Anti-PDCD1 monoclonal antibody, clone MIH4 [R-PE]

BACKGROUND & AIMS: Interferon-free direct-acting antiviral (DAA) therapies are effective in patients with hepatitis C virus-induced cryoglobulinemia vasculitis (HCV-CV). We analyzed blood samples from patients with HCV-CV before and after DAA therapy to determine mechanisms of these drugs and their effects on cellular immunity. METHODS: We performed a prospective study of 27 consecutive patients with HCV-CV (median age, 59 y) treated with DAA therapy (21 patients received sofosbuvir plus ribavirin for 24 weeks, 4 patients received sofosbuvir plus daclatasvir for 12 weeks, and 2 patients received sofosbuvir plus simeprevir for 12 weeks) in Paris, France. Blood samples were collected from these patients before and after DAA therapy, and also from 12 healthy donors and 12 individuals with HCV infection without CV. HCV load, cryoglobulins, and cytokines were quantified by flow cytometry, cytokine multiplex assays, and enzyme-linked immunosorbent assay. RESULTS: Twenty-four patients (88.9%) had a complete clinical response of CV to DAA therapy at week 24, defined by improvement of all the affected organs and the absence of relapse. Compared with healthy donors and patients with HCV infection without CV, patients with HCV-CV, before DAA therapy, had a lower percentage of CD4+CD25hiFoxP3+ regulatory T cells (P<.01), but higher proportions of IgM+CD21-/low memory B cells (P<.05), CD4+IFN gamma+ cells (P<.01), CD4+IL17A+ cells (P<.01), and CD4+CXCR5+interleukin 21+ follicular T-helper (Tfh) cells (P<.01). In patients with HCV-CV, there was a negative correlation between numbers of IgM+CD21-/low memory B cells and T-regulatory cells (P=.03), and positive correlations with numbers of Tfh cells (P=.03) and serum levels of cryoglobulin (P=.01). DAA therapy increased patients' numbers of Tregulatory cells (1.5% +/- 0.18% before therapy vs 2.1% +/- 0.18% after therapy), decreased percentages of IgM+CD21-/low memory B cells (35.7% +/- 6.1% before therapy vs 14.9% +/- 3.8% after therapy), and decreased numbers of Tfh cells (12% +/- 1.3% before therapy vs 8% +/- 0.9% after therapy). Expression levels of B lymphocyte stimulator receptor 3 and programmed cell death 1 on B cells increased in patients with HCV-CV after DAA-based therapy (mean fluorescence units, 37 +/- 2.4 before therapy vs 47 +/- 2.6 after therapy, P<.01; and 29 +/- 7.3 before therapy vs 48 +/- 9.3 after therapy, P<.05, respectively). CONCLUSIONS: In a prospective clinical trial of patients with HCV-CV, DAA-based therapy restored disturbances in peripheral B-and T-cell homeostasis.

Objective: Programmed cell death-1 (PD-1) and its ligands (PD-L1 and PD-L2) inhibit T-cell proliferation and activation. This inhibition down-regulates the immune responses. The association of a PD-L1 polymorphism with Graves' disease (GD) was studied. Design: The association of an A/C polymorphism at position 8923 in PD-L1 intron 4 with GD was Studied. Patients: The study included 327 GD patients and 192 controls, of which 252 GD patients were followed over 5-10 years. Measurements: PD-L1 intron 4 position 8923 A/C polymorphism was typed using the PCR-restriction fragment length polymorphism method. Results: The A/C genotype frequencies were significantly different between GD patients and controls. The A/C and C/C frequencies were higher in GD patients than in controls. The A/A frequencies were lower in GD patients than in controls. C-allele frequency was higher in GD patients than in controls. A total of 2 52 GD patients were followed over 5-10 years; 200 had discontinued antithyroid drugs (ATD) while 52 continued to take ATD. Of these 200. 1.76 continued to be in remission and 24 had relapsed into hyperthyroidism. Significant. differences in the duration of positive TBII positive thyroid-stimulating antibodies, and ATD treatment were noted between the patients in remission and those that had relapsed. Significant differences in the A- and C-allele frequencies were noted between the two. The C-allele frequency was higher in GD patients who did not achieve remission than in those who achieved remission. Conclusion: An A/C polymorphism at position 8923 in PD-L1 is associated with GD. The PD-L1. polymorphism plays a role in GD development. GD patients with the C allele at position 892 3 in PD-L1, gene had difficulty in achieving remission.