Folate-targeted immunotherapy effectively treats established adjuvant and collagen-induced arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation of the joints and destruction of cartilage and bone. Activated macrophages have been identified as a key mediator of the disease, as numbers and level of macrophage activation correlate with the extent of joint inflammation and bone degradation [1-4]. In addition, neutralization of inflammatory mediators secreted by activated macrophages suppresses symptoms of the disease [1-5].Many therapies for RA are specifically designed to eliminate pro-inflammatory byproducts of activated macrophages [6]. Remicade and etanercept neutralize tumor necrosis factor alpha (TNF-α) [7-9], whereas anakinra blocks the activity of interleukin (IL)-1 [8-10]. Celecoxib and Vioxx are inhibitors of cyclooxygenase-2 [11], and anti-oxidants inactivate reactive oxygen species. Yet some patients require other remedies, either because of the ineffectiveness of the above therapies or due to their associated toxicities [12,13].Efforts have been made to eliminate the entire population of macrophages [14-19], but elimination of all mononuclear phagocytes can be harmful, because they are important in fighting infectious diseases and promoting tissue repair [20,21]. Thus, an attractive alternative to elimination of all macrophages might be to remove only that subpopulation that promotes RA (that is, the activated macrophage).Activated macrophages from patients and rodents with arthritis over-express a cell surface receptor for folic acid that also binds folate-linked compounds with high affinity (KD approximately 10-10 M) [22-24]. Recent studies have shown that folate-linked radiopharmaceuticals concentrate in arthritic joints, enabling visualization of such tissues by gamma scintigraphy [23-25]. We hypothesized therefore that selective removal of activated macrophages with folate-linked drugs could be exploited to treat RA with little toxicity to other tissues. Here, we report a test of this strategy in two distinct rode