Acta Medica Okayama. Pathophysiological functions of CD30+ CD4+ T cells in rheumatoid arthritis. DECEMBER Volume 57, Issue Article 1

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1 Acta Medica Okayama Volume 57, Issue Article 1 DECEMBER 2003 Pathophysiological functions of CD30+ CD4+ T cells in rheumatoid arthritis. Akira Okamoto Masahiro Yamamura Mitsuhiro Iwahashi Tetsushi Aita Akiko Ueno Masanori Kawashima Jiro Yamana Hidetoshi Kagawa Hirofumi Makino Okayama University, Okayama University, Okayama University, Okayama University, Okayama University, Okayama University, Okayama University, Okayama University, Okayama University, Copyright c 1999 OKAYAMA UNIVERSITY MEDICAL SCHOOL. All rights reserved.

2 Pathophysiological functions of CD30+ CD4+ T cells in rheumatoid arthritis. Akira Okamoto, Masahiro Yamamura, Mitsuhiro Iwahashi, Tetsushi Aita, Akiko Ueno, Masanori Kawashima, Jiro Yamana, Hidetoshi Kagawa, and Hirofumi Makino Abstract High levels of soluble CD30 (scd30) were detected in the serum and synovial fluid of patients with rheumatoid arthritis (RA), indicating the involvement of CD30+ T cells in the pathogenesis. We investigated the induction of CD30 and its functions in CD4+T cells from patients with established RA (disease duration > 2 years). CD4+ T cells from both the peripheral blood (PB) and synovial tissue (ST) of RA patients expressed surface CD30 when stimulated with anti-cd3 antibody (Ab) and anti-cd28 Ab, but their CD30 induction was slower and weaker compared with PB CD4+ T cells of healthy controls (HC). Immunohistochemical analysis showed that only a small proportion of lymphocytes expressed CD30 in the ST (-1%). RA PB CD4+ T cells, after recovery from 6-day stimulation with anti-cd3 Ab and anti-cd28 Ab, showed in intracellular cytokine staining that CD30+ T cells could produce more interleukin-4 (IL-4) but less interferon-gamma. In the culture of RA PB CD4+ T Cells with anti-cd3 Ab and anti-cd28 Ab, blocking anti-cd30 Ab similarly inhibited the cell proliferation and activation of nuclear factor-kappab on day 4 in RA and HC, but inhibited the apoptotic cell death on day 6 only in RA. These results indicate that despite high-level expression of scd30, the anti-inflammatory activity of IL-4-producing CD30+ CD4+ T cells may be limited in the ST due to a poor induction of surface CD30 and a susceptibility to CD30-mediated cell death. KEYWORDS: apoptosis, CD4 Tcells, CD30, interleukin-4(il=4), rheumatoid arthritis(ra) PMID: [PubMed - indexed for MEDLINE] Copyright (C) OKAYAMA UNIVERSITY MEDICAL SCHOOL

3 Okamoto et al.: Pathophysiological functions of CD30+ CD4+ T cells in rheumatoid Produced by The Berkeley Electronic Press,

4 Acta Medica Okayama, Vol. 57 [2003], Iss. 6, Art

5 Okamoto et al.: Pathophysiological functions of CD30+ CD4+ T cells in rheumatoid Produced by The Berkeley Electronic Press,

6 Acta Medica Okayama, Vol. 57 [2003], Iss. 6, Art

7 Okamoto et al.: Pathophysiological functions of CD30+ CD4+ T cells in rheumatoid Produced by The Berkeley Electronic Press,

8 Acta Medica Okayama, Vol. 57 [2003], Iss. 6, Art Okamoto et al. Acta Med. Okayama Vol. 57, No. 6 RA ST a MM bp β-actin 410bp CD30 614bp CD30L b Fig.3 (a)mrnaexpression ofcd30 and CD30 ligand (CD30L)in RAST, determined byreversetranscriptasepolymerase chain reaction. MM, molecular weight markers. (b)immunohistological localization ofcd30expressing cells in RAST. No isotypematched control mab staining was observed. CD30positive cells were distributedinat the peripheryof lymphoid aggregates. Fig.4 IL4 production byracd30 CD4 Tcells. PB CD4 Tcells after stimulation with anticd3 Ab and anticd28 Ab for 6 days were determined for IFNγ, IL4, and CD30 production by intracellular cytokines and fl owcytometry. (a)a representative result is shown. (b)the intensityofcd30 expression byrapb CD4 Tcells producing IFNγor IL4. Data are expressed as the mean± SEM of the MFI ratio of CD30 antigen divided by the MFI of control samples. n, number of studied subjects. (1.0± 0.7) in RA. However, in HC, there was no difference in themfi ofcd30 expression between IL4± ± PB CD4 T cells fromra patients and IFNγproducing cells ( vs )(Fig. (n 9)and HC (n 4)wererecovered after 6daystimu- 4b). lation with anticd3 Ab and anticd28 Ab foranalysis of κ intracellular cytokine staining. The frequency of CD30 The levels of NFκB cells was decreased to acertain extent afteractivation with activation in both RA and HC PB CD4 T cells after PMA and A23187, presumably due to the shedding of stimulation with anticd3 Ab and anticd28 Ab were surface CD30. As shown in a representative experiment signifi cantlydetectable on day4 but not on day6. These (Fig. 4a), RA CD30 cells predominantlyproduced high activities were similarly inhibited in the presence of levels ofifnγ, but CD30 cells produced lowlevels of anticd30 Ab in RA and HC (Fig. 5). both IL4 and IFNγ. The mean MFI ratio of surface CD30 expression was signifi cantly greater in IL4PB CD4 T cells from RA ± producing cells ( )than in IFNγproducing cells patients and HC wereexamined for theeffects ofblocking 6

9 Okamoto et al.: Pathophysiological functions of CD30+ CD4+ T cells in rheumatoid Produced by The Berkeley Electronic Press,

10 Acta Medica Okayama, Vol. 57 [2003], Iss. 6, Art

11 Okamoto et al.: Pathophysiological functions of CD30+ CD4+ T cells in rheumatoid Produced by The Berkeley Electronic Press,

12 Acta Medica Okayama, Vol. 57 [2003], Iss. 6, Art

13 Okamoto et al.: Pathophysiological functions of CD30+ CD4+ T cells in rheumatoid Produced by The Berkeley Electronic Press,