Evaluation of TNF-α and IL-1 Blockade in Collagen-Induced Arthritis and Comparison with Combined Anti-TNF-α/Anti-CD4 Therapy

Abstract

We have evaluated the effects of anti-TNF-α, anti-IL-1, and combined anti-TNF-α/anti-CD4 therapy in collagen-induced arthritis. Blockade of TNF-α or IL-1 before disease onset delayed, but did not prevent, the induction of arthritis. When treatment was initiated after onset of arthritis, anti-TNF-α, anti-IL-1β, and anti-IL-1R (which blocks IL-1α and IL-1β) were all found to be effective in reducing the severity of arthritis, with anti-IL-1R and anti-IL-1β showing greater efficacy than anti-TNF-α. Anti-IL-1β was equally as effective as anti-IL-1R, indicating that IL-1β plays a more prominent role than IL-1α in collagen-induced arthritis. An additive effect was observed between anti-TNF-α and anti-IL-1R in the prevention of joint erosion and in normalization of the levels of serum amyloid P. Combined anti-TNF-α/anti-CD4 therapy also caused normalization of serum amyloid P levels. The therapeutic effect of anti-TNF-α plus anti-CD4 was comparable to that of anti-TNF-α plus anti-IL-1R, suggesting that combined anti-TNF-α/anti-CD4 therapy prevents both TNF-α- and IL-1-mediated pathology. Anti-TNF-α treatment reduced IL-1β expression in the joint and, conversely, anti-IL-1β treatment reduced TNF-α expression. Combined anti-TNF-α/anti-CD4 treatment almost completely blocked the expression of IL-1β, thereby confirming the ability of this form of combination therapy to prevent IL-1β-mediated pathology.

Therapeutic effect of tolerogenic dendritic cells in established collagen‐induced arthritis is associated with a reduction in Th17 responses

“…The tolerogenic DCs used by those investigators, which were generated by short-term LPS treatment, also inhibited established arthritis without changing the IgG2a:IgG1 ratio; however, their tolerogenic DC treatment did inhibit IFN␥ production (30). Earlier studies of anti-TNF treatment of established arthritis also did not show a change in the IgG2a:IgG1 ratio (41,42). It could therefore be contended that a reduction of type II collagen-specific IgG2a is important for the prevention of arthritis but may be of less importance after disease onset.…”

TNFα blockade in human diseases: Mechanisms and future directions

“…Combined anti-TNFα/anti CD4 therapy suppressed both TNFα and IL-1β expression in the DBA/1 CIA mouse model. In addition, this combined therapy also caused the normalization of serum amyloid P levels [60]. In a separate study, anti-TNFα blockade, but not anti-CD4 Abs, significantly reduced the frequency of cells expressing TNFα, IL-1β, VLA-4, VCAM-1 and CD4 + Tcells and macrophages in the joint of CIA-induced mice model [61].…”

Inflammation is preceded by tumor necrosis factor‐dependent infiltration of mesenchymal cells in experimental arthritis

“…Previously, we and others have shown that TNF blockade during the induction phase of CIA delays the onset of arthritis and reduces its subsequent clinical severity (12)(13)(14). To evaluate the possible role played by TNF in the subclinical changes observed in this study, mice were immunized on day 0 with CFA alone, then injected intraperitoneally with 300 g of anti-TNF mAb (TN3-19.12) or PBS (6 animals in each group) on days 7, 9, and 11.…”