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Donor/recipient molecular human leukocyte antigen (HLA) mismatch predicts primary B-cell alloimmune activation, yet the impact on de novo donor-specific T-cell alloimmunity (dnDST) remains undetermined. The hypothesis of our study is that donor/recipient HLA mismatches assessed at the molecular level may also influence a higher susceptibility to the development of posttransplant primary T-cell alloimmunity. In this prospective observational study, 169 consecutive kidney transplant recipients without preformed donor-specific antibodies (DSA) and with high resolution donor/recipient HLA typing were evaluated for HLA molecular mismatch scores using different informatic algorithms [amino acid mismatch, eplet MM, and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II)]. Primary donor-specific alloimmune activation over the first 2 years posttransplantation was assessed by means of both dnDSA and dnDST using single antigen bead (SAB) and IFN-γ ELISPOT assays, respectively. Also, the predominant alloantigen presenting pathway priming DST alloimmunity and the contribution of main alloreactive T-cell subsets were further characterized in vitro . Pretransplantation, 78/169 (46%) were DST+ whereas 91/169 (54%) DST−. At 2 years, 54/169 (32%) patients showed detectable DST responses: 23/54 (42%) dnDST and 31/54 (57%) persistently positive (persistDST+). 24/169 (14%) patients developed dnDSA. A strong correlation was observed between the three distinct molecular mismatch scores and they all accurately predicted dnDSA formation, in particular at the DQ locus. Likewise, HLA molecular incompatibility predicted the advent of dnDST, especially when assessed by PIRCHE-II score (OR 1.014 95% CI 1.001–1.03, p=0.04). While pretransplant DST predicted the development of posttransplant BPAR (OR 5.18, 95% CI=1.64–16.34, p=0.005) and particularly T cell mediated rejection (OR 5.33, 95% CI=1.45–19.66, p=0.012), patients developing dnDST were at significantly higher risk of subsequent dnDSA formation (HR 2.64, 95% CI=1.08–6.45, p=0.03). In vitro experiments showed that unlike preformed DST that is predominantly primed by CD8+ direct pathway T cells, posttransplant DST may also be activated by the indirect pathway of alloantigen presentation, and predominantly driven by CD4+ alloreactive T cells in an important proportion of patients. De novo donor-specific cellular alloreactivity seems to precede subsequent humoral alloimmune activation and is influenced by a poor donor/recipient HLA molecular matching.

Circulating donor DNA has emerged as a valuable tool for clinical decision-making in kidney transplantation. While most studies focus on cell-free DNA, the role of donor DNA associated with extracellular vesicles (EVs) remains unexplored. To address this, we analyzed donor-derived exosomal DNA (dd-exoDNA) in 100 kidney transplant recipients (KTR) undergoing surveillance or indicated biopsies. Serum exosomes were isolated using precipitation-based technology, and dd-exoDNA was analyzed via digital PCR targeting donor/recipient HLA-DRB1 mismatches. Dd-exoDNA levels were higher in rejection versus non-rejection (2.66 [0.56–7.10] ×10 −3 vs. 0.69 [0.28–1.71] ×10 −3 , p = 0.004) and were associated with Banff score items: glomerulitis ≥1 ( p = 0.037), peritubular capillaritis ≥1 ( p = 0.040), and tubulitis ≥2 ( p = 0.043). In multivariate analysis, dd-exoDNA remained independently associated with rejection, although with wide confidence intervals (OR [95%CI] 3.68 [1.32–10.26], P = 0.013). Exploratory threshold analyses suggested moderate discriminative performance. These findings indicate that donor DNA associated with circulating EVs may offer complementary information to existing biomarkers, warranting validation in external cohorts and comparison with established assays.

Rheumatoid arthritis (RA) is an autoimmune disease influenced by genetic factors, particularly alleles. The objective of this study was to characterize the distribution of alleles in Chilean RA patients and healthy controls (HC) and evaluate associations with susceptibility or protection, autoantibody seropositivity, and disease activity. We genotyped 367 RA patients and 623 HC for using PCR-SSO. Then, we examined allele frequencies and distribution, including known RA risk alleles of the \"Shared Epitope\" (SE) of HLA-DRB1 and protective (PR) alleles, using the Chi-square or Fisher's exact tests. Odds ratios with 95% confidence intervals were calculated to measure the degree of association, and unpaired T-tests were used to compare continuous variables. The most frequent SE alleles among RA patients were * (16.1%), * (13.9%), and * (11.7%). SE alleles * , * , * , * , and * , along with non-SE alleles * and * , were associated with RA susceptibility. In addition, allele * showed an association with the presence of anti-cyclic citrullinated peptides (anti-CCP) antibodies. Meanwhile, PR alleles * (14.8%) and * (9.8%) were observed most frequently in HC and RA patients, respectively. PR alleles * , * , and * , as well as the non-PR alleles * , * , * , * , and * , were associated with protection from RA, and showed no significant associations with autoantibody seropositivity. This study provides a comprehensive overview of allele distribution in the Chilean population, identifying both well-known and novel allele associations with RA susceptibility, protection, and disease activity.

High levels of HIV-1 replication during the chronic phase of infection usually correlate with rapid progression to severe immunodeficiency. However, a minority of highly viremic individuals remains asymptomatic and maintains high CD4⁺ T cell counts. This tolerant profile is poorly understood and reminiscent of the widely studied nonprogressive disease model of SIV infection in natural hosts. Here, we identify transcriptome differences between rapid progressors (RPs) and viremic nonprogressors (VNPs) and highlight several genes relevant for the understanding of HIV-1-induced immunosuppression. RPs were characterized by a specific transcriptome profile of CD4⁺ and CD8⁺ T cells similar to that observed in pathogenic SIV-infected rhesus macaques. In contrast, VNPs exhibited lower expression of interferon-stimulated genes and shared a common gene regulation profile with nonpathogenic SIV-infected sooty mangabeys. A short list of genes associated with VNP, including CASP1, CD38, LAG3, TNFSF13B, SOCS1, and EEF1D, showed significant correlation with time to disease progression when evaluated in an independent set of CD4⁺ T cell expression data. This work characterizes 2 minimally studied clinical patterns of progression to AIDS, whose analysis may inform our understanding of HIV pathogenesis.

Background Rheumatoid Arthritis (RA) is an autoimmune disease in which HLA-DRB1 alleles encoding the “Shared Epitope” (SE), located in the β-chain of class II HLA-DR molecules, constitute the main genetic risk factor. However, there is scarce information about the role of HLA class I genes ( HLA-ABC ) in RA susceptibility. The present work aimed to evaluate the distribution of HLA-ABC allele groups in a cohort of Chilean RA patients and healthy subjects (HS), and to explore the influence of HLA-DRB1 SE alleles on this distribution. Results 135 RA patients and 122 HS were genotyped for HLA-ABC . The most frequent allele groups were HLA-A*02 (24.0%), HLA-B*39.1 (14.2%), and HLA-C*07 (24.7%) for RA patients, and HLA-A*02 (31.5%), HLA-A*24 (12.8%) and HLA-C*07 (17.7%) for HS. RA patients presented a significantly higher frequency of HLA-C*07 ( p  = 0.0015) and HLA-B*39.1 ( p  = 0.037) allele groups compared to HS. After applying the Bonferroni correction, the significant difference remained only for the HLA-C*07 allele group ( p  = 0.015). In a subset of RA patients (n = 60), positive for HLA-DRB1 SE alleles, the most frequent HLA-ABC allele groups were HLA-A*02 (0–33.3%), HLA-B*39.1 (0–16.7%), and HLA-C*07 (22.2–60.0%), whereas HLA-B*39.2 and HLA-B*52 were the least frequent ones. Overall, HLA-C*07 was the most frequent allele group across RA patients carrying HLA-DRB1 SE alleles. Conclusions The HLA-C*07 allele group shows a significantly higher presence in RA patients compared to HS. In contrast, the distribution of most other HLA-ABC allele groups in this cohort displays a similar frequency between RA patients and HS, consistent with data from different populations.

Cytotoxic T lymphocyte (CTL) responses targeting specific HIV proteins, in particular Gag, have been associated with relative control of viral replication in vivo. However, Gag-specific CTL can also be detected in individuals who do not control the virus and it remains thus unclear how Gag-specific CTL may mediate the beneficial effects in some individuals but not in others. Here, we used a 10mer peptide set spanning HIV Gag-p24 to determine immunogen-specific T-cell responses and to assess functional properties including functional avidity and cross-reactivity in 25 HIV-1 controllers and 25 non-controllers without protective HLA class I alleles. Our data challenge the common belief that Gag-specific T cell responses dominate the virus-specific immunity exclusively in HIV-1 controllers as both groups mounted responses of comparable breadths and magnitudes against the p24 sequence. However, responses in controllers reacted to lower antigen concentrations and recognized more epitope variants than responses in non-controllers. These cross-sectional data, largely independent of particular HLA genetics and generated using direct ex-vivo samples thus identify T cell responses of high functional avidity and with broad variant reactivity as potential functional immune correlates of relative HIV control.

Complete and high-resolution (HR) HLA typing improves the accurate assessment of donor–recipient compatibility and pre-transplant donor-specific antibodies (DSA). However, the value of this information to identify de novo immune-mediated graft events and its impact on outcomes has not been assessed. In 241 donor/recipient kidney transplant pairs, DNA samples were re-evaluated for six-locus (A/B/C/DRB1/DQB1+A1/DPB1) HR HLA typing. De novo anti-HLA antibodies were assessed using solid-phase assays, and dnDSA were classified either (1) as per current clinical practice according to three-locus (A/B/DRB1) low-resolution (LR) typing, estimating donor HLA-C/DQ typing with frequency tables, or (2) according to complete six-locus HR typing. The impact on graft outcomes was compared between groups. According to LR HLA typing, 36 (15%) patients developed dnDSA (LR_dnDSA+). Twenty-nine out of 36 (80%) were confirmed to have dnDSA by HR typing (LR_dnDSA+/HR_dnDSA+), whereas 7 (20%) did not (LR_dnDSA+/HR_dnDSA−). Out of 49 LR_dnDSA specificities, 34 (69%) were confirmed by HR typing whereas 15 (31%) LR specificities were not confirmed. LR_dnDSA+/HR_dnDSA+ patients were at higher risk of ABMR as compared to dnDSA− and LR_dnDSA+/HR_dnDSA− (logRank < 0.001), and higher risk of death-censored graft loss (logRank = 0.001). Both LR_dnDSA+ (HR: 3.51, 95% CI = 1.25–9.85) and LR_dnDSA+/HR_dnDSA+ (HR: 4.09, 95% CI = 1.45–11.54), but not LR_dnDSA+/HR_dnDSA− independently predicted graft loss. The implementation of HR HLA typing improves the characterization of biologically relevant de novo anti-HLA DSA and discriminates patients with poorer graft outcomes.

Background Chronic active antibody-mediated rejection (c-aABMR) is an important cause of allograft failure and graft loss in long-term kidney transplants. Methods To determine the efficacy and safety of combined therapy with rituximab, plasma exchange (PE) and intravenous immunoglobulins (IVIG), a cohort of patients with transplant glomerulopathy (TG) that met criteria of active cABMR, according to BANFF’17 classification, was identified. Results We identified 62 patients with active c-aABMR and TG (cg ≥ 1). Twenty-three patients were treated with the combination therapy and, 39 patients did not receive treatment and were considered the control group. There were no significant differences in the graft survival between the two groups. The number of graft losses at 12 and 24 months and the decline of eGFR were not different and independent of the treatment. A decrease of eGFR≥13 ml/min between 6 months before and c-aABMR diagnosis, was an independent risk factor for graft loss at 24 months (OR = 5; P  = 0.01). Infections that required hospitalization during the first year after c-aABMR diagnosis were significantly more frequent in treated patients (OR = 4.22; P  = 0.013), with a ratio infection/patient-year of 0.65 and 0.20 respectively. Conclusions Treatment with rituximab, PE, and IVIG in kidney transplants with c-aABMR did not improve graft survival and was associated with a significant increase in severe infectious complications. Trial registration Agencia Española de Medicametos y Productos Sanitarios (AEMPS): 14566/RG 24161. Study code: UTR-INM-2017-01.

The aim of the present study was to determine humoral and T-cell responses after four doses of mRNA-1273 vaccine in solid organ transplant (SOT) recipients, and to study predictors of immunogenicity, including the role of previous SARS-CoV-2 infection in immunity. Secondarily, safety was also assessed. Liver, heart, and kidney transplant recipients eligible for SARS-CoV-2 vaccination from three different institutions in Barcelona, Spain were included. IgM/IgG antibodies and T cell ELISpot against the S protein four weeks after receiving four consecutive booster doses of the vaccine were analyzed. One hundred and forty-three SOT recipients were included (41% liver, 38% heart, and 21% kidney). The median time from transplantation to vaccination was 6.6 years (SD 7.4). In total, 93% of the patients developed SARS-CoV-2 IgM/IgG antibodies and 94% S-ELISpot positivity. In total, 97% of recipients developed either humoral or cellular response (100% of liver recipients, 95% of heart recipients, and 88% of kidney recipients). Hypogammaglobulinemia was associated with the absence of SARS-CoV-2 IgG/IgM antibodies and S-ELISpot reactivity after vaccination, whereas past symptomatic SARS-CoV-2 infection was associated with SARS-CoV-2 IgG/IgM antibodies and S-ELISpot reactivity. Local and systemic side effects were generally mild or moderate, and no recipients experienced the development of de novo DSA or graft dysfunction following vaccination.