Treatment of established adjuvant arthritis in rats with monoclonal antibody to CD18 and very late activation antigen-4 integrins suppresses neutrophil and T-lymphocyte migration to the joints and improves clinical disease

The migration of leucocytes from blood into the joint is a key feature of human and experimental arthritis. Adhesion molecules on leucocytes and vascular endothelium are important in this process and may be therapeutic targets for intervention in arthritis. We investigated whether monoclonal antibody treatment to block the α₄ integrin, very late activation antigen-4 (VLA-4), and β₂ integrins (CD11/CD18) administered to rats during the preclinical (day 5) or clinical phase (day 10+) would modify disease. When treatment was initiated 5 days after induction of disease, development of arthritis was significantly reduced by either anti-α₄ (TA-2) or anti-β₂ (WT.3) monoclonal antibodies (mAb) and the combination of both mAb was even more effective (clinical scores: control 11.4; anti-α₄ 6.6; anti-β₂ 6.8; anti-α₄ + anti-β₂ 3.9). When treatment was delayed until arthritis was apparent (day 10), the anti-α₄ + anti-β₂ mAb combination still significantly diminished the arthritis score on day 14 (control 13; anti-α₄ + anti-β₂ 7.9). Treatment with anti-α₄ + anti-β₂ mAb decreased the migration to the joints of blood polymorphonuclear leucocytes (PMNL) by 66-79% and of spleen T lymphocytes by 56-75%, depending on the joint. In contrast, PMNL migration was abolished (> 98%) and T-cell migration markedly (87%) inhibited to dermal inflammatory reactions in the same animals. These findings demonstrate: that blocking mAb to α₄ and β₂ integrins can reduce the severity of adjuvant arthritis, even after joint inflammation has developed; that this treatment can markedly inhibit PMNL and T-lymphocyte migration to the joints; and that yet to be defined mechanisms distinct from α₄ (CD49d) and β₂ (CD11/CD18) integrins, also contribute to leucocyte migration to inflamed joints. Identifying these additional adhesion mechanisms may be required to control joint inflammation further.