Hepatitis C virus (HCV) infection causes significant morbidity and mortality worldwide. T cells play a central role in HCV clearance; however, there is currently little understanding of whether the disease outcome in HCV infection is influenced by the choice of TCR repertoire. TCR repertoires used against two immunodominant HCV determinants—the highly polymorphic, HLA-B*0801 restricted 1395HSKKKCDEL1403 (HSK) and the comparatively conserved, HLA-A*0101–restricted, 1435ATDALMTGY1443 (ATD)—were analyzed in clearly defined cohorts of HLA-matched, HCV-infected individuals with persistent infection and HCV clearance. In comparison with ATD, TCR repertoire selected against HSK was more narrowly focused, supporting reports of mutational escape in this epitope, in persistent HCV infection. Notwithstanding the Ag-driven divergence, T cell repertoire selection against either Ag was comparable in subjects with diverse disease outcomes. Biased T cell repertoires were observed early in infection and were evident not only in persistently infected individuals but also in subjects with HCV clearance, suggesting that these are not exclusively characteristic of viral persistence. Comprehensive clonal analysis of Ag-specific T cells revealed widespread use of public TCRs displaying a high degree of predictability in TRBV/TRBJ gene usage, CDR3 length, and amino acid composition. These public TCRs were observed against both ATD and HSK and were shared across diverse disease outcomes. Collectively, these observations indicate that repertoire diversity rather than particular Vβ segments are better associated with HCV persistence/clearance in humans. Notably, many of the anti-HCV TCRs switched TRBV and TRBJ genes around a conserved, N nucleotide-encoded CDR3 core, revealing TCR sequence mosaicism as a potential host mechanism to combat this highly variant virus.

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To analyse the immune correlates in a setting of recurrent exposure to hepatitis C virus (HCV), we studied T CD8 responses in injecting drug users (IDUs) with different disease outcomes. Ex vivo HCV-specific T CD8 responses assessed by interferon-c (IFNc) enzyme-linked immunospot (ELISPOT) were comparable in human lymphocyte antigen (HLA)-matched IDUs with spontaneous HCV clearance or persistent infection. A detailed characterization of these T CD8 cells in age and HLA-matched IDUs demonstrated that HCV clearance and protection from reinfection correlated with HCV-specific T CD8 cells that could proliferate in vitro, possessed cytotoxic potential and produced IFNc and tumour-necrosis factor-a, rather than with the circulating frequency of responding T CD8 cells determined ex vivo. While validating the importance of multifunctional T CD8 in mediating protection in IDUs with recurrent exposure to HCV our findings highlight that the magnitude and/or breadth of HCV-specific T CD8 determined in ex vivo ELISPOT may not be the sole determinant of protection especially in a setting of recurrent exposure. Keywords: hepatitis C virus; injecting drug users; T-cell responseInfection with hepatitis C virus (HCV) is a major public health problem worldwide, with injecting drug use being the most common route of HCV transmission. 1 HCV seroprevalence in long-term injecting drug users (IDUs) ranges from 60 to 90%. Cellular immunity, comprised of T CD8 and T CD4 responses, is known to be essential for spontaneous resolution of acute HCV infection and long-term protection from persistent infection. [2][3][4][5][6][7][8][9] There are, however, conflicting reports in regards to the frequency of HCV-specific T CD8 cells in different disease outcomes. 2,[7][8][9] This discrepancy can be due to the wide spectrum in duration of persistent HCV infection (6 months to 420 years). MHC-I polymorphism can also influence the study of T CD8 responses due to (1) differences in ethnic backgrounds affecting the response to different epitopes and (2) the influence of the number of T CD8 determinants known/tested for each human lymphocyte antigen (HLA) type. As well, certain HLA phenotypes have been implicated in the outcome of HCV infection. 10,11 It is reported that specific HLA-B alleles such as HLA-B8 can play a dominant role in the outcome and evolution of HCV. 10 Towards a better understanding of the role of T CD8 across the clinical spectrum of HCV infection and to identify the correlates of protection in a setting of recurrent exposure, our aim was to compare T CD8 responses in IDUs who clear HCV naturally versus those who get persistent HCV infection. To control for the differences in HLA types and for the variable number of peptide determinants, we stratified donors for the common MHC-1 allotypes, HLA-A1 and B8 across the different clinical outcomes. HCV-specific T CD8 responses were then examined comprehensively, in age-and HLA-matched HCV-infected IDUs who had either cleared HCV spontaneously or were persistently infected and had an ong...

In this multicentre study, sera from 803 retransplant candidates, including 775 kidney transplant recipients, were analysed with regard to the presence and specificity of anti-HLA alloantibodies of the IgA isotype using a modified microsphere-based platform. Of the kidney recipients, nearly one-third (n = 237, 31%) had IgA alloantibodies. Mostly, these antibodies were found in sera that also harboured IgG alloantibodies that could be found in a total of 572 (74%) of patients. Interestingly, IgA anti-HLA antibodies were preferentially targeting HLA class I antigens in contrast to those of the IgG isotype, which targeted mostly both HLA class I and II antigens. Donor specificity of the IgA alloantibodies could be established for over half of the 237 patients with IgA alloantibodies (n = 124, 52%). A further 58 patients had specificities against HLA-C or HLA-DP, for which no information regarding donor typing was available. In summary, these data showed in a large cohort of retransplant candidates that IgA alloantibodies occur in about one-third of patients, about half of these antibodies being donor specific.

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SummaryWe reported previously on the widespread occurrence of anti-HLA alloantibodies of the IgA isotype (anti-HLA IgA) in the sera of solid-organ re-transplantation (re-tx)candidates (Arnold et al., 2013). Specifically focussing on kidney re-tx patients, we now extended our earlier findings by examining the impact of the presence and donor specificity of anti-HLA IgA on graft survival. We observed frequent concurrence of anti-HLA IgA and anti-HLA IgG in 27% of our multicenter collective of 694 kidney re-tx patients. This subgroup displayed significantly reduced graft survival as evidenced by the median time to first dialysis after transplantation (TTD 77 months)

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