Skip to main content
  • Poster presentation
  • Published:

BiP induces IL-4-dependent regulatory cells

Background

Previously we have described the stress protein BiP as a putative autoantigen in RA [1]. The administration of BiP intravenously (i.v.) prior to induction of collagen-induced arthritis (CIA) resulted in almost complete amelioration of disease [1]. Our studies now indicate that BiP has several immunomodulatory actions including the skewing of T-cell differentiation towards Th2 [2].

Aim

This study focused on the therapy of CIA and investigated subcutaneous administration of BiP in comparison with intravenous administration and whether adoptive transfer of BiP-treated cells could successfully inhibit the onset of disease. Finally, IL-4 knockout mice were used to determine the importance of the T cell in the therapeutic role of BiP

Methods

CIA was induced in DBA-1 mice by injection of bovine collagen type II (CII) in complete Freund's adjuvant followed by a booster injection in incomplete Freund's adjuvant at day 21. At the first appearance of swollen joints, the mice were injected subcutaneously (s.c.) with BiP, a control protein, BSA or vehicle control (PBS). Disease progression was followed by measurement of swollen joints. At termination, splenocytes and draining lymph node cells were removed and T-cell cytokine secretion was assessed. Mixed spleens and lymph nodes from groups of DBA-1 mice that had been immunized s.c. with BiP or BSA (200 μg), or i.v. with BiP or BSA (10 μg), were collected 12 days after immunization. Cell cultures (2.5 × 106 cells/ml) were set up with 20 μg of the respective protein (BiP or BSA) for 5 days. Cells were then washed and injected intraperitoneally into DBA/1 mice (20 × 106 cells/mouse) that had received the first CII immunization 24 days previously. DR1+/+ IL-4 knockout mice, (n = 20) developed by backcrossing C57Bl/6 IL4-/- mice to DR1+/+ mice, were immunized with CII, and on day 24 after immunization were given 10 μg BiP i.v. Wild-type HLA-DR1+/+ transgenic mice (n = 20/group) were administered 10 μg BiP or PBS i.v.

Results

Administration i.v. or s.c. of BiP significantly reduced (P < 0.05) the incidence and severity of CIA when given at the onset of disease. A lower incidence of arthritis was also recorded from groups of mice treated with BiP s.c. and i.v. (37.5% and 64%, respectively) as compared with 100% recorded from the control group by day 70. T cells removed from mice that had been treated with BiP via both routes were shown to secrete IL-4 in response to in vitro BiP stimulation. In response to CII, results indicated upregulation of IL-5 and IL-10 production from BiP-treated groups compared with the arthritic control group. In the adoptive transfer studies the mice receiving subcutaneous BiP-primed cells had a significant suppression of arthritis by day 48, and by day 66 in those receiving intravenous BiP-primed cells, compared with mice that had received BSA-primed T cells (P < 0.05). When the IL-4-/- mice were scored for disease severity the IL-4-/- mice treated with BiP were no different from wild-type mice treated with PBS whereas wild-type mice treated with BiP had a significant suppression of arthritis (P ≤ 0.05, Students test).

Conclusion

These findings suggest that treatment of CIA with BiP is mediated at least in part by induction of IL-4-dependent regulatory T cells.

References

  1. Corrigall VM, Bodman-Smith MD, Fife MS, Canas B, Myers LK, Wooley P, Soh C, Staines NA, Pappin DJ, Berlo SE, et al: The human endoplasmic reticulum molecular chaperone BiP is an autoantigen for rheumatoid arthritis and prevents the induction of experimental arthritis. J Immunol. 2001, 166: 1492-1498.

    Article  CAS  PubMed  Google Scholar 

  2. Bodman-Smith MD, Corrigall VM, Kemeny DM, Panayi GS: BiP, a putative autoantigen in rheumatoid arthritis, stimulates IL-10-producing CD8-positive T cells from normal individuals. Rheumatology. 2004, 42: 637-644. 10.1093/rheumatology/keg204.

    Article  Google Scholar 

Download references

Acknowledgement

Research was funded by Immune Regulation Ltd (GSP, VMC and MBS are shareholders in the company).

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brownlie, R., Myers, L., Corrigall, V. et al. BiP induces IL-4-dependent regulatory cells. Arthritis Res Ther 7 (Suppl 1), P55 (2005). https://doi.org/10.1186/ar1576

Download citation

  • Received:

  • Published:

  • DOI: https://doi.org/10.1186/ar1576

Keywords