Participation of B-cell-activating factor receptors in the pathogenesis of immune thrombocytopenia.

UNLABELLED: ESSENTIALS: Dysfunctional B-cell-activating factor (BAFF) system is related to many autoimmune diseases. The regulatory functions of BAFF/BAFF receptors were investigated in an in vitro coculture system. Different regulatory roles of BAFF were investigated via different receptors in immune thrombocytopenia. The upregulated BAFF receptors on autoreactive lymphocytes lead to their hypersensitivity to BAFF. BACKGROUND: The pathogenesis of immune thrombocytopenia (ITP) remains enigmatic. B-cell-activating factor (BAFF) and its receptors (BAFF receptor [BAFF-R], transmembrane activator and calcium modulator and cyclophilin ligand interactor [TACI], and B-cell maturation antigen) play central roles in the integrated homeostatic regulation of lymphocytes. OBJECTIVES: To investigate the pathologic roles of BAFF receptors in regulating the bioactivities of lymphocytes in ITP. METHODS: An in vitro culture system was established by stimulating CD14(-) peripheral lymphocytes with platelet-preloaded dendritic cells in the presence of recombinant human BAFF (rhBAFF; 20 ng mL(-1)). The functions of BAFF receptors were specifically blocked with blocking antibodies. RESULTS: BAFF-R, besides prolonging the survival of B cells in both patients and healthy controls, prominently promoted the survival of CD8(+) T cells and the proliferation of B cells in patients with ITP. TACI, as a positive regulator, not only promoted the proliferation of CD4(+) and CD8(+) T cells, but also significantly enhanced the secretion of interleukin-4 in patients with ITP, but not in controls. Besides revealing the pathologic roles of BAFF receptors, these results also indicate that lymphocytes of patients with ITP have enhanced antiapoptotic or proliferative capacity as compared with those from healthy controls when exposed under similar stimulation of rhBAFF. Further study demonstrated that activated autoreactive B cells and CD4(+) T cells from patients with ITP showed significantly higher expression of BAFF-R or TACI than those from healthy controls. CONCLUSIONS: Both BAFF-R and TACI are pathogenic participants in ITP. Their dysregulated expression in patients with ITP may lead to hyperreactivity of activated autoreactive lymphocytes in response to rhBAFF, and thus is highly significant in the pathogenesis of ITP.

Pharmacokinetics, pharmacodynamics, and tolerability of single ascending doses of RCT-18 in Chinese patients with rheumatoid arthritis.

BACKGROUND AND OBJECTIVES: RCT-18 is a novel recombinant fusion protein that targets and neutralizes B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL). This first in-human study investigated the safety, tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics of RCT-18 in patients with rheumatoid arthritis (RA). METHODS: This was a single-center, randomized, single-blind, placebo-controlled study in 28 RA patients. Eligible patients were randomized 3:1 to receive single subcutaneous doses of RCT-18 (1.2, 6, 18, 60, 180, 360, 540 mg) or placebo. A 71-day observation period was scheduled for each patient, during which serial blood sampling for pharmacokinetic, pharmacodynamic, and immunogenicity assessments was performed. Safety was assessed throughout the study. RESULTS: RCT-18 was well tolerated, although mild infections and skin irritation occurred more frequently in patients receiving this drug. After single-dose RCT-18, the maximal serum concentration (C max) of total and free RCT-18 was reached within 1-2 days, followed by a multi-exponential decline. Mean elimination half-life for total RCT-18 and free RCT-18 was 5.7-12.8 days and 3.2-11.3 days at 6-60 mg, and 15.1-17.5 days and 18.8-36.8 days with 180-540 mg RCT-18. The formation and elimination of BLyS-RCT-18 complex were much slower, with a time to C max of 5-29 days and the elimination half-life mounting from 13.3 to 32.8 days with dose escalation. No positive reaction was detected in the immunogenicity assessments. Substantial IgM reduction was only evidenced with 540 mg RCT-18, while the response profiles of IgM/IgG were distinguishable from placebo after 180, 360, or 540 mg RCT-18. CONCLUSION: RCT-18 was safe and well tolerated up to 540-mg single doses. The serum exposure of total and free RCT-18 is linearly correlated to the weight-normalized doses of RCT-18 in dose groups receiving 180-540 mg RCT-18. The elimination half-life of BLyS-RCT-18 increased with RCT-18 doses, suggesting a shift from target-mediated disposition in 1.2-18 mg RCT-18 groups to non-specific clearance in 60-540 mg RCT-18 groups. Assuming the concentration of BLyS-RCT-18 complex and the IgM/IgG ratio are surrogate biomarkers for clinical effects of RCT-18, the dose-response relationship suggests 180-540 mg are pharmacodynamically effective doses in RCT-18 for RA patients, but the effect profile of 540 mg RCT-18 on IgM is similar to that of atacicept at pharmacodynamically effective but clinically ineffective doses.

Expression of B-cell activating factor of the tumour necrosis factor family (BAFF) in T cells in active systemic lupus erythematosus: the role of BAFF in T cell-dependent B cell pathogenic autoantibody production.

OBJECTIVES: To determine whether B cell activating factor of the tumour necrosis factor family (BAFF) is involved in T cell-dependent B cell pathogenic autoantibody production in systemic lupus erythematosus (SLE). METHODS: Peripheral blood mononuclear cells (PBMCs) from 23 SLE patients were analysed by flow cytometry to examine the intracellular expression of BAFF in CD4+ and CD8+ T cells and the surface expression of BAFF-receptor (R) and TACI on CD20+ B cells. Moreover, peripheral blood was used to determine the level of BAFF messenger RNA (mRNA) in CD4+ and CD8+ T cells and the level of BAFF-R mRNA in CD20+ B cells. Blocking of BAFF function with TACI-Ig measured anti-double-stranded DNA (dsDNA) antibodies by enzyme-linked immunosorbent assay (ELISA). RESULTS: CD4+ and CD8+ T cells from patients with active SLE expressed intracellular BAFF whereas those from normal subjects did not. BAFF-R and TACI were expressed on B cells from both normal controls and patients with active SLE and there was no significant difference. CD4+ and CD8+ T cells from SLE patients expressed BAFF mRNA whereas those from normal controls did not. Expression of BAFF-R mRNA in CD20+ B cells showed no significant difference between SLE patients and normal controls. TACI-Ig suppressed spontaneous in vitro T cell-dependent B cell anti-dsDNA antibodies production on active SLE with kidney involvement. CONCLUSIONS: BAFF may play a pathogenic role in SLE by stimulating T cell-dependent B cell autoantibodies production. Blockade of BAFF is a promising therapeutic approach for SLE especially in patients with kidney involvement.