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

Abstract

Pristane-induced arthritis (PIA) in rats, a model for rheumatoid arthritis (RA), is a T cell-dependent disease. However, pristane itself is a lipid and unable to form a stable complex with a MHC class II molecule. Therefore, the specificity and function of the T cells in PIA are as unclear as in rheumatoid arthritis. In this study, we show that activated CD4+ αβT cells, which target peripheral joints, transfer PIA. The pristane-primed T cells are of oligo or polyclonal origin as determined by their arthritogenicity after stimulation with several mitogenic anti-TCRVβ and anti-TCRVα mAbs. Arthritogenic cells secreted IFN-γ and TNF-α (but not IL-4) when stimulated with Con A in vitro, and pretreatments of recipient rats with either anti-IFN-γ or a recombinant TNF-α receptor before transfer ameliorated arthritis development. Most importantly, we show that these T cells are MHC class II restricted, because treatment with Abs against either DQ or DR molecules ameliorates arthritis development. The MHC class II restriction was confirmed by transferring donor T cells to irradiated recipients that were syngenic, semiallogenic, or allogenic to MHC class II molecules, in which only syngenic and semiallogenic recipients developed arthritis. These data suggest that the in vivo administration of a non-antigenic adjuvant, like pristane, activates CD4+ αβT cells that are MHC class II restricted and arthritogenic.

T cell surface redox levels determine T cell reactivity and arthritis susceptibility

“…Rats were immunized with 500 l of pristane. At day 14, spleen cells and inguinal LN CD4 ϩ T cells (purified by panning; Ͼ94% CD4 ϩ T cells) were cultured for 48 h in DMEM ϩϩϩ with 3 g͞ml concanavalin A (Sigma) at 37°C (6). Then, cells were treated with 4 mM GSH in PBS or PBS as a control (in 5 ml for 175 ϫ 10 6 cells) for 15 min on ice.…”

“…Because CFSE staining diluted out to background levels within 2 days, an allelic marker was used to follow the transferred cells for a longer time. A similar transfer protocol was used as described for the CFSE transfer, but the cells were now injected in irradiated congenic DA.1I rats, which do not express the MHC class I molecule RT1A a (6). Rats were killed at day 7 after transfer, at Concanavalin A cultured T cells from spleen or purified TCR ϩ CD4 ϩ T cells from inguinal LNs from immunized DA.Ncf1 E3 rats were CFSE-labeled and subsequently treated with PBS or GSH before i.v.…”

“…In the rat model, only T cells from DA.Ncf1 DA rats [Dark Agouti (DA) rats with the mutated Ncf1 DA allele from the DA rat] can transfer disease to naïve DA.Ncf1 DA recipients, whereas T cells from the congenic DA.Ncf1 E3 rats (DA rats with the WT Ncf1 E3 allele from the E3 rat) cannot (3,6). In the mouse model, a mutation in Ncf1 results in an increased delayed-type hypersensitivity response and serum levels of anti-collagen type II (CII) IgG antibodies (4), indicating enhanced activation of autoreactive T cells.…”

Autoimmune priming, tissue attack and chronic inflammation — The three stages of rheumatoid arthritis

“…Unspecific trauma might serve as a trigger for activating the downstream paths of humoral autoimmunity in the joint, as exemplified by arthritis induction in CIIimmunized, clinically healthy mice upon intra-articular injection of saline [53]. In the PIA model, there is no known role of antibodies, but the disease is induced by activated, polyclonal, and autoreactive MHC class II-restricted αβ T cells [54]. Similarly to autoantibodies, autoreactive T cells need a few days to initiate a full-blown clinical arthritis.…”

Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases

“…We performed a treatment trial with SL5 in the pristaneinduced MHC class II-restricted chronic arthritis model (PIA) in Dark Agouti rats (28,29). Rats were given single daily s.c.…”