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Folate-Targeted Immunotherapy Effectively Treats Established Adjuvant and Collagen-Induced Arthritis Chrystal M

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Folate-Targeted Immunotherapy Effectively Treats Established Adjuvant and Collagen-Induced Arthritis Chrystal M Purdue University Purdue e-Pubs Department of Chemistry Faculty Publications Department of Chemistry 4-28-2006 Folate-Targeted Immunotherapy Effectively Treats Established Adjuvant and Collagen-Induced Arthritis Chrystal M. Paulos Purdue University Bindu Varghese Purdue University William R. Widmer Purdue University Gert J. Breur Purdue University, [email protected] Erina Vlashi Purdue University See next page for additional authors Follow this and additional works at: http://docs.lib.purdue.edu/chempubs Recommended Citation Paulos, Chrystal M.; Varghese, Bindu; Widmer, William R.; Breur, Gert J.; Vlashi, Erina; and Low, Philip S., "Folate-Targeted Immunotherapy Effectively Treats Established Adjuvant and Collagen-Induced Arthritis" (2006). Department of Chemistry Faculty Publications. Paper 2. http://dx.doi.org/10.1186/ar1944 This document has been made available through Purdue e-Pubs, a service of the Purdue University Libraries. Please contact [email protected] for additional information. Authors Chrystal M. Paulos, Bindu Varghese, William R. Widmer, Gert J. Breur, Erina Vlashi, and Philip S. Low This article is available at Purdue e-Pubs: http://docs.lib.purdue.edu/chempubs/2 Available online http://arthritis-research.com/content/8/3/R77 ResearchVol 8 No 3 article Open Access Folate-targeted immunotherapy effectively treats established adjuvant and collagen-induced arthritis Chrystal M Paulos1*, Bindu Varghese1*, William R Widmer2, Gert J Breur2, Erina Vlashi1 and Philip S Low1 1Department of Chemistry, 560 Oval Drive, 1393 Brown Bldg., Purdue University, West Lafayette, IN 47907-1175, USA 2Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907-1175, USA * Contributed equally Corresponding author: Philip S Low, [email protected] Received: 5 Jan 2006 Revisions requested: 7 Feb 2006 Revisions received: 12 Mar 2006 Accepted: 22 Mar 2006 Published: 28 Apr 2006 Arthritis Research & Therapy 2006, 8:R77 (doi:10.1186/ar1944) This article is online at: http://arthritis-research.com/content/8/3/R77 © 2006 Paulos et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Activated macrophages express a cell surface receptor for the macrophages are eliminated. Administration of folate-FITC vitamin folic acid. Because this receptor is inaccessible or not conjugates to rodents with experimental arthritis attenuates (a) measurably expressed on other normal cells, folic acid has been systemic and peri-articular inflammation, (b) bone and cartilage recently exploited to selectively deliver attached radio-emitters degradation, and (c) arthritis-related body weight loss. to sites of activated macrophage accumulation, allowing Treatment with folate-hapten conjugates is comparable to scintigraphic imaging of inflamed joints and organs of arthritic methotrexate, etanercept, anakinra, and celecoxib at alleviating rats. We demonstrate here that folate-linked haptens can also the symptoms of arthritis. We conclude that reduction of be targeted to activated macrophages, decorating their cell activated macrophages by folate-targeted immunotherapy can surfaces with highly immunogenic molecules. Under conditions ameliorate the symptoms of arthritis in two rodent models of the in which the rodent has already been immunized against keyhole disease. limpet hemocyanine-(fluorescein isothiocyanate) FITC, activated Introduction cyclooxygenase-2 [11], and anti-oxidants inactivate reactive Rheumatoid arthritis (RA) is an autoimmune disease charac- oxygen species. Yet some patients require other remedies, terized by inflammation of the joints and destruction of carti- either because of the ineffectiveness of the above therapies or lage and bone. Activated macrophages have been identified due to their associated toxicities [12,13]. as a key mediator of the disease, as numbers and level of mac- rophage activation correlate with the extent of joint inflamma- Efforts have been made to eliminate the entire population of tion and bone degradation [1-4]. In addition, neutralization of macrophages [14-19], but elimination of all mononuclear inflammatory mediators secreted by activated macrophages phagocytes can be harmful, because they are important in suppresses symptoms of the disease [1-5]. fighting infectious diseases and promoting tissue repair [20,21]. Thus, an attractive alternative to elimination of all mac- Many therapies for RA are specifically designed to eliminate rophages might be to remove only that subpopulation that pro- pro-inflammatory byproducts of activated macrophages [6]. motes RA (that is, the activated macrophage). Remicade and etanercept neutralize tumor necrosis factor alpha (TNF-α) [7-9], whereas anakinra blocks the activity of Activated macrophages from patients and rodents with arthri- interleukin (IL)-1 [8-10]. Celecoxib and Vioxx are inhibitors of tis over-express a cell surface receptor for folic acid that also AIA = adjuvant-induced arthritis; CIA = collagen-induced arthritis; CL = clodronate liposomes; FITC = fluorescein isothiocyanate; FR = folate recep- tor; FTI = folate-targeted immunotherapy; HRP = horseradish peroxidase; Ig = immunoglobulin; IL = interleukin; KLH = keyhole limpet hemocyanine; MTX = methotrexate; PBS = phosphate-buffered saline; RA = rheumatoid arthritis; RAD score = radiographic score; TNF-α = tumor necrosis factor alpha. Page 1 of 10 (page number not for citation purposes) Arthritis Research & Therapy Vol 8 No 3 Paulos et al. binds folate-linked compounds with high affinity (KD approxi- serum folate levels to their physiologic range (approximately mately 10-10 M) [22-24]. Recent studies have shown that 25 nM) [28]. folate-linked radiopharmaceuticals concentrate in arthritic joints, enabling visualization of such tissues by gamma scintig- Folate-targeted immunotherapy in experimental arthritis raphy [23-25]. We hypothesized therefore that selective Folate-FITC was administered i.p. to KLH-FITC-immunized removal of activated macrophages with folate-linked drugs rodents according to the doses/schedules described in each could be exploited to treat RA with little toxicity to other tis- figure legend. For negative controls, KLH-FITC-immunized sues. Here, we report a test of this strategy in two distinct rodents were treated with the non-targeted aminofluorescein, rodent animal models of the disease. which displays no affinity for folate receptors. Alternatively, non-immunized rodents were treated with folate-FITC, which Materials and methods binds readily to FR+ cells but cannot mediate anti-FITC anti- Heat-killed Mycoplasma butyricum (BD Biosciences, Sparks, body binding in the absence of KLH-FITC immunization. MD, USA); light mineral oil, methotrexate (MTX), clodronate, Folate-targeted immunotherapy (FTI) was compared with bovine serum albumin, keyhole limpet hemocyanine (KLH), other therapies by treating AIA rats (base-of-tail method) 7 anti-rat immunoglobulin G (IgG)-horseradish peroxidase days after arthritis induction with one of the following: FTI (HRP), IgG-phycoerythrin conjugates, and alum (Sigma, St. (KLH-FITC + Folate-FITC, 300 nmole/kg per day, i.p.), MTX Louis, MO, USA); biotin-conjugated goat anti-rat IgG1, IgG2a, (0.75 mg/kg per week, i.p.) [29], celecoxib (20 mg/kg, oral and IgG (H+L), and streptavidin-conjugated HRP (Caltag Lab- gavage every other day) [11], etanercept (4 mg/kg per day, oratories, Burlingame, CA, USA); aminofluorescein (single iso- i.p.) [7-9], clodronate liposomes (3.6 mg/kg on days 8, 16, and mer) and fluorescein isothiocyanate (FITC) (Molecular Probes, 23, i.p.) [16], or anakinra (1.5 mg/kg per hour, continuous infu- Eugene, OR, USA); Microcon-30 membranes (Millipore Corp., sion via subcutaneously implanted pump; Alzet, Cupertino, Bedford, MA, USA); TiterMax Gold® adjuvant (CytRx Corpora- CA, USA) [8-10]. tion, Los Angeles, CA, USA); Celecoxib (Pfizer, Ann Arbor, MI, USA); entanercept and anakinra (Amgen, Inc., Thousand Evaluation of therapeutic potencies Oaks, CA, USA); EC20 (a folate-linked chelator of 99mTc) and To determine whether FTI could ameliorate the symptoms of folate-FITC (Endocyte, Inc., West Lafayette, IN, USA) were experimental arthritis in rodent models, disease status was obtained from commercial sources. The studies were assessed by monitoring changes in limb volume/ankle diame- approved by the Purdue University Animal Care and Use ter, radiological score (RAD score), and systemic inflamma- Committee. tion. Limb volume was determined by calculating the product of the measured length, width, and height of the limb (average Induction and detection of anti-FITC antibodies ± SD, 8 rats/group). To determine the impact of the therapies Anti-FITC antibodies were induced in rodent models with on bone/cartilage degradation, lateral radiographic projec- experimental arthritis by vaccination with KLH-FITC (KLH-FITC tions of the tarsus of each rat were scored at the end of each molar ratio of 1:13), using a modification of a published proce- study. Radiographs were taken with direct exposure (1:1) on dure [26]. Rodents were immunized subcutaneously with an un-screen KODAK X-OMAT TL film (Kodak, Rochester NY, emulsion of 150 µg KLH-FITC/200 µl adjuvant comprised of USA) using a Faxitron X-ray system with a 0.5-mm focal spot either TiterMax Gold® (two injections
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