Neutrophils and adjuvant arthritis

The role of neutrophils in immunologically mediated inflammatory reactions has been controversial, especially for reactions that involve a morphological predominance of lymphocytes. Another matter of controversy has been the extent to which infiltration of monocytes and lymphocytes into tissues requires a prior presence of neutrophils, as opposed to the complete independence of a mononuclear cell/lymphocyte influx on the prior accumulation of neutrophils. The resolution of these questions as well as the extent to which cytokine/chemokine-dependent inflammatory reactions exclusively reflect monocyte, macrophage and lymphocyte involvement has been made more difficult by the realization that neutrophils can also express mRNA and proteins for a wide array of cytokines/chemokines [1]. Early approaches to address the role of neutrophils in inflammatory models involved the use of cytotoxic drugs, such as nitrogen mustard or cyclophosphamide, which tended to show, at least within the first 72 h, selective depletion of neutrophils. However, it is well known that such drug-related effects are not specific for this cell lineage, making observed results difficult to interpret. A key to resolving some of these questions has been access to blocking reagents that are highly specific for epitopes contained on neutrophils and devoid of reactivity with epitopes on monocytes and lymphocytes. Requirements for neutrophils have been established in a large number of immunologically mediated types of tissue injury in which the key event is triggering of an inflammatory response [2]. Neutrophil involvement is especially prominent in lesions associated with deposition of immune complexes, and often in other conditions featuring the presence of complement activation products. In rats antigen-induced arthritis and collagen type IIinduced arthritis have been found to be neutrophiland complement-dependent [3]. Adjuvant arthritis is a type of progressive inflammatory polyarthritis that displays many of the features of human rheumatoid arthritis, with a prominence of synovial thickening and hypercellularity and numerous inflammatory cells, including neutrophils as well as mononuclear and lymphoid cells. Progressive erosion of articular cartilage is a prominent feature of this disease. Not surprisingly, immunosuppressive approaches such as blockade of CD4 þ lymphocytes effectively reduce the intensity of damage and the progression of adjuvant arthritis. The current report of Santos et al. [4] convincingly demonstrates a requirement not only for CD4 þ lymphocytes but also for neutrophils, the latter being determined by the protective effects of neutrophil depletion, even though another report suggested that methotrexate-induced neutropenia was not effective in reducing the arthritic symptoms in adjuvant arthritis [5]. However, these discrepant findings may be a reflection of insufficiently sensitive endpoints of measurement or inadequate levels of neutrophil depletion. In the studies of Santos et al. [4] it is clear that interventions with antibody either to neutrophils or to CD4 þ