Abstract
IntroductionBinding immunoglobulin protein (BiP) has previously shown powerful anti-inflammatory properties in the collagen-induced arthritis (CIA) model, where a single dose of BiP has proved to be both a long-term prophylactic and therapeutic. In both CIA and human in vitro studies, BiP induced regulatory T cells. The present investigation looked at the anti-inflammatory effect of BiP on inflamed human synovial tissue transplanted into severe combined immunodeficient mice (SCID), a chimaeric in vivo model previously used to test the efficacy of biologic therapies.MethodsRheumatoid arthritis synovial membrane (RASM) was engrafted into SCID mice. Following successful engraftment, mice were intravenously injected with BiP or human serum albumin in the presence or absence of anti-IL-10 mAb. Twelve days later the grafts were removed for analysis and human cytokines in the sera were quantified by ELISA. The extent of residual inflammatory cellular infiltrate in the synovial explants was determined by weight of the explants.ResultsThe RASM transplants from mice treated with BiP showed visual reduction in cellular infiltrate and downregulation of all quantifiable features of inflammation as assessed by the Koizumi or Rooney histological criteria. Also downregulated were HLA-DR, CD86, IL-6 and TNFα expression as assessed by immunohistology. ELISA detected significantly less human IL-6 circulating in the BiP-treated mouse serum. After removal of transplanted tissue 12 days post administration of BiP, the RASM explants from the BiP-treated SCID mice weighed significantly less, indicating a suppression of tissue inflammation. Mice given concomitant neutralising anti-IL-10 antibody and BiP showed no such suppression.ConclusionsBiP has anti-inflammatory properties partially dependent on the downregulation of HLA-DR and co-stimulatory molecules and the predominant production of IL-10.
Highlights
Binding immunoglobulin protein (BiP) has previously shown powerful anti-inflammatory properties in the collagen-induced arthritis (CIA) model, where a single dose of BiP has proved to be both a long-term prophylactic and therapeutic
We have previously shown that binding immunoglobulin protein (BiP) downregulates both immune and inflammatory responses in vitro in our
BiP abrogates inflammation in human rheumatoid arthritis synovial membrane (RASM) transplanted into severe combined immunodeficient mice (SCID) mice Twelve days following intravenous injection of BiP into the RASM/SCID chimaeric mice, the histological features of the RASM taken from the control mice were unchanged (Figure 1a) compared with the markedly reduced cellular infiltrate in the RASM grafts from the BiP-treated mice (Figure 1b)
Summary
Binding immunoglobulin protein (BiP) has previously shown powerful anti-inflammatory properties in the collagen-induced arthritis (CIA) model, where a single dose of BiP has proved to be both a long-term prophylactic and therapeutic. In both CIA and human in vitro studies, BiP induced regulatory T cells. We chose a xenogeneic in vivo model involving transplant of human rheumatoid arthritis synovial membrane (RASM) into severe combined immunodeficient (SCID) mice This model has been validated previously as a robust screen for therapeutic efficacy since anti-TNFa [4] and antisoluble IL-6 receptor [5] antibodies suppress inflammation in similar models
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