Cysteine carboxyethylation generates neoantigens to induce HLA-restricted autoimmunity.

Autoimmune diseases such as ankylosing spondylitis (AS) can be driven by emerging neoantigens that disrupt immune tolerance. Here, we developed a workflow to profile posttranslational modifications involved in neoantigen formation. Using mass spectrometry, we identified a panel of cysteine residues differentially modified by carboxyethylation that required 3-hydroxypropionic acid to generate neoantigens in patients with AS. The lysosomal degradation of integrin αIIb [ITGA2B (CD41)] carboxyethylated at Cys96 (ITGA2B-ceC96) generated carboxyethylated peptides that were presented by HLA-DRB1*04 to stimulate CD4+ T cell responses and induce autoantibody production. Immunization of HLA-DR4 transgenic mice with the ITGA2B-ceC96 peptide promoted colitis and vertebral bone erosion. Thus, metabolite-induced cysteine carboxyethylation can give rise to pathogenic neoantigens that lead to autoreactive CD4+ T cell responses and autoantibody production in autoimmune diseases.

Meplazumab in hospitalized adults with severe COVID-19 (DEFLECT): a multicenter, seamless phase 2/3, randomized, third-party double-blind clinical trial.

Meplazumab, a humanized CD147 antibody, has shown favourable safety and efficacy in our previous clinical studies. In DEFLECT (NCT04586153), 167 patients with severe COVID-19 were enroled and randomized to receive three dosages of meplazumab and a placebo. Meplazumab at 0.12 mg/kg, compared to the placebo group, showed clinical benefits in significantly reducing mortality by 83.6% (2.4% vs. 14.6%, p = 0.0150), increasing the proportion of patients alive and discharged without supplemental oxygen (82.9% vs. 70.7%, p = 0.0337) and increasing the proportion of patients who achieved sustained clinical improvement (41.5% vs. 31.7%). The response rate in the 0.2 mg/kg group was relatively increased by 16.0% compared with the placebo group (53.7% vs. 46.3%). Meplazumab also reduced the viral loads and multiple cytokine levels. Compare with the placebo group, the 0.3 mg/kg significantly increased the virus negative rate by 40.6% (p = 0.0363) and reduced IL-8 level (p = 0.0460); the 0.2 mg/kg increased the negative conversion rate by 36.9%, and reduced IL-4 (p = 0.0365) and IL-8 levels (p = 0.0484). In this study, the adverse events occurred at a comparable rate across the four groups, with no unexpected safety findings observed. In conclusion, meplazumab promoted COVID-19 convalescence and reduced mortality, viral load, and cytokine levels in severe COVID-19 population with good safety profile.

Prediction of post-transplant graft survival by different definitions of early allograft dysfunction.

BACKGROUND: The efficacy of early allograft dysfunction (EAD) definitions in predicting post-transplant graft survival in a Chinese population is still unclear. METHODS: A total of 607 orthotopic liver transplants (OLT) have been included in the current study. Model accuracy was evaluated using receiver operating characteristic (ROC) analysis. Risk factors for EAD was evaluated using univariable analysis and multivariable logistic regression model. RESULTS: The 3-, 6-, and 12-month patient/graft survival were 91.6%/91.4%, 91.1%/90%, and 87.5%/87.3%, respectively. MELDPOD5 had a superior discrimination of 3-month graft survival (C statistic, 0.83), compared with MEAF (C statistic, 0.77) and Olthoff criteria (C statistic, 0.72). Multivariate analysis of risk factors for EAD defined by MELDPOD5, showed that donor body mass index (P=0.001), donor risk index (P=0.006), intraoperative use of packed red blood cells (P=0.001), hypertension of recipient (P=0.004), and preoperative total bilirubin (P<0.001) were independent risk factors. CONCLUSIONS: The results suggest that MLEDPOD5 is a better criterion of EAD for the Chinese population, which might serve as a surrogate end-point for graft survival in clinical study.