TACI-Ig Neutralizes Molecules Critical for B Cell Development and Autoimmune Disease

Gross, Jane A.; Dillon, Stacey R.; Mudri, Sherri; Johnston, Janet V.; Littau, Alisa; Roque, Richard; Rixon, Mark W.; Schou, Ole; Foley, Kevin P.; Haugen, Harald S.; McMillen, Susan; Waggie, Kim; Schreckhise, Randy W; Shoemaker, Kim; Vu, Tuyen; Moore, Margaret D.; Grossman, Angelika; Clegg, Christopher H.

doi:10.1016/s1074-7613(01)00183-2

Cited by 577 publications

(510 citation statements)

References 46 publications

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“…Although both canonical and noncanonical NF-kB pathways are functional during B-cell development, recent work (Batten et al, 2000;Schiemann et al, 2001;Claudio et al, 2002) has underscored the importance of BAFF ligation in selectively activating the non-canonical NF-kB pathway and the consequent expression of antiapoptotic Bcl-2 family members in transitional B cells (see Mackay et al, 2003). Indeed, BAFF knockout mice exhibit a complete failure of transitional B-cell maturation, which mirrors that seen in Bcl-X L knockout mice (Motoyama et al, 1995;Gross et al, 2001;Schiemann et al, 2001). Thus, only those knockouts that target both the canonical and noncanonical NF-kB pathways have an effect that approximates the phenotype seen in BAFF or Bcl-X L deficiency.…”

Section: Nf-kb In Development Of B and T Cellsmentioning

confidence: 94%

NF-κB and the immune response

2006

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Section: Nf-kb In Development Of B and T Cellsmentioning

confidence: 94%

NF-κB and the immune response

2006

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“…4 In addition, TACI-Ig treatment inhibits development of proteinurea in NZB/W F1 mice, and the production of collagen-specific Abs and the progression of disease in a mouse model of rheumatoid arthritis (RA). 4,11,22 Recently, increase of BLyS level was also reported in the serum or synovial fluid of human SLE, RA and Sjö gren's syndrome. [23][24][25] Serum BLyS level was shown to be correlated with those of anti-dsDNA antibody and rheumatoid factor (RF), 24 although another study failed to show correlation with RF or with anti-Ro, anti-La with BLyS.…”

Section: Introductionmentioning

confidence: 97%

“…1,2,[6][7][8][9][10] In BLyS deficient mice, the number of B cells, serum IgG and IgM levels were decreased, and B cell development was blocked at the transitional T1 stage. 11 BLyS and a proliferation-inducing ligand (APRIL) bind to B cell maturation antigen (BCMA) and transmembrane activator and CAML-interactor (TACI), 4,12,13 which belong to the tumor necrosis factor receptor superfamily and are mainly expressed in B cells. [14][15][16][17] The intracellular domains of BCMA and TACI associate with TNFreceptor-associated factors (TRAFs), leading to activation of NF-kB.…”

Section: Introductionmentioning

confidence: 99%

Analysis on the association of human BLYS (BAFF, TNFSF13B) polymorphisms with systemic lupus erythematosus and rheumatoid arthritis

et al. 2002

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Recent studies indicated a substantial role of BLyS (BAFF, TNFSF13B) in the pathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in humans and in animal models. This study was conducted to screen for polymorphisms of human BLYS, and to examine whether they are involved in the genetic susceptibility to human SLE and RA. A systematic polymorphism screening was performed in the coding region, 5 0 and 3 0 untranslated regions, and promoter region of human BLYS. Association of the detected polymorphisms with SLE and RA was analyzed in 221 Japanese patients with RA, 156 with SLE, and 227 healthy individuals, using the case-control approach. Four single nucleotide polymorphisms (SNPs) in the promoter, one SNP in intron 1, and one rare nonsynonymous substitution (Ala105Thr) in the coding region were detected. The BLYS SNPs were found to form three common haplotypes. Significant association with the susceptibility to SLE or RA was not observed. However, a tendency for the increase of À871T/T genotype was observed in SLE patients with anti-Sm antibody (P ¼ 0.082). BLYS mRNA level was significantly elevated in the monocytes from individuals carrying À871T (P ¼ 0.010). In addition, although statistically not significant, 105Thr allele was slightly increased in patients with RA compared with controls (P ¼ 0.058). Characterizing the functional and clinical significance of these new SNPs requires further study.

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“…In light of the potential role of BLyS and APRIL in autoimmune diseases, targeting these cytokines is a rational approach to therapy. Indeed, neutralization of BLyS and APRIL in an animal model of RA has been shown to reduce disease activity (20,21).…”

mentioning

confidence: 99%

Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: Results of a phase II, randomized, placebo-controlled, dose-finding trial

Genovese¹,

Kinnman²,

Bourdonnaye³

et al. 2011

Arthritis & Rheumatism

116

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Objective. To assess the efficacy, safety, and biologic activity of atacicept in patients with rheumatoid arthritis (RA) in whom the response to treatment with tumor necrosis factor antagonists was inadequate.Methods. The Atacicept for Reduction of Signs and Symptoms in Rheumatoid Arthritis Trial (AUGUST I) was a multicenter, phase II, double-blind, placebo-controlled dose-finding study involving 256 patients randomized 1:1:1:1 to receive atacicept (25 mg, 75 mg, or 150 mg) or placebo twice weekly for 4 weeks, then weekly for 21 weeks, with a 13-week treatment-free followup period (week 38). The primary end point was a response at week 26 according to the American College of Rheumatology criteria for 20% improvement in disease severity, using the C-reactive protein level. Results.No statistically significant differences were observed in the efficacy end points at week 26 (P ‫؍‬ 0.410 for overall treatment effect). However, atacicept significantly reduced immunoglobulin and rheumatoid factor (RF) levels, but not anti-citrullinated protein antibody levels, in a dose-dependent manner, with levels returning toward baseline values during followup. The effects of treatment on IgG-RF and IgA-RF were more pronounced than the effects on total IgG and IgA. Adverse events (AEs), including serious AEs, leading to withdrawal were more common among patients treated with atacicept compared with placebo. AEs were variable in nature, and no dose-dependent trends were observed. The frequency of infection-related AEs was similar across treatments. No notable effect of treatment on immunization status (protective versus nonprotective titer) was observed after initiation of treatment.Conclusion. This study did not meet the primary efficacy end point. However, clear biologic activity consistent with the proposed mechanism of action was observed. The results suggest that decreasing the expression of RF may not be sufficient to induce clinical improvement in RA. The safety of atacicept was considered acceptable in this patient population.

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TACI-Ig Neutralizes Molecules Critical for B Cell Development and Autoimmune Disease

Cited by 577 publications

References 46 publications

NF-κB and the immune response

NF-κB and the immune response

Analysis on the association of human BLYS (BAFF, TNFSF13B) polymorphisms with systemic lupus erythematosus and rheumatoid arthritis

Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: Results of a phase II, randomized, placebo-controlled, dose-finding trial

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