Abstract

The endoplasmic reticulum chaperone and stress protein BiP has hitherto been considered as having only crucial intracellular cell protective functions. However, we have shown that BiP can be present in the extracellular environment and that it binds to a putative but as yet uncloned cell surface receptor. It will stimulate human monocytes via this receptor to express a gene profile that is anti-inflammatory. It will generate T cells with a regulatory function from human peripheral blood most likely by altering dendritic cell development. Intravenous BiP will both prevent and treat ongoing collagen induced arthritis in the DBA/1 mouse. Part of the suppression of arthritis is linked to interleukin (IL)4 as BiP-specific lymph node and spleen cells from these mice secrete IL4, and BiP has no suppressive effect on collagen induced arthritis in IL4 knockout mice. Lymph node and spleen cells isolated from mice administered intravenous BiP will suppress arthritis when transferred intravenously into recipient arthritic mice without any further BiP having to be given. Thus, both in vitro work with human peripheral blood mononuclear cells and in vivo work in the collagen arthritis model lead to the conclusion that BiP induces regulatory cells. Finally, intravenous BiP will ablate the inflammatory cell infiltrate and inflammatory cytokine expression in rheumatoid synovial membrane tissue transplanted subcutaneously into SCID mice. The conclusion from all this experimental work is that BiP may be a novel therapy for the treatment of patients with rheumatoid arthritis.