Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Jul 15;98(2):271–278. doi: 10.1172/JCI118789

Therapeutic effect of the anti-Fas antibody on arthritis in HTLV-1 tax transgenic mice.

K Fujisawa 1, H Asahara 1, K Okamoto 1, H Aono 1, T Hasunuma 1, T Kobata 1, Y Iwakura 1, S Yonehara 1, T Sumida 1, K Nishioka 1
PMCID: PMC507427  PMID: 8755634

Abstract

We have recently demonstrated Fas-mediated apoptosis in the synovium, of patients with rheumatoid arthritis (RA) and suggested that it may be one factor responsible for the regression of RA. To examine whether the induction of apoptosis caused by anti-Fas mAb may play a potential role as a new therapeutic strategy for RA, we investigated the effect of anti-Fas mAb (RK-8) on synovitis in an animal model of RA, the human T cell leukemia virus type I (HTLV-1) tax transgenic mice. We report here that administration of anti-Fas mAb into mice intra-articularly improved the paw swelling and arthritis within 48 h. Immunohistochemical study and in vitro culture studies showed that 35% of synovial fibroblasts, 75% of mononuclear cells, and some of polymorphonuclear leukocytes infiltrating in synovium underwent apoptosis by anti-Fas mAb. In situ nick end labeling analysis and electron microscope analysis clearly showed that many cells in synovium were induced apoptosis by anti-Fas mAb administration. However, local administration of anti-Fas mAb did not produce systemic side effects. Results demonstrated that administration of anti-Fas mAb in arthritic joints of the HTLV-1 tax transgenic mice produced improvement of arthritis. These findings suggest that local administration of anti-Fas mAb may represent a useful therapeutic strategy for proliferative synovitis such as RA.

Full Text

The Full Text of this article is available as a PDF (4.0 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arai N., Nomura D., Villaret D., DeWaal Malefijt R., Seiki M., Yoshida M., Minoshima S., Fukuyama R., Maekawa M., Kudoh J. Complete nucleotide sequence of the chromosomal gene for human IL-4 and its expression. J Immunol. 1989 Jan 1;142(1):274–282. [PubMed] [Google Scholar]
  2. Chlichlia K., Moldenhauer G., Daniel P. T., Busslinger M., Gazzolo L., Schirrmacher V., Khazaie K. Immediate effects of reversible HTLV-1 tax function: T-cell activation and apoptosis. Oncogene. 1995 Jan 19;10(2):269–277. [PubMed] [Google Scholar]
  3. Cross S. L., Feinberg M. B., Wolf J. B., Holbrook N. J., Wong-Staal F., Leonard W. J. Regulation of the human interleukin-2 receptor alpha chain promoter: activation of a nonfunctional promoter by the transactivator gene of HTLV-I. Cell. 1987 Apr 10;49(1):47–56. doi: 10.1016/0092-8674(87)90754-9. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Gavrieli Y., Sherman Y., Ben-Sasson S. A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. doi: 10.1083/jcb.119.3.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Gessain A., Barin F., Vernant J. C., Gout O., Maurs L., Calender A., de Thé G. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet. 1985 Aug 24;2(8452):407–410. doi: 10.1016/s0140-6736(85)92734-5. [DOI] [PubMed] [Google Scholar]
  7. Green J. E., Hinrichs S. H., Vogel J., Jay G. Exocrinopathy resembling Sjögren's syndrome in HTLV-1 tax transgenic mice. Nature. 1989 Sep 7;341(6237):72–74. doi: 10.1038/341072a0. [DOI] [PubMed] [Google Scholar]
  8. Harris E. D., Jr Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med. 1990 May 3;322(18):1277–1289. doi: 10.1056/NEJM199005033221805. [DOI] [PubMed] [Google Scholar]
  9. Hinuma Y., Nagata K., Hanaoka M., Nakai M., Matsumoto T., Kinoshita K. I., Shirakawa S., Miyoshi I. Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6476–6480. doi: 10.1073/pnas.78.10.6476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Itoh N., Yonehara S., Ishii A., Yonehara M., Mizushima S., Sameshima M., Hase A., Seto Y., Nagata S. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell. 1991 Jul 26;66(2):233–243. doi: 10.1016/0092-8674(91)90614-5. [DOI] [PubMed] [Google Scholar]
  11. Iwakura Y., Saijo S., Kioka Y., Nakayama-Yamada J., Itagaki K., Tosu M., Asano M., Kanai Y., Kakimoto K. Autoimmunity induction by human T cell leukemia virus type 1 in transgenic mice that develop chronic inflammatory arthropathy resembling rheumatoid arthritis in humans. J Immunol. 1995 Aug 1;155(3):1588–1598. [PubMed] [Google Scholar]
  12. Iwakura Y., Tosu M., Yoshida E., Takiguchi M., Sato K., Kitajima I., Nishioka K., Yamamoto K., Takeda T., Hatanaka M. Induction of inflammatory arthropathy resembling rheumatoid arthritis in mice transgenic for HTLV-I. Science. 1991 Aug 30;253(5023):1026–1028. doi: 10.1126/science.1887217. [DOI] [PubMed] [Google Scholar]
  13. Kitajima I., Maruyama I., Maruyama Y., Ijichi S., Eiraku N., Mimura Y., Osame M. Polyarthritis in human T lymphotropic virus type I-associated myelopathy. Arthritis Rheum. 1989 Oct;32(10):1342–1344. doi: 10.1002/anr.1780321030. [DOI] [PubMed] [Google Scholar]
  14. Maruyama M., Shibuya H., Harada H., Hatakeyama M., Seiki M., Fujita T., Inoue J., Yoshida M., Taniguchi T. Evidence for aberrant activation of the interleukin-2 autocrine loop by HTLV-1-encoded p40x and T3/Ti complex triggering. Cell. 1987 Jan 30;48(2):343–350. doi: 10.1016/0092-8674(87)90437-5. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Nishimura Y., Ishii A., Kobayashi Y., Yamasaki Y., Yonehara S. Expression and function of mouse Fas antigen on immature and mature T cells. J Immunol. 1995 May 1;154(9):4395–4403. [PubMed] [Google Scholar]
  17. Nishioka K., Maruyama I., Sato K., Kitajima I., Nakajima Y., Osame M. Chronic inflammatory arthropathy associated with HTLV-I. Lancet. 1989 Feb 25;1(8635):441–441. doi: 10.1016/s0140-6736(89)90038-x. [DOI] [PubMed] [Google Scholar]
  18. Oehm A., Behrmann I., Falk W., Pawlita M., Maier G., Klas C., Li-Weber M., Richards S., Dhein J., Trauth B. C. Purification and molecular cloning of the APO-1 cell surface antigen, a member of the tumor necrosis factor/nerve growth factor receptor superfamily. Sequence identity with the Fas antigen. J Biol Chem. 1992 May 25;267(15):10709–10715. [PubMed] [Google Scholar]
  19. Ogasawara J., Watanabe-Fukunaga R., Adachi M., Matsuzawa A., Kasugai T., Kitamura Y., Itoh N., Suda T., Nagata S. Lethal effect of the anti-Fas antibody in mice. Nature. 1993 Aug 26;364(6440):806–809. doi: 10.1038/364806a0. [DOI] [PubMed] [Google Scholar]
  20. Osame M., Usuku K., Izumo S., Ijichi N., Amitani H., Igata A., Matsumoto M., Tara M. HTLV-I associated myelopathy, a new clinical entity. Lancet. 1986 May 3;1(8488):1031–1032. doi: 10.1016/s0140-6736(86)91298-5. [DOI] [PubMed] [Google Scholar]
  21. Sagawa K., Mochizuki M., Masuoka K., Katagiri K., Katayama T., Maeda T., Tanimoto A., Sugita S., Watanabe T., Itoh K. Immunopathological mechanisms of human T cell lymphotropic virus type 1 (HTLV-I) uveitis. Detection of HTLV-I-infected T cells in the eye and their constitutive cytokine production. J Clin Invest. 1995 Feb;95(2):852–858. doi: 10.1172/JCI117735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Suda T., Takahashi T., Golstein P., Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell. 1993 Dec 17;75(6):1169–1178. doi: 10.1016/0092-8674(93)90326-l. [DOI] [PubMed] [Google Scholar]
  23. Takahashi T., Tanaka M., Brannan C. I., Jenkins N. A., Copeland N. G., Suda T., Nagata S. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell. 1994 Mar 25;76(6):969–976. doi: 10.1016/0092-8674(94)90375-1. [DOI] [PubMed] [Google Scholar]
  24. Terada K., Katamine S., Eguchi K., Moriuchi R., Kita M., Shimada H., Yamashita I., Iwata K., Tsuji Y., Nagataki S. Prevalence of serum and salivary antibodies to HTLV-1 in Sjögren's syndrome. Lancet. 1994 Oct 22;344(8930):1116–1119. doi: 10.1016/s0140-6736(94)90630-0. [DOI] [PubMed] [Google Scholar]
  25. Trauth B. C., Klas C., Peters A. M., Matzku S., Möller P., Falk W., Debatin K. M., Krammer P. H. Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science. 1989 Jul 21;245(4915):301–305. doi: 10.1126/science.2787530. [DOI] [PubMed] [Google Scholar]
  26. Watanabe-Fukunaga R., Brannan C. I., Copeland N. G., Jenkins N. A., Nagata S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992 Mar 26;356(6367):314–317. doi: 10.1038/356314a0. [DOI] [PubMed] [Google Scholar]
  27. Watanabe-Fukunaga R., Brannan C. I., Itoh N., Yonehara S., Copeland N. G., Jenkins N. A., Nagata S. The cDNA structure, expression, and chromosomal assignment of the mouse Fas antigen. J Immunol. 1992 Feb 15;148(4):1274–1279. [PubMed] [Google Scholar]
  28. Yamada T., Yamaoka S., Goto T., Nakai M., Tsujimoto Y., Hatanaka M. The human T-cell leukemia virus type I Tax protein induces apoptosis which is blocked by the Bcl-2 protein. J Virol. 1994 May;68(5):3374–3379. doi: 10.1128/jvi.68.5.3374-3379.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Yamamoto H., Sekiguchi T., Itagaki K., Saijo S., Iwakura Y. Inflammatory polyarthritis in mice transgenic for human T cell leukemia virus type I. Arthritis Rheum. 1993 Nov;36(11):1612–1620. doi: 10.1002/art.1780361117. [DOI] [PubMed] [Google Scholar]
  30. Yonehara S., Ishii A., Yonehara M. A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor. J Exp Med. 1989 May 1;169(5):1747–1756. doi: 10.1084/jem.169.5.1747. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES