Treatment of murine collagen-induced arthritis by the stress protein BiP via interleukin-4-producing regulatory T cells: a novel function for an ancient protein.
OBJECTIVE
Following the demonstration that the stress protein, BiP, prevented induction of collagen-induced arthritis (CIA) in HLA-DRB*0101+/+ (HLA-DR1+/+) mice, we investigated the immunotherapeutic ability of BiP to suppress disease during the active phase of CIA in HLA-DR1+/+ and DBA/1 mice.


METHODS
BiP was administered either subcutaneously or intravenously to DBA/1, HLA-DR1+/+, or interleukin-4 (IL-4)-knockout mice at the onset of arthritis. Immune cells were used in adoptive transfer studies or were restimulated in culture with BiP or type II collagen (CII). Proliferation and cytokine release were measured. In addition, serum anti-CII antibodies were measured by enzyme-linked immunosorbent assay. Disease progression was scored using a visual analog scale.


RESULTS
BiP was successful in suppressing established CIA in HLA-DR1+/+ and DBA/1 mice. Serum levels of anticollagen IgG antibodies were reduced in BiP-treated mice. T cells from BiP-immunized mice produced Th2 cytokines, in particular, IL-4. Treatment with BiP was also shown to increase the production of CII-specific IL-5, IL-10, and interferon-gamma at the termination of the study. Development of severe CIA was prevented by the intravenous transfer of BiP-specific cells at the time of CIA induction in HLA-DR1+/+ mice or by transferring BiP-specific cells to DBA/1 mice at the onset of disease. BiP failed to ameliorate the development of CIA in IL-4-/-, HLA-DR1+/+ mice.


CONCLUSIONS
These novel results show that BiP can suppress active CIA by the induction of regulatory cells that act predominantly via IL-4. Thus, BiP is a potential immunotherapeutic agent for the treatment of patients with rheumatoid arthritis.
Brownlie
Rebecca J
RJ
King's College London, London, UK.
Myers
Linda K
LK
Wooley
Paul H
PH
Corrigall
Valerie M
VM
Bodman-Smith
Mark D
MD
Panayi
Gabriel S
GS
Thompson
Stephen J
SJ
D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000097:blood; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D024043:Collagen Type II / Q000008:administration & dosage / Q000276:immunology; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000032:analysis; D015847:Interleukin-4 / Q000096:biosynthesis*; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
D000906:Antibodies; D024043:Collagen Type II; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007074:Immunoglobulin G; D018832:Molecular Chaperones; D015847:Interleukin-4