Skip to main content

Advertisement

SpringerLink
Log in

Optimization of Folate-Targeted Immunotherapy for the Treatment of Experimental Arthritis

  • ORIGINAL ARTICLE
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Folate-targeted immunotherapy constitutes a powerful method for the treatment of established arthritis in multiple animal models of the disease. The therapy involves immunization of the animal against a hapten to induce anti-hapten antibodies, followed by injection with a folate-hapten conjugate to decorate the surface of folate receptor-positive (activated) macrophages with the antigenic hapten. The hapten-marked macrophages are then recognized by the anti-hapten antibodies and eliminated by immune mechanisms, leading to attenuation of disease symptoms. In the following paper, we optimize the therapy for elimination of inflammatory macrophages and suppression of rheumatoid arthritis symptoms. We also demonstrate a tight correlation between folate receptor-positive macrophage abundance in the liver and inflammation of affected joints. The results suggest that therapies that reduce folate receptor-positive macrophage populations in the body should constitute effective treatments for rheumatoid arthritis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Barrera, P., A. Blom, P.L. van Lent, L. van Bloois, J.H. Beijnen, N. van Rooijen, et al. 2000. Synovial macrophage depletion with clodronate-containing liposomes in rheumatoid arthritis. Arthritis and Rheumatism 43(9): 1951–9.

    Article  CAS  PubMed  Google Scholar 

  2. Beckmann, N., R. Falk, S. Zurbrugg, J. Dawson, and P. Engelhardt. 2003. Macrophage infiltration into the rat knee detected by MRI in a model of antigen-induced arthritis. Magnetic Resonance in Medicine 49(6): 1047–55.

    Article  PubMed  Google Scholar 

  3. Cauli, A., G. Yanni, and G.S. Panayi. 1997. Interleukin-1, interleukin-1 receptor antagonist and macrophage populations in rheumatoid arthritis synovial membrane. British Journal of Rheumatology 36(9): 935–40.

    Article  CAS  PubMed  Google Scholar 

  4. Danks, L., A. Sabokbar, R. Gundle, and N.A. Athanasou. 2002. Synovial macrophageosteoclast differentiation in inflammatory arthritis. Annals of the Rheumatic Diseases 61(10): 916–921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. De Rycke, L., D. Baeten, D. Foell, E. Kruithof, E.M. Veys, J. Roth, et al. 2005. Differential expression and response to anti-TNFalpha treatment of infiltrating versus resident tissue macrophage subsets in autoimmune arthritis. The Journal of Pathology 206(1): 17–27.

    Article  PubMed  Google Scholar 

  6. Xia, W., Hilgenbrink, A.R., Matteson, E.L., Lockwood, M.B., Cheng, J.X., and Low, PS. 2008. A functional folate receptor is induced during macrophage activation and can be used to target drugs to activated macrophages. Blood.

  7. Paulos, C.M., B. Varghese, W.R. Widmer, G.J. Breur, E. Vlashi, and P.S. Low. 2006. Folate-targeted immunotherapy effectively treats established adjuvant and collagen-induced arthritis. Arthritis Research and Therapy 8(3): R77.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Nakashima-Matsushita, N., T. Homma, S. Yu, T. Matsuda, N. Sunahara, T. Nakamura, et al. 1999. Selective expression of folate receptor beta and its possible role in methotrexate transport in synovial macrophages from patients with rheumatoid arthritis. Arthritis and Rheumatism 42(8): 1609–16.

    Article  CAS  PubMed  Google Scholar 

  9. Turk, M.J., G.J. Breur, W.R. Widmer, C.M. Paulos, L.C. Xu, L.A. Grote, et al. 2002. Folate-targeted imaging of activated macrophages in rats with adjuvant-induced arthritis. Arthritis and Rheumatism 46(7): 1947–55.

    Article  PubMed  Google Scholar 

  10. Nagayoshi, R., M. Nakamura, K. Ijiri, H. Yoshida, S. Komiya, and T. Matsuyama. 2003. LY309887, antifolate via the folate receptor suppresses murine type II collagen induced arthritis. Clinical and Experimental Rheumatology 21(6): 719–25.

    CAS  PubMed  Google Scholar 

  11. Nagayoshi, R., T. Nagai, K. Matsushita, K. Sato, N. Sunahara, T. Matsuda, et al. 2005. Effectiveness of anti-folate receptor beta antibody conjugated with truncated Pseudomonas exotoxin in the targeting of rheumatoid arthritis synovial macrophages. Arthritis and Rheumatism 52(9): 2666–75.

    Article  CAS  PubMed  Google Scholar 

  12. Varghese, B., N. Haase, and P.S. Low. 2007. Depletion of folate-receptor-positive macrophages leads to alleviation of symptoms and prolonged survival in two murine models of systemic lupus erythematosus. Molecular Pharmaceutics 4(5): 679–85.

    Article  CAS  PubMed  Google Scholar 

  13. Siebelt, M., N. Korthagen, W. Wei, H. Groen, Y. Bastiaansen-Jenniskens, C. Müller, J.H. Waarsing, M. de Jong, and H. Weinans. 2015. Triamcinolone acetonide activates an anti-inflammatory and folate receptor-positive macrophage that prevents osteophytosis in vivo. Arthritis Research and Therapy 17(5): 352.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Jager, N.A., J. Westra, R. Golestani, G.M. van Dam, P.S. Low, R.A. Tio, R.H. Slart, H.H. Boersma, M. Bijl, and C.J. Zeebregts. 2014. Folate receptor-β imaging using 99mTc-folate to explore distribution of polarized macrophage populations in human atherosclerotic plaque. Journal of Nuclear Medicine 55(12): 1945–51.

    Article  CAS  PubMed  Google Scholar 

  15. Tsuneyoshi, Y., M. Tanaka, T. Nagai, N. Sunahara, T. Matsuda, T. Sonoda, K. Ijiri, S. Komiya, and T. Matsuyama. 2012. Functional folate receptor beta-expressing macrophages in osteoarthritis synovium and their M1/M2 expression profiles. Scandinavian Journal of Rheumatology 41(2): 132–40.

    Article  CAS  PubMed  Google Scholar 

  16. Yi, Y.-S., W. Ayala-Lopez, S.A. Kularatne, and P.S. Low. 2009. Folate-targeted hapten immunotherapy of adjuvant-induced arthritis: comparison of hapten potencies. Molecular Pharmaceutics 6(4): 1228–1236.

    Article  CAS  PubMed  Google Scholar 

  17. Lu, Y., P.J. Klein, E. Westrick, L.C. Xu, H.K. Santhapuram, A. Bloomfield, S.J. Howard, I.R. Vlahov, P.R. Ellis, P.S. Low, and C.P. Leamon. 2009. The AAPS Journal 11(3): 628–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lu, Y., and P.S. Low. 2002. Folate targeting of haptens to cancer cell surfaces mediates immunotherapy of syngeneic murine tumors. Cancer Immunology, Immunotherapy 51(3): 153–62.

    Article  CAS  PubMed  Google Scholar 

  19. Fletcher, D.S., W.R. Widmer, S. Luell, A. Christen, C. Orevillo, S. Shah, et al. 1998. Therapeutic administration of a selective inhibitor of nitric oxide synthase does not ameliorate the chronic inflammation and tissue damage associated with adjuvant induced arthritis in rats. The Journal of Pharmacology and Experimental Therapeutics 284(2): 714–21.

    CAS  PubMed  Google Scholar 

  20. Yamada, H., Y. Nakashima, K. Okazaki, T. Mawatari, J.I. Fukushi, N. Kaibara, et al. 2008. Th1 but not Th17 cells predominate in the joints of patients with rheumatoid arthritis. Annals of the Rheumatic Diseases 67(9): 1299–304.

    Article  CAS  PubMed  Google Scholar 

  21. Chen, J., X.M. Zhang, and Q. Xu. 2004. Involvement of lymphocytes with a Th1 cytokine profile in bone cell damage associated with MMP-9 production in collagen-induced arthritis. Inflammation Research 53(12): 670–9.

    Article  CAS  PubMed  Google Scholar 

  22. van Roon, J.A., J.W. Bijlsma, and F.P. Lafeber. 2002. Suppression of inflammation and joint destruction in rheumatoid arthritis may require a concerted action of Th2 cytokines. Current Opinion in Investigational Drugs 3(7): 1011–6.

    PubMed  Google Scholar 

  23. Iwamoto, T., H. Okamoto, Y. Toyama, and S. Momohara. 2008. Molecular aspects of rheumatoid arthritis: chemokines in the joints of patients. The FEBS Journal 275(18): 4448–55.

    Article  CAS  PubMed  Google Scholar 

  24. Haas, C.S., R.J. Martinez, N. Attia, G.K. Haines 3rd, P.L. Campbell, and A.E. Koch. 2005. Chemokine receptor expression in rat adjuvant-induced arthritis. Arthritis and Rheumatism 52(12): 3718–30.

    Article  CAS  PubMed  Google Scholar 

  25. Gilman, S.C., J.F. Daniels, R.E. Wilson, R.P. Carlson, and A.J. Lewis. 1984. Lymphoid abnormalities in rats with adjuvant-induced arthritis. I. Mitogen responsiveness and lymphokine synthesis. Annals of the Rheumatic Diseases 43(6): 847–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Matteson, E.L., V.J. Lowe, F.G. Prendergast, C.S. Crowson, K.G. Moder, D.E. Morgenstern, et al. 2009. Assessment of disease activity in rheumatoid arthritis using a novel folate targeted radiopharmaceutical FolatescanTM. Clinical and Experimental Rheumatology 27(2): 253–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Marciani, D.J., J.B. Press, R.C. Reynolds, A.K. Pathak, V. Pathak, L.E. Gundy, et al. 2000. Development of semisynthetic triterpenoid saponin derivatives with immune stimulating activity. Vaccine 18(27): 3141–51.

    Article  CAS  PubMed  Google Scholar 

  28. Varghese, B., E. Vlashi, W. Xia, W. Ayala Lopez, C.M. Paulos, J. Reddy, et al. 2014. Folate receptor-β in activated macrophages: ligand binding and receptor recycling kinetics. Molecular Pharmaceutics 11(10): 3609–16.

    Article  CAS  PubMed  Google Scholar 

  29. Leamon, C.P., J.A. Reddy, R. Dorton, A. Bloomfield, K. Emsweller, N. Parker, et al. 2008. Impact of high and low folate diets on tissue folate receptor levels and antitumor responses towards folate-drug conjugates. The Journal of Pharmacology and Experimental Therapeutics 327(3): 918–25.

    Article  CAS  PubMed  Google Scholar 

  30. Lu, Y., E. Sega, and P.S. Low. 2005. Folate receptor-targeted immunotherapy: induction of humoral and cellular immunity against hapten-decorated cancer cells. International Journal of Cancer 116(5): 710–9.

    Article  CAS  PubMed  Google Scholar 

  31. Hua, J., S. Suguro, S. Hirano, K. Sakamoto, and I. Nagaoka. 2005. Preventive actions of a high dose of glucosamine on adjuvant arthritis in rats. Inflammation Research 54(3): 127–32.

    Article  CAS  PubMed  Google Scholar 

  32. Pohlers, D., A. Siegling, E. Buchner, C.B. Schmidt-Weber, E. Palombo-Kinne, F. Emmrich, et al. 2005. Expression of cytokine mRNA and protein in joints and lymphoid organs during the course of rat antigen-induced arthritis. Arthritis Research and Therapy 7(3): R445–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry, Purdue University, 720 Clinic Drive, West Lafayette, IN, 47907-2084, USA

    Bindu Varghese, Chrystal Paulos & Philip S. Low

Authors
  1. Bindu Varghese
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chrystal Paulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philip S. Low
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Philip S. Low.

Ethics declarations

All animal studies were approved by the Purdue Animal Care and Use Committee (PACUC).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Varghese, B., Paulos, C. & Low, P.S. Optimization of Folate-Targeted Immunotherapy for the Treatment of Experimental Arthritis. Inflammation 39, 1345–1353 (2016). https://doi.org/10.1007/s10753-016-0366-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-016-0366-7

KEY WORDS

Search

Navigation