Arthritis induced in rats by cloned T lymphocytes responsive to mycobacteria but not to collagen type II.

Abstract

Abstract. We have been studying the pathogenesis of adjuvant arthritis in rats using a long-term cell line of T lymphocytes, the A2 line, which can induce polyarthritis and can also be used to vaccinate rats against adjuvant arthritis. Although line A2 was selected for its proliferative response to mycobacteria, it also responded to collagen type II. To elucidate its role of responsiveness to collagen type II and the relationship between arthritogenicity and vaccination, we cloned A2 and selected a subline A2b. We now report that subline A2b, which bore a marker of helper/delayed hypersensitivity T lymphocytes, was strongly arthritogenic, but could not vaccinate against arthritis. Moreover, A2b showed no response to collagen type II. Therefore, reactivity to collagen type II is not a requisite for arthritogenicity, and mediation of arthritis and vaccination can be distinct properties of different populations of T lymphocytes. (7) and in humans with rheumatoid arthritis (8), it has been suggested that collagen type II may be a critical self-antigen in autoimmune arthritis (7).To investigate the pathogenesis of AA we developed lines of T lymphocytes from the draining lymph nodes of Lewis rats immunized to CFA (9). Line A2, selected because of its proliferative response to whole MT, could induce polyarthritis upon intravenous injection into irradiated Lewis rats. Cells of line A2 could also be used to vaccinate rats against subsequent attempts to induce AA by active immunization to CFA. We observed that in addition to responding strongly to MT, line A2 proliferated in vitro to a relatively slight but significant degree to collagen type II. Hence it was conceivable that some MT antigens might cross-react with self-collagen type II and that induction of arthritis and/or vaccination against AA might be the property of line cells reactive to collagen type II (9).The present experiments were done to test this hypothesis. Accordingly, we prepared a cloned subline, A2b, that was found to be more strongly arthritogenic than the parent A2 line. However, unlike the A2 line, the A2b subline could not induce resistance to AA. Moreover, subline A2b responded in vitro strongly to MT antigens but not at all to collagen type II. Thus, arthritogenicity and vaccination may be produced by separate populations of cells, and reactivity to collagen type II is not required to induce autoimmune arthritis. Finally, we were able to transfer arthritis with line cells that had been activated by the mitogen concanavalin A (Con A) in place of MT. This argues against the notion that disseminated MT antigens are the requisite target for AA and suggests that a target self-antigen exists in the joints. 211Line-mediated Arthritis in Rats J. Clin. Invest.

Anti-Very Late Antigen-1 Monoclonal Antibody Modulates the Development of Secondary Lesion and T-Cell Response in Experimental Arthritis

“…These data, together with the finding that swelling in the contralateral paw was inhibited by anti VLA-1 mAb, suggest that treatment with HA31/8 antibody is able to delay the disease development. It is likely that the beneficial effect of the anti-VLA-1 mAb is linked to a reduced activation and, as a consequence, trafficking and proliferation of the T cells through the lymph node, which have been shown to be key features in this experimental model of arthritis (Cohen et al, 1985;Haskard, 1993;Holoshitz et al, 1984;Yednock and Rosen, 1989). Indeed, treatment with HA31/8 caused also a significant inhibition of the total cell count harvested by DLN.…”

Pristane, a Non-Antigenic Adjuvant, Induces MHC Class II-Restricted, Arthritogenic T Cells in the Rat

“…Additional studies to reveal the MHC specificity/restriction, T cell specificity, and effector function have been hampered with a multitude of difficulties. Nevertheless, it has been reported that T cells specific for heat shock protein can transfer arthritis; the mechanism was believed to be due to cross-reactivity of the transferred T cells with various joint Ags (31). However, these studies have not been reproduced, and histological evidence showed no or possibly only very mild synovitis (32).…”

Prevention of adjuvant arthritis in rats by a nonapeptide from the 65-kD mycobacterial heat-shock protein

“…We now add another mechanism to the list of possibilities, namely the induction of a protective immune response to the autoimmune disease-inducing epitope (ADIE), SNP in the case of AA. Of course, SNP itself has not been shown to be arthritogenic, but a T cell clone (A2b) which responds in vitro to SNP is arthritogenic (Holoshitz et al, 1984;Cohen et al, 1985). So far the common opinion postulates the induction of tolerance to ADIE or suppression ofthe immune response to ADIE as ways of achieving prevention or therapy of autoimmune diseases.…”

“…A nonapeptide (Thr-Phe-Gly-Leu-Gln-Leu-Glu-Leu-Thr), representing amino acid sequence 180-188 ofthe 65-kD mycobacterial HSP, has been suggested to carry the critical epitope(s) for A A because of its ability to stimulate the arthritis-inducing T cell clone A2b as well as the arthritis-protective T cell clone A2c in vitro (Holoshitz, Matitiau & Cohen, 1984;Cohen et at., 1985;van Eden et al, 1988;, Based on these observations, it was suspected that immunization with the Correspondence: Dr X,-D, Yang, R-1056. 1,18, Ciba-Geigy, CH-4002 Basle, Switzerland, synthetic nonapeptide (SNP) would either activate an A2b-like T cell subset to induce arthritis or it would stimulate an A2c-like T cell subset resulting in a protective response against AA (van Eden era/,, 1988;Yang era/,, 1990), In a previous study, we have shown that administration of SNP suspended in mineral oil did not induce AA but was able to suppress AA partially in Lewis rats (Yang et al, 1989(Yang et al, , 1990.…”