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

Chrystal M Paulos,Erina Vlashi,Bindu Varghese,Philip S Low,Gert J Breur,William R Widmer

doi:10.1186/ar1944

Chrystal M Paulos, Erina Vlashi + Show 4 more

Open Access

https://doi.org/10.1186/ar1944

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Abstract

Activated macrophages express a cell surface receptor for the vitamin folic acid. Because this receptor is inaccessible or not measurably expressed on other normal cells, folic acid has been recently exploited to selectively deliver attached radio-emitters to sites of activated macrophage accumulation, allowing scintigraphic imaging of inflamed joints and organs of arthritic rats. We demonstrate here that folate-linked haptens can also be targeted to activated macrophages, decorating their cell surfaces with highly immunogenic molecules. Under conditions in which the rodent has already been immunized against keyhole limpet hemocyanine-(fluorescein isothiocyanate) FITC, activated macrophages are eliminated. Administration of folate-FITC conjugates to rodents with experimental arthritis attenuates (a) systemic and peri-articular inflammation, (b) bone and cartilage degradation, and (c) arthritis-related body weight loss. Treatment with folate-hapten conjugates is comparable to methotrexate, etanercept, anakinra, and celecoxib at alleviating the symptoms of arthritis. We conclude that reduction of activated macrophages by folate-targeted immunotherapy can ameliorate the symptoms of arthritis in two rodent models of the disease.

Highlights

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation of the joints and destruction of cartilage and bone
folate-targeted immunotherapy (FTI) reduces localized and systemic folate-binding macrophages With the ability of folic acid to deliver attached imaging agents to activated macrophages in rodents with experimental arthritis well established [23,24,25], the question naturally arose whether therapeutic drugs might benefit from FRspecific targeting
It has been demonstrated that some cancer cells over-express a folate receptor and that the surfaces of cancer cells can be decorated with highly immunogenic haptens by targeting their FRs with folate-hapten conjugates [26]

Summary

Introduction

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 [1,2,3,4]. Neutralization of inflammatory mediators secreted by activated macrophages suppresses symptoms of the disease [1,2,3,4,5]. Many therapies for RA are designed to eliminate pro-inflammatory byproducts of activated macrophages [6]. Remicade and etanercept neutralize tumor necrosis factor alpha (TNF-α) [7,8,9], whereas anakinra blocks the activity of interleukin (IL)-1 [8,9,10]. Some patients require other remedies, either because of the ineffectiveness of the above therapies or due to their associated toxicities [12,13]

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