Quantitation and kinetics of polymorphonuclear leukocyte and lymphocyte accumulation in joints during adjuvant arthritis in the rat

Abstract

Infiltration of polymorphonuclear leukocytes (PMNL) and lymphocytes into joints is a prominent feature of human and experimental arthritis. Here we evaluated the usefulness of techniques previously employed for measuring blood PMNL and small, inflammatory site-seeking T-lymphocytes, used in models of dermal inflammation, to monitor the migration of these leukocytes into the joints of rats with adjuvant arthritis. One week after immunization of rats with adjuvant (Mycobacterium butyricum in oil), 51Cr-labeled rat blood PMNL migrated into the hind- and forelimb joints, 5- to 7-fold more than in control animals. This preceded 111In-labeled lymphocyte accumulation, plasma 125I-labeled albumin extravasation, and clinical disease by 4 to 6 days. At 2 weeks, PMNL accumulation in joints increased further, and T-lymphocyte accumulation increased to 6 times that in control animals. PMNL localization in joints maximized at 3 weeks, reaching 20 to 35 times that in control animals; T-lymphocyte accumulation plateaued between 2 and 3 weeks; and all parameters tended to decline by 4 weeks. Migration of T lymphocytes to lymph nodes and to skin inflammatory sites was normal, whereas PMNL migration to zymosan activated serum (C5adesArg) was increased in rats with adjuvant arthritis. Treatment of arthritic rats with dexamethasone (1 mg/kg for 2 to 3 days) caused a dramatic inhibition of plasma albumin extravasation and PMNL migration into arthritic joints and improved clinical scores. In contrast, small T-lymphocyte migration into the joints or into lymph nodes was not inhibited even though lymphocyte migration in the same animals into dermal inflammatory reactions induced by interferon gamma, tumor necrosis factor-alpha, endotoxin, and polyinosine-cytosine was markedly suppressed. These results indicate distinctive patterns of lymphocyte migration into arthritic joint inflammation as compared with dermal inflammation. The experiments demonstrate that the radiolabeled PMNL and lymphocyte migration assays employed here are sensitive and reproducible and allow simultaneous quantitation of leukocyte infiltration during arthritis. These techniques should be useful for studies of the mechanisms involved in leukocyte migration in arthritis and the modulation of joint inflammation.