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. 1997 Oct 15;100(8):1951–1957. doi: 10.1172/JCI119726

Amelioration of collagen-induced arthritis by CD95 (Apo-1/Fas)-ligand gene transfer.

H Zhang 1, Y Yang 1, J L Horton 1, E B Samoilova 1, T A Judge 1, L A Turka 1, J M Wilson 1, Y Chen 1
PMCID: PMC508384  PMID: 9329958

Abstract

Both rheumatoid arthritis and animal models of autoimmune arthritis are characterized by hyperactivation of synovial cells and hyperplasia of the synovial membrane. The activated synovial cells produce inflammatory cytokines and degradative enzymes that lead to destruction of cartilage and bones. Effective treatment of arthritis may require elimination of most or all activated synovial cells. The death factor Fas/Apo-1 and its ligand (FasL) play pivotal roles in maintaining self-tolerance and immune privilege. Fas is expressed constitutively in most tissues, and is dramatically upregulated at the site of inflammation. In both rheumatoid arthritis and animal models of autoimmune arthritis, high levels of Fas are expressed on activated synovial cells and infiltrating leukocytes in the inflamed joints. Unlike Fas, however, the levels of FasL expressed in the arthritic joints are extremely low, and most activated synovial cells survive despite high levels of Fas expression. To upregulate FasL expression in the arthritic joints, we have generated a recombinant replication-defective adenovirus carrying FasL gene; injection of the FasL virus into inflamed joints conferred high levels of FasL expression, induced apoptosis of synovial cells, and ameliorated collagen-induced arthritis in DBA/1 mice. The Fas-ligand virus also inhibited production of interferon-gamma by collagen-specific T cells. Coadministration of Fas-immunoglobulin fusion protein with the Fas-ligand virus prevented these effects, demonstrating the specificity of the Fas-ligand virus. Thus, FasL gene transfer at the site of inflammation effectively ameliorates autoimmune disease.

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Selected References

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  1. Bandara G., Mueller G. M., Galea-Lauri J., Tindal M. H., Georgescu H. I., Suchanek M. K., Hung G. L., Glorioso J. C., Robbins P. D., Evans C. H. Intraarticular expression of biologically active interleukin 1-receptor-antagonist protein by ex vivo gene transfer. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10764–10768. doi: 10.1073/pnas.90.22.10764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bellgrau D., Gold D., Selawry H., Moore J., Franzusoff A., Duke R. C. A role for CD95 ligand in preventing graft rejection. Nature. 1995 Oct 19;377(6550):630–632. doi: 10.1038/377630a0. [DOI] [PubMed] [Google Scholar]
  3. Brunner T., Mogil R. J., LaFace D., Yoo N. J., Mahboubi A., Echeverri F., Martin S. J., Force W. R., Lynch D. H., Ware C. F. Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature. 1995 Feb 2;373(6513):441–444. doi: 10.1038/373441a0. [DOI] [PubMed] [Google Scholar]
  4. Casscells W., Willerson J. T. Amphotropic but not atherotropic: another caveat for adenoviral gene therapy. J Clin Invest. 1995 Jun;95(6):2425–2426. doi: 10.1172/JCI117938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chen Y., Inobe J., Weiner H. L. Induction of oral tolerance to myelin basic protein in CD8-depleted mice: both CD4+ and CD8+ cells mediate active suppression. J Immunol. 1995 Jul 15;155(2):910–916. [PubMed] [Google Scholar]
  6. Cohen P. L., Eisenberg R. A. The lpr and gld genes in systemic autoimmunity: life and death in the Fas lane. Immunol Today. 1992 Nov;13(11):427–428. doi: 10.1016/0167-5699(92)90066-G. [DOI] [PubMed] [Google Scholar]
  7. Dai Y., Schwarz E. M., Gu D., Zhang W. W., Sarvetnick N., Verma I. M. Cellular and humoral immune responses to adenoviral vectors containing factor IX gene: tolerization of factor IX and vector antigens allows for long-term expression. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1401–1405. doi: 10.1073/pnas.92.5.1401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. David C. S. Genes for MHC, TCR and MIs determine susceptibility to collagen induced arthritis. APMIS. 1990 Jul;98(7):575–584. doi: 10.1111/j.1699-0463.1990.tb04974.x. [DOI] [PubMed] [Google Scholar]
  9. Dhein J., Walczak H., Bäumler C., Debatin K. M., Krammer P. H. Autocrine T-cell suicide mediated by APO-1/(Fas/CD95) Nature. 1995 Feb 2;373(6513):438–441. doi: 10.1038/373438a0. [DOI] [PubMed] [Google Scholar]
  10. Doherty P. J. Gene therapy and arthritis. J Rheumatol. 1995 Jul;22(7):1220–1223. [PubMed] [Google Scholar]
  11. Engelhardt J. F., Yang Y., Stratford-Perricaudet L. D., Allen E. D., Kozarsky K., Perricaudet M., Yankaskas J. R., Wilson J. M. Direct gene transfer of human CFTR into human bronchial epithelia of xenografts with E1-deleted adenoviruses. Nat Genet. 1993 May;4(1):27–34. doi: 10.1038/ng0593-27. [DOI] [PubMed] [Google Scholar]
  12. Evans C. H., Robbins P. D. Progress toward the treatment of arthritis by gene therapy. Ann Med. 1995 Oct;27(5):543–546. doi: 10.3109/07853899509002466. [DOI] [PubMed] [Google Scholar]
  13. Firestein G. S., Yeo M., Zvaifler N. J. Apoptosis in rheumatoid arthritis synovium. J Clin Invest. 1995 Sep;96(3):1631–1638. doi: 10.1172/JCI118202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fujisawa K., Asahara H., Okamoto K., Aono H., Hasunuma T., Kobata T., Iwakura Y., Yonehara S., Sumida T., Nishioka K. Therapeutic effect of the anti-Fas antibody on arthritis in HTLV-1 tax transgenic mice. J Clin Invest. 1996 Jul 15;98(2):271–278. doi: 10.1172/JCI118789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Griffith T. S., Brunner T., Fletcher S. M., Green D. R., Ferguson T. A. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science. 1995 Nov 17;270(5239):1189–1192. doi: 10.1126/science.270.5239.1189. [DOI] [PubMed] [Google Scholar]
  16. Hahne M., Rimoldi D., Schröter M., Romero P., Schreier M., French L. E., Schneider P., Bornand T., Fontana A., Lienard D. Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science. 1996 Nov 22;274(5291):1363–1366. doi: 10.1126/science.274.5291.1363. [DOI] [PubMed] [Google Scholar]
  17. Holmdahl R., Andersson M., Goldschmidt T. J., Gustafsson K., Jansson L., Mo J. A. Type II collagen autoimmunity in animals and provocations leading to arthritis. Immunol Rev. 1990 Dec;118:193–232. doi: 10.1111/j.1600-065x.1990.tb00817.x. [DOI] [PubMed] [Google Scholar]
  18. Hung G. L., Galea-Lauri J., Mueller G. M., Georgescu H. I., Larkin L. A., Suchanek M. K., Tindal M. H., Robbins P. D., Evans C. H. Suppression of intra-articular responses to interleukin-1 by transfer of the interleukin-1 receptor antagonist gene to synovium. Gene Ther. 1994 Jan;1(1):64–69. [PubMed] [Google Scholar]
  19. Ju S. T., Panka D. J., Cui H., Ettinger R., el-Khatib M., Sherr D. H., Stanger B. Z., Marshak-Rothstein A. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature. 1995 Feb 2;373(6513):444–448. doi: 10.1038/373444a0. [DOI] [PubMed] [Google Scholar]
  20. Lau H. T., Yu M., Fontana A., Stoeckert C. J., Jr Prevention of islet allograft rejection with engineered myoblasts expressing FasL in mice. Science. 1996 Jul 5;273(5271):109–112. doi: 10.1126/science.273.5271.109. [DOI] [PubMed] [Google Scholar]
  21. Makarov S. S., Olsen J. C., Johnston W. N., Anderle S. K., Brown R. R., Baldwin A. S., Jr, Haskill J. S., Schwab J. H. Suppression of experimental arthritis by gene transfer of interleukin 1 receptor antagonist cDNA. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):402–406. doi: 10.1073/pnas.93.1.402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Makarov S. S., Olsen J. C., Johnston W. N., Schwab J. H., Anderle S. K., Brown R. R., Haskill J. S. Retrovirus mediated in vivo gene transfer to synovium in bacterial cell wall-induced arthritis in rats. Gene Ther. 1995 Aug;2(6):424–428. [PubMed] [Google Scholar]
  23. Myers L. K., Seyer J. M., Stuart J. M., Terato K., David C. S., Kang A. H. T cell epitopes of type II collagen that regulate murine collagen-induced arthritis. J Immunol. 1993 Jul 1;151(1):500–505. [PubMed] [Google Scholar]
  24. Nagata S., Golstein P. The Fas death factor. Science. 1995 Mar 10;267(5203):1449–1456. doi: 10.1126/science.7533326. [DOI] [PubMed] [Google Scholar]
  25. Nagata S., Suda T. Fas and Fas ligand: lpr and gld mutations. Immunol Today. 1995 Jan;16(1):39–43. doi: 10.1016/0167-5699(95)80069-7. [DOI] [PubMed] [Google Scholar]
  26. Nakajima T., Aono H., Hasunuma T., Yamamoto K., Shirai T., Hirohata K., Nishioka K. Apoptosis and functional Fas antigen in rheumatoid arthritis synoviocytes. Arthritis Rheum. 1995 Apr;38(4):485–491. doi: 10.1002/art.1780380405. [DOI] [PubMed] [Google Scholar]
  27. Otani K., Nita I., Macaulay W., Georgescu H. I., Robbins P. D., Evans C. H. Suppression of antigen-induced arthritis in rabbits by ex vivo gene therapy. J Immunol. 1996 May 1;156(9):3558–3562. [PubMed] [Google Scholar]
  28. Roessler B. J., Allen E. D., Wilson J. M., Hartman J. W., Davidson B. L. Adenoviral-mediated gene transfer to rabbit synovium in vivo. J Clin Invest. 1993 Aug;92(2):1085–1092. doi: 10.1172/JCI116614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Russell J. H., Rush B., Weaver C., Wang R. Mature T cells of autoimmune lpr/lpr mice have a defect in antigen-stimulated suicide. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4409–4413. doi: 10.1073/pnas.90.10.4409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Seino K., Kayagaki N., Okumura K., Yagita H. Antitumor effect of locally produced CD95 ligand. Nat Med. 1997 Feb;3(2):165–170. doi: 10.1038/nm0297-165. [DOI] [PubMed] [Google Scholar]
  31. Singer G. G., Abbas A. K. The fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice. Immunity. 1994 Aug;1(5):365–371. doi: 10.1016/1074-7613(94)90067-1. [DOI] [PubMed] [Google Scholar]
  32. Strand S., Hofmann W. J., Hug H., Müller M., Otto G., Strand D., Mariani S. M., Stremmel W., Krammer P. H., Galle P. R. Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells--a mechanism of immune evasion? Nat Med. 1996 Dec;2(12):1361–1366. doi: 10.1038/nm1296-1361. [DOI] [PubMed] [Google Scholar]
  33. Tanaka H., Ota K., Ikusaka M., Ejima M., Maruyama S. [Expression of Fas-antigen on T cells in multiple sclerosis]. Rinsho Shinkeigaku. 1995 Mar;35(3):299–301. [PubMed] [Google Scholar]
  34. Tsuboi M., Eguchi K., Kawakami A., Matsuoka N., Kawabe Y., Aoyagi T., Maeda K., Nagataki S. Fas antigen expression on synovial cells was down-regulated by interleukin 1 beta. Biochem Biophys Res Commun. 1996 Jan 5;218(1):280–285. doi: 10.1006/bbrc.1996.0049. [DOI] [PubMed] [Google Scholar]
  35. Vincenti M. P., Coon C. I., White L. A., Barchowsky A., Brinckerhoff C. E. src-related tyrosine kinases regulate transcriptional activation of the interstitial collagenase gene, MMP-1, in interleukin-1-stimulated synovial fibroblasts. Arthritis Rheum. 1996 Apr;39(4):574–582. doi: 10.1002/art.1780390406. [DOI] [PubMed] [Google Scholar]
  36. Wilson J. M. Cystic fibrosis. Vehicles for gene therapy. Nature. 1993 Oct 21;365(6448):691–692. doi: 10.1038/365691a0. [DOI] [PubMed] [Google Scholar]
  37. Yang Y., Ertl H. C., Wilson J. M. MHC class I-restricted cytotoxic T lymphocytes to viral antigens destroy hepatocytes in mice infected with E1-deleted recombinant adenoviruses. Immunity. 1994 Aug;1(5):433–442. doi: 10.1016/1074-7613(94)90074-4. [DOI] [PubMed] [Google Scholar]
  38. Yang Y., Li Q., Ertl H. C., Wilson J. M. Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses. J Virol. 1995 Apr;69(4):2004–2015. doi: 10.1128/jvi.69.4.2004-2015.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Yang Y., Nunes F. A., Berencsi K., Gönczöl E., Engelhardt J. F., Wilson J. M. Inactivation of E2a in recombinant adenoviruses improves the prospect for gene therapy in cystic fibrosis. Nat Genet. 1994 Jul;7(3):362–369. doi: 10.1038/ng0794-362. [DOI] [PubMed] [Google Scholar]
  40. Yang Y., Su Q., Grewal I. S., Schilz R., Flavell R. A., Wilson J. M. Transient subversion of CD40 ligand function diminishes immune responses to adenovirus vectors in mouse liver and lung tissues. J Virol. 1996 Sep;70(9):6370–6377. doi: 10.1128/jvi.70.9.6370-6377.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]

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