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BiP induces IL-4-dependent regulatory cells

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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].


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


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.


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).


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


  1. 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.

  2. 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.

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

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  • Adoptive Transfer
  • Drain Lymph Node
  • Lymph Node Cell
  • Swell Joint
  • Bovine Collagen