vs. 405 ± 27.4 μg/ml). In logistic regression analysis, pretransplant fetuin-A levels did not correlate with graft failure after 3 years' follow-up (p = 0.895). In COX regression analysis, fetuin-A levels were not associated with the time to graft loss. Moreover, fetuin-A levels correlated neither with renal and metabolic parameters nor with cellular or humoral rejection episodes. Conclusion: Pretransplant levels of fetuin-A are not a predictor for renal allograft loss or rejection episodes after 36 months' follow-up in transplant recipients. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Summary: To evaluate the immunoglobulin isotypes of anti-human leukocyte antigen (HLA) antibodies harbored in rejected renal allografts, we isolated proteins by acid elution accumulated in 94 rejected and explanted kidneys and characterized their antibody specificities by complement-dependent cytotoxicity, enzyme-linked immunosorbent assay, and flow cytometry (Luminex) techniques. In addition, we differentially analyzed non-complement-binding immunolglobulin (Ig) G2/4 and IgA1/2 antibodies in the eluates using two modified solid phase assays. We found non-complement-binding IgG2 and IgG4 antibodies in 16/58 (28%) of the IgGall-positive eluates, 15 eluates with anti-HLA class I and 4 with anti-HLA class II specificities, respectively. Anti-HLA class I IgG2/4 antibodies directed against the donor were found in 7 eluates (54% of the IgG2/4-pos. eluates), whereas 2 eluates (50%) had class II IgG2/4 antibodies directed against the donor. IgA1/2 antibodies could be detected in 9 eluates (16%); 5 of them had anti-HLA class I and 5 anti-HLA class II antibodies. We could clearly exhibit that explanted kidney allografts harbor anti-HLA antibodies. Moreover, our study demonstrates that non-complement-binding anti-HLA antibodies accumulate in rejected renal allografts. [Copyright &y& Elsevier]

Abstract: Previously we have reported on the development of antibodies against MICA alleles in kidney transplant recipients. These alloantibodies have now been determined using a new assay using Luminex beads bound to soluble recombinant MICA antigens produced in insect cells. In the present study we have analyzed sera from 85 kidney transplant recipients on the waiting list and 66 patients transplanted within the last 4 years and 59 acid eluates obtained from allograft nephrectomy specimens. Many of the patients in those groups were sensitized and some had previous transplants (waiting list: 15%; post-tx: 7.6%; eluates 22%) and their sera were found to contain anti-human leukocyte antigen (HLA) and anti-MICA antibodies. Anti-MICA antibodies were detected in 21/85 (24.7%) of the waiting list patients and in 15/66 (22.7%) of the transplanted recipients; 11 of the eluates (18.6%) were found to have MICA-specific antibodies (6 of them also had anti-HLA antibodies and 5 did not). These data suggested that immunization against mismatched MICA alleles induces development of anti-MICA antibodies. The finding of MICA allele-specific antibodies in eluates of kidney transplants suggests that anti-MICA antibodies can be involved in the pathogenesis of kidney allograft rejection. Further studies will be required to determine whether patients who produce alloantibodies against MICA alleles are at risk for transplant rejection even when no HLA antibodies are detected. [Copyright &y& Elsevier]

The human leukocyte antigen G (HLA-G) is an immune checkpoint molecule with a complex network of interactions with several inhibitory receptors. Although the effect of HLA-G on T cells and NK cells is well studied, the effect of HLA-G on B cells is still largely elusive. B cells are of particular interest in the context of the HLA-G-ILT-2 interaction because the ILT-2 receptor is constitutively expressed on most B cells, whereas it is only present on some subsets of T and NK cells. To characterize the effect of HLA-G5 molecules on B cells, we studied splenic B cells derived from cytomegalovirus (CMV) sero-positive donors after CMV stimulation with antigens in the presence and absence of soluble HLA-G5. In the presence of HLA-G5, increased expression of the ITIM-bearing Ig-like transcript (ILT-2) was observed on B cells, but its expression was not affected by stimulation with CMV antigens. Moreover, it became evident that HLA-G5 exposure resulted in a decreased expression of CD27 and CD38 and, accordingly, in lower proportions of CD19+CD27+CD38+ and higher proportions of CD19+CD27-CD38- B cells. Taken together, our in vitro findings demonstrate that soluble HLA-G5 suppresses markers of B cell activation, suggesting that HLA-G5 has an impact on splenic B cell differentiation and activation. Based on these results, further investigation regarding the role of HLA-G as a prognostic factor and a potential therapeutic agent with respect to B cell function appears reasonable. [ABSTRACT FROM AUTHOR]

Abstract: Living kidney donation provides the advantage of assessing immunologic risk in detail before transplantation. It was our aim to analyze how results of an amplified flow cytometry crossmatch (FCXM) predict antibody-mediated rejection. T-cell–specific antibodies were analyzed in 92 donor/recipient pairs (164 datasets, average of 1.8 datasets per pair) with negative lymphocytotoxic crossmatch. FCXM results were expressed as delta values of the median fluorescence intensity (MFI), i.e., donor-specific MFI minus negative control. Based on receiver operating curve analysis, positive FCXM results were defined as delta MFI > 22. Delta MFI values in recipients with vs. without antibody-mediated rejection were significantly higher (n = 6 vs n = 86, p < 0.005). Recipients were grouped into those with reproducibly negative, varying, and reproducibly positive results (n = 69, n = 12, and n = 11, respectively). Only one of 69 patients with reproducibly negative results displayed antibody-mediated rejection, yielding a negative predictive value of 99%. Furthermore Fisher''s exact test showed that the relative risk of a single positive FCXM result for antibody-mediated rejection is 10.1. Thus a negative T-cell FCXM before kidney transplantation is an excellent predictor of the absence of antibody-mediated rejection. [Copyright &y& Elsevier]

Background: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be life-threatening, and specific antiviral drugs are currently not available. However, first studies indicated that convalescent plasma treatment might improve the clinical outcome of coronavirus disease 2019 (COVID-19) patients.Study Design and Methods: In the current study, we investigated the efficacy of convalescent plasma treatment in eight COVID-19 patients. All the patients were critically ill, and seven of them were SARS-CoV-2 RNA-positive when starting treatment. SARS-CoV-2-specific antibodies were determined by an enzyme-linked immunosorbent assay detecting immunoglobulin G (IgG) antibodies against the S1 protein (Euroimmun), and the neutralizing titers were determined with a cell-culture-based neutralization assay. Plasma treatment started between 4 and 23 days after the onset of symptoms. The patients were usually treated by three plasma units, each containing 200-280 ml, which was applied at day 1, 3, and 5.Results: Donor sera had on average lower IgG antibody ratios and neutralizing titers than the COVID-19 patients before the onset of treatment (median ratio of 5.8 and neutralizing titer of 1:320 vs. 7.5 and 1:640, respectively). Nevertheless, we observed an increase of antibody ratios in seven and of neutralizing titers in five patients after treatment; which did, however, not correlate with patient survival. Plasma treatment was effective in three patients, but five deceased despite treatment. Patients who deceased had a later treatment onset than survivors and finally died from multiple organ failure.Conclusion: Our data indicate that the efficacy of convalescent plasma treatment of critically ill COVID-19 patients who already had developed strong antiviral immune responses and organ complications is limited. [ABSTRACT FROM AUTHOR]

We investigated immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among a group of convalescent, potential blood donors in Germany who had PCR-confirmed SARS-CoV-2 infection. Sixty days after onset of symptoms, 13/78 (17%) study participants had borderline or negative results to an ELISA detecting IgG against the S1 protein of SARS-CoV-2. We analyzed participants with PCR-confirmed infection who had strong antibody responses (ratio >3) as positive controls and participants without symptoms of SARS-CoV-2 infection and without household contact with infected patients as negative controls. Using interferon-γ ELISpot, we observed that 78% of PCR-positive volunteers with undetectable antibodies showed T-cell immunity against SARS-CoV-2. We observed a similar frequency (80%) of T-cell immunity in convalescent donors with strong antibody responses but did not detect immunity in negative controls. We concluded that, in convalescent patients with undetectable SARS-CoV-2 IgG, immunity may be mediated through T cells. [ABSTRACT FROM AUTHOR]

The immunosuppressive non-classical human leukocyte antigen-G (HLA-G) promotes transplant tolerance as well as viral immune escape. HLA-G expression is associated with regulatory elements targeting certain single nucleotide polymorphisms (SNPs) in the HLA-G 3 ′ untranslated region (UTR). Thus, we evaluated the impact of HLA-G 3′UTR polymorphisms as surrogate markers for BK polyomavirus (BKPyV) replication or nephropathy (PyVAN) and acute cellular and antibody mediated rejection (ACR/AMR) in 251 living-donor kidney-transplant recipient pairs. After sequencing of the HLA-G 3 ′ UTR, fourteen SNPs between +2960 and +3227 and the 14 bp insertion/deletion polymorphism, which arrange as UTR haplotypes, were identified. The UTR-4 haplotype in donors and recipients was associated with occurrence of BKPyV/PyVAN compared to the other UTR haplotypes. While the UTR-4 recipient haplotype provided protection against AMR, the UTR-2 donor haplotype was deleteriously associated with ACR/AMR. Deduction of the UTR-2/4 haplotypes to specific SNPs revealed that the +3003C variant (unique for UTR-4) in donors as well as in recipients is responsible for BKPyV/PyVAN and also provides protection against AMR; whereas the +3196G variant (unique for UTR-2) promotes allograft rejection. Thus, HLA-G 3′UTR variants are promising genetic predisposition markers both in donors and recipients that may help to predict susceptibility to either viral infectious complication of BKPyV or allograft rejection. [ABSTRACT FROM AUTHOR]

In this study, we examined the impact of the rs9264942 single-nucleotide polymorphism, previously shown to be associated with human immunodeficiency virus infection status and HLA-C expression, on the hepatitis C virus status in 359 people who inject drugs (PWID). The linkage of rs9264942 alleles to HLA-C antigens assigned to different expression levels was confirmed. Multivariate analysis revealed the age (P = .003) and the rs9264942 genotype (P = .006) to be independent factors for the classification to the PWID groups. Our study showed that the presence of the rs9264942 C/C genotype was associated with persistent seronegativity. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) causes serious complications among solid organ transplant recipients. We report the positive correlation between the presence of the HLA-E*01:03 allele in living-donor kidney recipients and CMV reactivation during the first year after transplantation. Thus, HLA-E genotyping may help identify CMV replication-prone patients who require individualized patient-based CMV management. [ABSTRACT FROM AUTHOR]

The expression modulation of the immunosuppressive non-classical Human leukocyte antigen-G (HLA-G) molecule and its soluble isoforms is an immune evasion strategy being deployed by cytomegalovirus (CMV). The +3142 C>G single nucleotide polymorphism (SNP) located within the 3' untranslated region (3'UTR) is of crucial importance for the regulation of HLA-G expression. Therefore, we analyzed the influence of the +3142 C>G HLA-G SNP on the occurrence of CMV infection in a cohort of 178 living-donor kidney recipients and their 178 corresponding donors. In addition, soluble HLA-G (sHLA-G) levels were quantified before and after transplantation. The presence of the HLA-G +3142 CC genotype in recipients, but not donors of our cohort as along with elevated sHLA-G levels (≥6.1 ng/mL) were associated with higher susceptibility to CMV infection after transplantation. Our results provided evidence that (i) HLA-G is implicated in the establishment of CMV after living-donor kidney transplantation and (ii) recipient HLA-G +3142 CC genotype and sHLA-G concentration levels could represent important predictive risk markers for CMV infection. [ABSTRACT FROM AUTHOR]

Background & Aims Natural killer (NK) cell function is regulated by inhibitory and activating receptors including killer cell immunoglobulin-like receptors (KIRs). Here, we analyzed the impact of different KIR/KIR-ligand genotypes on the outcome of hepatitis C virus (HCV) infection in people who inject drugs (PWID). Methods KIR/KIR-ligand genotypes associated with spontaneous clearance of HCV infection were identified in a cohort of PWID from Germany (n = 266) and further validated in a second anti-HCV positive cohort of PWID recruited in North America (n = 342). NK cells of PWID and healthy donors were functionally characterized according to their KIR/KIR-ligand genotype by flow cytometry. Results Multivariate logistic regression analysis revealed that KIR3DL1 /HLA-Bw4 80(T) was associated with spontaneous clearance of HCV infection in PWID, which was confirmed in the PWID cohort from North America. Compared with PWID with detectable HCV RNA, the frequency of individuals with multiple HLA-Bw4 alleles was significantly higher in anti-HCV positive PWID with resolved HCV infection (29.7% vs. 15.2%; p = 0.0229) and in anti-HCV seronegative PWID (39.2%; p = 0.0006). KIR3DL1 + NK cells from HLA-Bw4 80(T)-positive PWID showed superior functionality compared to HLA-Bw4 80(I)-positive PWID. This differential impact was not observed in healthy donors; however, the HLA-Bw4 copy number strongly correlated with the functionality of KIR3DL1 + NK cells. Conclusions HLA-Bw4-80(T) and multiple HLA-Bw4 copies in combination with KIR3DL1 are associated with protection against chronic hepatitis C in PWID by distinct mechanisms. Better licensing of KIR3DL1 + NK cells in the presence of multiple HLA-Bw4 copies is beneficial prior to seroconversion whereas HLA-Bw4 80(T) may be beneficial during acute hepatitis C. Lay summary: Natural killer (NK) cells are part of the innate immune system and are regulated by a complex network of activating and inhibiting receptors. The regulating receptor-ligand pairs of an individual are genetically determined. Here, we identified a particular set of ligand and receptor genes that are associated with better functionality of NK cells and better outcome upon exposure to HCV in a high-risk group. [ABSTRACT FROM AUTHOR]

Background Donor-specific antibodies ( DSAs) are an important cause of complications after solid organ transplant. Risk factors and, thus, strategies for preventing DSA development are not well defined. Methods The DSA status of 400 patients who underwent liver transplant ( LT) at the outpatient clinic of the University Hospital Essen was determined. Human leukocyte antigen ( HLA) antibodies were detected by single-antigen bead technology. The strength of DSAs was reported as mean fluorescence intensity. Results Detectable DSAs were found in 74 (18.5%) patients and significantly more often in patients who underwent LT for autoimmune liver disease than for all other indications (29.3%; P=.022), but significantly less often found in patients who underwent LT for hepatocellular carcinoma (7.6%, P=.005). The incidence of DSAs increased with time after LT, and the risk was generally higher for female patients. The frequency of DSA detection was significantly lower (10.6%) for patients receiving immunosuppressive treatment with mammalian target of rapamycin ( mTOR) inhibitors than for those receiving other regimens (20.5%; P=.025). Conclusion Autoimmune liver diseases, female sex, and time of more than 8 years since LT predispose patients to the development of DSAs. Immunosuppression with the mTOR inhibitor everolimus protects against DSA development after liver transplant. [ABSTRACT FROM AUTHOR]

Non-classical Human Leukocyte Antigen (HLA)-E preferentially presents leader peptides derived from classical HLA-class I molecules. HLA-E can trigger opposed immune responses by interacting with inhibitory NKG2A or by activating NKG2C receptors on NK and T-cells. We studied the impact of HLA-E on renal allograft survival during acute cellular rejection. HLA-E expression was up-regulated in acute cellular rejection (ACR) biopsies (n = 12) compared to biopsies from 13 renal allografts with no rejection-signs. HLA-E up-regulation was correlated with numbers of HLA-class I leader peptide mismatches (p = 0.04). CD8+ and CD56+ infiltrating cells correlated with HLA-E expression (p < 0.0001 and p = 0.0009, respectively). Activating NKG2C receptor dominated on effector cells in biopsies and peripheral blood during ACR potentially allowing HLA-E-mediated immune activation. Moreover, HLA-E expression correlated with deterioration in renal allograft function (p < 0.008) and reduced allograft survival (p = 0.002). Our findings provide evidence that during renal allograft rejection HLA-E along with high numbers of mismatched HLA-class I leader peptides might represent additional targets for immune-activating responses. [ABSTRACT FROM AUTHOR]

CD8+ T cells are an essential component of successful adaptive immune responses against hepatitis C virus (HCV). A major obstacle to vaccine design against HCV is its inherent viral sequence diversity. Here, we test the hypothesis that different sequence variants of an immunodominant CD8+ T cell epitope, all binding with high affinity to HLA class I, target different T cell receptor repertoires and thereby influence the quality of the CD8+ T cell response. The impacts of sequence differences in the HLA-A*02-restricted HCV NS31406-1415 epitope on in vitro priming of naive CD8+ T cells from seronegative donors and cross-reactivity of primed T cells with other epitope variants were characterized. Although the six epitope variants tested were all high-affinity binders to HLA-A*02:01, substantial differences in priming and cross-reactivity of CD8+ T cells were observed. The variant associated with the most reproducible priming and induction of T cells with broad cross-reactivity was a genotype 1b variant (KLSAL GLNAV) that is more common in HCV isolates collected in Asia but is rare in sequences from Europe and North America. The superior immunogenicity and cross-reactivity of this relatively rare epitope variant were confirmed by using HCV-specific memory CD8+ T cells from people who inject drugs, who are frequently exposed to HCV. Collectively, the data suggest that sequence differences at the epitope level between HCV isolates substantially impact CD8+ T cell priming and the degree of cross-reactivity with other epitope variants. [ABSTRACT FROM AUTHOR]

Non-responsiveness to conventional hepatitis B vaccines in individuals at high risk of exposure to hepatitis B virus (HBV) is an important public health problem and of particular relevance in health care providers. Yeast-derived conventional HBsAg vaccines fail to induce protective antibody titers in up to 10% of immune competent vaccinees. Therefore, a third generation HBV vaccine, Sci-B-Vac™, was developed which contains in addition to the small S antigen the PreS1 and PreS2 antigens. This vaccine proved to induce a highly potent cellular and humoral immune response in healthy individuals as well as protective antibody levels in non- and low-responders to conventional HBV vaccines. The aim of the study was to examine whether Sci-B-Vac™ triggers cellular and humoral immunity in individuals who failed immunization with conventional vaccines. We immunized 21 volunteers (15 non- and 6 low-responders) according to the standard vaccination schedule (0, 4 and 24 weeks), determined the cellular immunity by proliferation assay and interferon (IFN)-γ ELISpot and measured the anti-HBs antibody titers prior to each vaccination and four weeks after the third vaccine dose. Following three vaccinations, PreS/S-specific T-cell proliferation was detected in 8 out of 15 non-responders and 5 out of 6 low-responders. Specific IFN-γ responses were measured in 2 out of 15 non-responders and 4 out of 6 low-responders. All but one (20/21) study participants developed anti-HBs titers ≥10 IU/l after three vaccinations. Anti-HBs ≥100 IU/L were detected in 12 out of 15 non-responders and in 6 out of 6 low-responders. Anti-HBs ≥10 IU/l and <100 IU/l were found in 2 non-responders. These results indicate that Sci-B-Vac™ induces cellular immunity as well as protective anti-HBs antibody titers in non- and low-responders. In conclusion, these results confirm that Sci-B-Vac™ should be administered to non-responders to conventional HBV vaccines and patients with impaired immune function. [ABSTRACT FROM AUTHOR]

Despite continuous high-risk behavior, a subgroup among people who inject drugs (PWID) remains seronegative for hepatitis C virus (HCV) suggesting that a state of "natural resistance" to HCV Infection may exist. Homozygosity for KIR2DL3 and its ligand HLA-C1 group alleles has been associated with control of HCV infection, however, the mechanism mediating this protective effect remained unclear. Methods Peripheral NK cells from PWID (n=104) were phenotypically and functionally characterized by multicolor flow cytometry. Expression levels of the NK cell receptor ligands were analysed in liver biopsies and primary human hepatocytes. Results HCV seronegative PWID (n=34) had increased levels of KIR2DL3+NKG2A− NK cells compared to healthy controls (n=10; p<0.001) and PWID with chronic (n=38; p<0.001) or resolved infection (n=37; p<0.001). There was an inverse correlation between the frequency of KIR2DL3+ and NKG2A+ NK cells (r=−0.53; p<0.0001). Importantly, expression of HLA-E, the ligand for NKG2A, was significantly upregulated in liver biopsies of HCV infected patients (n=51) compared to HBV infected patients (n=22; p<0.01) and correlated with HCV viral load (r=0.32; p<0.0029). In functional analyses KIR2DL3−NKG2A+ NK cells but not KIR2DL3+NKG2A− NK cells were significantly inhibited by HLA-E ligation. Accordingly, interferon gamma secretion of NK cells from PWID with chronic infection but not from HCV seronegative PWID was significantly suppressed in the presence of HLA-E. Conclusions KIR2DL3+NKG2A− NK cells are not sensitive to HLA-E-mediated inhibition and may thereby control early HCV infection prior to seroconversion and result in an apparent state of "natural resistance" to HCV in PWID. [ABSTRACT FROM AUTHOR]

Background ABO incompatibility is no longer a barrier in kidney transplantation. C4d is frequently positive in ABO-incompatible (iABO) biopsies without further signs of microcirculation injury. This phenomenon is assumed to represent graft accommodation. However, ultrastructural examination of glomerular and peritubular capillary endothelium might reveal subtle endothelial damage. Methods We studied the ultrastructural appearance of the endothelium in 67 biopsies from 21 patients with iABO allografts and compared it with 20 patients (29 biopsies) with ABO-compatible (cABO) grafts with C4d positivity and 25 ABO-compatible control patients (25 biopsies) without serological or histological evidence of humoral rejection (C4d negative). Ten ultrastructural parameters indicative of chronic and acute glomerular and peritubular capillary damage in transmission electron microscopy (TEM) were semi-quantitatively graded and expressed in a sum score. Clinico-pathological data were compared as well as graft function at the time of biopsy and follow-up. Results Ultrastructural parameters did not significantly differ between iABO and controls. In contrast, C4d-positive cABO had the highest TEM sum score (P = 0.001 versus iABO, P = 0.002 versus controls). The sum score did not differ between C4d-positive and C4d-negative iABO but did differ between patients with and without anti-HLA donor-specific antibodies (DSA). Graft function in iABO at the time of biopsy and at follow-up was similar to controls. Conclusions Our ultrastructural observations support the concept of endothelial accommodation in iABO renal transplants. C4d positivity in the ABO-incompatible situation does not indicate injurious activation of the complement cascade and does not seem to impact on the graft function, in contrast to C4d deposition in cABO with antibody-mediated rejection. [ABSTRACT FROM AUTHOR]

Background & Aims: The antiviral immune response against HCV by CD8+ T cells plays a central role in viral containment. In a large HCV genotype 1b outbreak in Ireland, HLA-B∗08 was identified as a risk allele for chronic infection and HLA-A∗03 and HLA-B∗27 were associated with higher clearance rates. Here we took advantage of a similar large common source HCV genotype 1b outbreak (East-German cohort) to determine the role of HLA class I alleles and the sequence of the infection source, in immunodominant CD8+ T cell epitopes for disease outcome. Methods: HLA-type and IL28B genotype were determined in 216 patients with chronic and 95 with spontaneously resolved HCV infection. The viral sequence in immunodominant epitopes was determined in the infection source and in patients with chronic infection. Results: In contrast to the Irish cohort, HLA-B∗08, HLA-A∗03 and HLA-B∗27 were neutral for disease outcome even when the cohort was stratified for the IL28B genotype. Sequence analysis of the immunodominant epitopes revealed that pre-existing substitutions in the infection source of both cohorts influenced the impact of the corresponding HLA-allele. The immunodominant epitopes presented by the “protective” alleles HLA-A∗03 and -B∗27 in the Irish cohort contained substitutions in the source virus of the East-German outbreak. Importantly, the pre-existing substitutions altered subsequent selection pressure and viral evolution in the East-German cohort. Conclusions: This study highlights that subtle sequence differences in the infection source may have profound effects on the ability to clear HCV infection in the presence of particular HLA class I alleles. [ABSTRACT FROM AUTHOR]

Abstract: Background: In kidney transplant recipients endothelial dysfunction is almost a universal risk factor for allograft failure. Adiponectin, an adipocyte derived hormone, has endothelial-protective properties and the high-molecular weight (HMW) multimer is the major active form, exerting anti-inflammatory and anti-apoptotic effects on endothelial cells. This study evaluated, whether pre-transplant total and HMW multimer adiponectin levels are associated with markers of endothelial dysfunction and arteriosclerosis and predict long-term graft survival in patients after kidney transplantation. Methods: In 206 renal transplant recipients pre-transplant total and HMW adiponectin levels were measured in serum by ELISA and Western blot, respectively. During the 36months active follow up (median [interquartile range] 1249 [1020; 1445] days) 13 patients died (94% patient survival) and renal allograft failure was reported in 18 patients (91% graft survival). Results: Pre-transplant total and HMW adiponectin levels were significantly associated with lipid and glucose parameters at baseline. After 3years follow-up pre-transplant total and HMW adiponectin levels were significantly inversely associated with the incidence of allograft failure (adiponectin: r=−0.216; p=0.002: HMW: r=−0.218; p=0.002). In multivariable adjusted Cox proportional hazard regression models patients in the lowest total and HMW adiponectin quartile had a significantly increased risk for allograft failure within 3years post-transplantation: odds ratio [95%CI]: total adiponectin: 4.25 [1.27–14.24; p=0.019], and HMW multimers: 3.35 [1.04–10.76; p=0.042], respectively. Conclusion: Low pre-transplant levels of total and HMW adiponectin reflect a pro-atherogenic endothelial milieu and independently predict an increased risk of allograft failure in kidney-transplant recipients. Measurement of adiponectin levels may identify patients at risk for adverse allograft outcomes after kidney transplantation. [Copyright &y& Elsevier]

Background Biliary strictures after liver transplantation ( LT) are a major cause of morbidity and reduced graft survival. Aims The purpose of this study was to investigate genetic, immunological and clinical risk factors for the occurrence of post- LT ischaemic type biliary lesions ( ITBLs) and biliary anastomotic strictures ( AS). Methods Clinical and laboratory data, chemokine receptor ( CCR) genotypes, chemotactic cytokines and anti-major-histocompatibility complex antibodies in serum were investigated in 162 LT patients. Results In the univariate analysis, older donor and recipient age, partial LT, high peak aspartate aminotransaminase ( AST) levels and CC chemokine receptor 5 delta32 loss-of-function mutation ( CCR5Δ32) were associated with ITBL, whereas LT for acute liver failure ( ALF), ABO-compatible non-identical LT, presence of donor-specific anti-human leucocyte antigen ( HLA) class II antibodies and fractalkine receptor ( CX3 CR1)-249 II allele were associated with AS. In the multivariate analysis, CCR5Δ32 was an independent risk factor for ITBL, whereas LT for ALF, ABO-compatible non-identical LT, and CX3 CR1-249 II allele remained predictive for AS. Serum levels of interferon-gamma and interleukin ( IL)-6 as well as IL-10 were significantly increased in patients with biliary strictures. Conclusion Specific chemokine receptor polymorphisms of the recipient are associated with development of post- LT biliary strictures. Altered cytokine profile may contribute to enhanced fibrotic tissue remodelling and biliary stricture formation. Screening of anti- HLA antibodies might be useful for early identification of at-risk patients who could benefit from closer surveillance and tailored immunosuppressive regimen. Our findings may have relevance for prediction and management of post- LT biliary strictures. [ABSTRACT FROM AUTHOR]

T follicular helper (T FH) cells are a heterogeneous subset of immunocompetent T helper (T H) cells capable of augmenting B cell responses in lymphoid tissues. In transplantation, exposure to allogeneic tissue activates T FH cells increasing the risk of the emergence of de novo donor-specific HLA-antibodies (dnDSA). These can cause antibody-mediated rejection (AMR) and allograft loss. Follicular regulatory T (T FR) cells counteract T FH cell activity. Here, we investigated the implications of T FH and T FR cells on dnDSA formation after renal transplantation (RTX). Considering T FH cells to be CXCR5+ and IL-21+, we found by flow cytometry that patients with dnDSA produced IL-21 more abundantly compared to healthy volunteers. In in vitro alloreactivity assays, patients with dnDSA featured an enhanced alloreactive T H cell pool in response to donor-specific HLA antigens. Besides, longitudinal investigations suggested enhanced alloreactivity shortly after transplantation increasing the risk of dnDSA development. Taken together, in spite of continuous immunosuppression we report a strong IL-21 response in T FH cells and an expanded reservoir of donor-specific memory T H cells in patients with dnDSA. This warrants further investigations if aberrant T FH cell activation may precede the formation of dnDSA promoting AMR. • CNI are in principle potent suppressors of IL-21 producing T FH cells • T FH cells show unaltered frequencies after RTX in patients with DSA • T FH cell cytokine profile is not different comparing patients with DSA versus without DSA • Patients with dnDSA featured an enhanced alloreactive Th cell pool in response to donor-specific HLA antigens [ABSTRACT FROM AUTHOR]

Human leukocyte antigen (HLA)-E is important for the regulation of anti-viral immunity. BK polyomavirus (BKPyV) reactivation after kidney transplant is a serious complication that can result in BKPyV-associated nephropathy (PyVAN) and subsequent allograft loss. To elucidate whether HLA-E polymorphisms influence BKPyV replication and nephropathy, we determined the HLA-E genotype of 278 living donor and recipient pairs. A total of 44 recipients suffered from BKPyV replication, and 11 of these developed PyVAN. Homozygosity of the recipients for the HLA-E*01:01 genotype was associated with the protection against PyVAN after transplant (p = 0.025, OR 0.09, CI [95%] 0.83–4.89). Considering the time course of the occurrence of nephropathy, recipients with PyVAN were more likely to carry the HLA-E*01:03 allelic variant than those without PyVAN (Kaplan–Meier analysis p = 0.03; OR = 4.25; CI (95%) 1.11–16.23). Our findings suggest that a predisposition based on a defined HLA-E genotype is associated with an increased susceptibility to develop PyVAN. Thus, assessing HLA-E polymorphisms may enable physicians to identify patients being at an increased risk of this viral complication. [ABSTRACT FROM AUTHOR]

The polymorphic major histocompatibility complex class I chain-related molecule A (MICA) and its soluble form (sMICA) interact with activating receptor natural-killer group 2 member D (NKG2D) on natural-killer (NK) and T cells, thereby modifying immune responses to transplantation and infectious agents (e.g., cytomegalovirus). Two single-nucleotide polymorphisms (SNPs), rs2596538GA in the MICA promoter and rs1051792AG in the coding region (MICA-129Val/Met), influence MICA expression or binding to NKG2D, with MICA-129Met molecules showing higher receptor affinity. To investigate the impact of these SNPs on the occurrence of cytomegalovirus infection or acute rejection (AR) in individuals who underwent simultaneous pancreas–kidney transplantation (SPKT), 50 recipient-donor pairs were genotyped, and sMICA levels were measured during the first year post-transplantation. Recipients with a Val-mismatch (recipient Met/Met and donor Val/Met or Val/Val) showed shorter cytomegalovirus infection-free and shorter kidney AR-free survival. Additionally, Val mismatch was an independent predictor of cytomegalovirus infection and kidney AR in the first year post-transplantation. Interestingly, sMICA levels were lower in rs2596538AA and MICA129Met/Met-homozygous recipients. These results provide further evidence that genetic variants of MICA influence sMICA levels, and that Val mismatch at position 129 increases cytomegalovirus infection and kidney AR risk during the first year post-SPKT. [ABSTRACT FROM AUTHOR]

An abstract of the article "Escape from a Dominant HLA-B*15-Restricted CD8+ T Cell Response against Hepatitis C Virus Requires Compensatory Mutations outside the Epitope," by Marianne Ruhl and colleagues is presented.