A Major Portion of Polymorphonuclear Leukocyte and T Lymphocyte Migration to Arthritic Joints in the Rat Is via LFA-1/MAC-1-Independent Mechanisms

Abstract

The importance of the leukocyte CD11/CD18 β 2 integrins for leukocyte adhesion and for leukocyte migration to inflamed tissues is well recognized. However, the role of CD11/CD18 molecules and their subtypes, such as LFA-1 and MAC-1, in leukocyte migration to arthritis is not known. Here we report the effects of a new monoclonal antibody (mAb) TA-3, which recognizes and blocks rat LFA-1 (CD11a/CD18), on the migration of 51Cr-labeled rat blood polymorphonuclear leukocytes (PMNL) and 111In-labeled spleen T lymphocytes into the inflamed joints of rats with adjuvant arthritis and to dermal inflammation. The mAb MRC OX-42, which reacts with and blocks rat MAC-1 (CD11b/CD18), was also evaluated. In established arthritis, iv anti-LFA-1 (TA-3) inhibited, up to 50% ( P < 0.006) of PMNL accumulation in the talar and metatarsal joints but had no effect on T lymphocyte migration to the joints. In the same animals, antiLFA-1 partially (35-50%) inhibited PMNL accumulation in acute dermal inflammation induced by zymosan-activated serum (ZAS, C5a des Arg), IL-1 or endotoxin ( P < 0.01) and suppressed T lymphocyte migration to dermal DTH, IFN-γ, LPS, and poly-I:C-induced inflammation by 60-80%. AntiMAC-1 (OX-42) by itself had no effect on PMNL migration. Anti-MAC-1 combined with anti-LFA-1 did not inhibit PMNL or T lymphocyte migration to joints any more than anti-LFA-1 alone. However, the addition of anti-MAC-1 to anti-LFA-1 further inhibited PMNL migration to acute dermal inflammation by up to 90%. These findings demonstrate that LFA-1 on PMNL plays a major role in PMNL migration but not in T cell migration to arthritic joints. MAC-1 on PMNL appears less important. Furthermore, while LFA-1 and MAC-1 on PMNL and LFA-1 on T lymphocytes mediate much of the migration to dermal inflammation, the migration of these cells to arthritis has a major LFA-1/MAC-1-independent component.