The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells

Interleukin (IL) 6 is a proinflammtory cytokine produced by antigen-presenting cells and nonhematopoietic cells in response to external stimuli. It was initially identified as a B cell growth factor and inducer of plasma cell differentiation in vitro and plays an important role in antibody production and class switching in vivo. However, it is not clear whether IL-6 directly affects B cells or acts through other mechanisms. We show that IL-6 is sufficient and necessary to induce IL-21 production by naive and memory CD4+ T cells upon T cell receptor stimulation. IL-21 production by CD4+ T cells is required for IL-6 to promote B cell antibody production in vitro. Moreover, administration of IL-6 with inactive influenza virus enhances virus-specific antibody production, and importantly, this effect is dependent on IL-21. Thus, IL-6 promotes antibody production by promoting the B cell helper capabilities of CD4+ T cells through increased IL-21 production. IL-6 could therefore be a potential coadjuvant to enhance humoral immunity

Single-Agent Ibrutinib for Rituximab-Refractory Waldenstrom Macroglobulinemia: Final Analysis of the Substudy of the Phase III Innovate (TM) Trial

Purpose: The first report from the open-label substudy of the phase III iNNOVATE study (PCYC-1127; NCT02165397) demonstrated that single-agent ibrutinib was efficacious and well tolerated in patients with heavily pretreated, rituximab-refractory Waldenstrom macroglobulinemia. Results from the final analysis are now reported. Patients and Methods: Ibrutinib 420 mg was administered once daily to patients (N = 31) who failed to achieve at least a minor response (MR) or who relapsed <12 months after their last rituximab-containing therapy. Endpoints included progression-free survival (PFS) and overall response rate (ORR; MR or better) per independent review committee, hemoglobin improvement, overall survival (OS), and safety; serum IgM was also assessed. Results: After a median follow-up of 58 months (range: 9-61), median PFS was 39 months [95% confidence interval (CI): 25-not evaluable]; 60-month PFS rate was 40%. In MYD88(L265P)/CXCR4(WHIM) and MYD88(L265P)/CXCR4(WT) subtypes, median PFS was 18 months and not reached, respectively. In all patients, ORR was 87%; responses deepened over time with major response (>= partial response) rates increasing from 61% at 6 months to 77% at 60 months. Median OS was not reached. Seventeen of 21 patients (81%) with baseline hemoglobin <= 11.0 g/dL had sustained hemoglobin improvement. Improvements in serum IgM levels were sustained, reaching a maximum median change of similar to 37 g/L at 54 months. Ibrutinib maintained a manageable safety profile, with no new safety signals identified. There were no events of major hemorrhage or atrial fibrillation. Conclusions: In the final analysis from iNNOVATE, single-agent ibrutinib continued to showsustained efficacy in patients with heavily pretreated, rituximab-refractory Waldenstrom macroglobulinemia