The Biologic IRL201805 Alters Immune Tolerance Leading to Prolonged Pharmacodynamics and Efficacy in Rheumatoid Arthritis Patients.

A homologue of binding immunoglobulin protein/BiP-IRL201805 alters the function of immune cells in pre-clinical in vivo and in vitro studies. The aim of the study was to select biomarkers that clearly delineate between RA patients who respond to IRL201805 and placebo patients and reveal the immunological mode of action of IRL201805 driving the extended pharmacodynamics observed in responding patients. Biomarkers that distinguished between responding patients and placebo patients included downregulation of serum interferon-γ and IL-1β; upregulation of anti-inflammatory mediators, serum soluble CTLA-4, and intracellular monocyte expression of IDO; and sustained increased CD39 expression on CD3CD4CD25 CD127 regulatory T cells.

The therapeutic mavericks: Potent immunomodulating chaperones capable of treating human diseases.

Two major chaperones, calreticulin (CRT) and binding immunoglobulin protein (GRP78/BiP) dependent on their location, have immunoregulatory or anti-inflammatory functions respectively. CRT induces pro-inflammatory cytokines, dendritic cell (DC) maturation and activates cytotoxic T cells against tumours. By contrast, GRP78/BiP induces anti-inflammatory cytokines, inhibits DC maturation and heightens T-regulatory cell responses.

Binding Immunoglobulin Protein (BIP) Inhibits TNF-α-Induced Osteoclast Differentiation and Systemic Bone Loss in an Erosive Arthritis Model.

Objective: The association between inflammation and dysregulated bone remodeling is apparent in rheumatoid arthritis and is recapitulated in the human tumor necrosis factor transgenic (tg) mouse model. We investigated whether extracellular binding immunoglobulin protein (BiP) would protect the tg mouse from both inflammatory arthritis as well as extensive systemic bone loss and whether BiP had direct antiosteoclast properties in vitro.

Methods: tg mice received a single intraperitoneal administration of BiP at onset of arthritis.

Inflammatory cytokines compromise programmed cell death-1 (PD-1)-mediated T cell suppression in inflammatory arthritis through up-regulation of soluble PD-1.

The programmed cell death 1 (PD-1) receptor plays a major role in regulating T cell activation. Our aim was to determine how inflammation influences PD-1-mediated T cell suppression. Flow cytometry analysis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) synovial fluid (SF) mononuclear cells showed an increase in the percentage of PD-1 cells within the CD4 and CD8 T cell compartment compared to paired peripheral blood (PB).

Safety and patient response as indicated by biomarker changes to binding immunoglobulin protein in the phase I/IIA RAGULA clinical trial in rheumatoid arthritis.

Objectives: Binding immunoglobulin protein (BiP) is a human endoplasmic reticulum-resident stress protein. In pre-clinical studies it has anti-inflammatory properties due to the induction of regulatory cells. This randomized placebo-controlled, dose ascending double blind phase I/IIA trial of BiP in patients with active RA, who had failed accepted therapies, had the primary objective of safety.

Immunoglobulin heavy-chain-binding protein (BiP): a stress protein that has the potential to be a novel therapy for rheumatoid arthritis.

Immunoglobulin heavy-chain-binding protein (BiP) or glucose-regulated protein 78 (Grp78) is a vital ubiquitous resident of the endoplasmic reticulum (ER). As an intracellular chaperone, BiP correctly folds nascent polypeptides within the ER and regulates the unfolded protein response ensuring protection of the cell from denatured protein and reinforcing its anti-apoptotic role, when the cell is under stress. Additionally, BiP is a member of the heat-shock protein (HSP) 70 family and, as a stress protein, is up-regulated by conditions of reduced oxygen and glucose.

Systemic gene transfer of binding immunoglobulin protein (BiP) prevents disease progression in murine collagen-induced arthritis.

Summary Recombinant human binding immunoglobulin protein (BiP) has previously demonstrated anti-inflammatory properties in multiple models of inflammatory arthritis. We investigated whether these immunoregulatory properties could be exploited using gene therapy techniques. A single intraperitoneal injection of lentiviral vector containing the murine BiP (Lenti-mBiP) or green fluorescent protein (Lenti-GFP) transgene was administered in low- or high-dose studies during early arthritis.

Defective CD8+CD28+ regulatory T cell suppressor function in rheumatoid arthritis is restored by tumour necrosis factor inhibitor therapy.

Balanced immunoregulatory networks are essential for maintenance of systemic tolerance. Disturbances in the homeostatic equilibrium between inflammatory mediators, immune regulators and immune effector cells are implicated directly in the pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). In this study we characterize the peripheral blood CD8(+) CD28(-) regulatory T cells (Treg) contribution to the immunoregulatory network in health and in RA.

Autoantibodies to posttranslationally modified type II collagen as potential biomarkers for rheumatoid arthritis.

Objective: Type II collagen (CII) posttranslationally modified by reactive oxygen species (ROS-CII) that are present in the inflamed joint is an autoantigen in rheumatoid arthritis (RA). The aim of this study was to investigate the potential use of anti-ROS-CII autoantibodies as a biomarker of RA.

Methods: CII was exposed to oxidants that are present in the rheumatoid joint.

A New-Age for Biologic Therapies: Long-Term Drug-Free Therapy with BiP?

Heat shock proteins (HSPs) and other members of the much broader stress protein family have been shown to play important roles in coordinating multiple phases of immunological reactions; from facilitating immunological recognition, to promoting and regulating immunological responses and finally augmenting the resolution of inflammation and return to immunological homeostasis. In this review, we consider the challenges facing the stress protein field as we enter 2012; in particular we consider the role that HSPs and stress proteins may play in the initiation and termination of immunological responses. Special attention is afforded to the resolution-associated molecular pattern, binding immunoglobulin protein (BiP, also known as glucose regulated protein-78).

Pro-resolution immunological networks: binding immunoglobulin protein and other resolution-associated molecular patterns.

Appropriate regulation and subsequent resolution of acute inflammatory events is critical to the prevention of autoinflammatory diseases. Indeed, the chronic inflammation observed in diseases such as RA is at least partially consequent on the failure of endogenous immunoregulation. Current RA therapies (e.

Monocyte-platelet interaction induces a pro-inflammatory phenotype in circulating monocytes.

Background: Activated platelets exert a pro-inflammatory action that can be largely ascribed to their ability to interact with leukocytes and modulate their activity. We hypothesized that platelet activation and consequent formation of monocyte-platelet aggregates (MPA) induces a pro-inflammatory phenotype in circulating monocytes.

Methodology/principal Findings: CD62P(+) platelets and MPA were measured, and monocytes characterized, by whole blood flow cytometry in healthy subjects, before and two days after receiving influenza immunization.

Binding immunoglobulin protein resolves rheumatoid synovitis: a xenogeneic study using rheumatoid arthritis synovial membrane transplants in SCID mice.

Introduction: 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. 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.

Resolution-associated molecular patterns (RAMP): RAMParts defending immunological homeostasis?

The resolution of inflammation is central to the maintenance of good health and immune homeostasis. Recently, several intracellular stress proteins have been described as having extracellular properties that are anti-inflammatory or favour the resolution of inflammation. We propose that these molecules should be defined as resolution-associated molecular patterns (RAMPs).

Binding immunoglobulin protein-treated peripheral blood monocyte-derived dendritic cells are refractory to maturation and induce regulatory T-cell development.

Binding immunoglobulin protein (BiP) has been shown previously to have immunomodulatory functions. Herein we investigated whether BiP could affect the differentiation of monocytes into dendritic cells (DCs) and thence the development of regulatory T cells. Peripheral blood monocyte-derived DCs were matured with lipopolysaccharide in the presence or absence of BiP.

Decreased platelet nitric oxide contributes to increased circulating monocyte-platelet aggregates in hypertension.

Aims: The aim of this study was to determine the effect of blood pressure (BP) on platelet nitric oxide (NO) signalling and on formation of circulating monocyte-platelet aggregates (MPA), as well as the role of platelet NO in modulating MPA in hypertension.

Methods And Results: We first examined platelet NO signalling in 23 untreated hypertensive (UH) and 23 normotensive (NT) subjects. Platelets from hypertensives exhibited reduced NO synthase activation by albuterol or collagen, as well as suppressed basal and stimulated NO-attributable cyclic guanosine-3',5'-monophosphate, compared with NT.

Glucose-regulated protein 78 (Grp78/BiP) is secreted by human oviduct epithelial cells and the recombinant protein modulates sperm-zona pellucida binding.

Objective: To determine the secretion of Grp78 by human oviduct epithelial cells, its association to spermatozoa, and its involvement in gamete interaction.

Design: Prospective study.

Setting: Basic research laboratory.

The role of the chemokines MCP-1, GRO-alpha, IL-8 and their receptors in the adhesion of monocytic cells to human atherosclerotic plaques.

Monocyte adhesion to the arterial endothelium and subsequent migration into the intima are central events in the pathogenesis of atherosclerosis. Previous experimental models have shown that chemokines can enhance monocyte-endothelial adhesion by activating monocyte integrins. Our study assesses the role of chemokines IL-8, MCP-1 and GRO-alpha, together with their monocyte receptors CCR2 and CXCR2 in monocyte adhesion to human atherosclerotic plaques.

BiP, an anti-inflammatory ER protein, is a potential new therapy for the treatment of rheumatoid arthritis.

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.

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).

BiP regulates autoimmune inflammation and tissue damage.

The endoplasmic reticulum chaperone BiP, in addition to its many important intracellular functions, has anti-inflammatory and immunomodulatory properties when present in the extracellular environment by the stimulation of an anti-inflammatory gene programme from human monocytes and by the development of T-cells that secrete regulatory cytokines such as interleukin-10 and interleukin-4. It can both prevent as well as treat ongoing collagen-induced arthritis. It is, therefore, a potential new biologic therapy for rheumatoid arthritis.

Generation of neoantigenic epitopes after posttranslational modification of type II collagen by factors present within the inflamed joint.

Objective: Collagen-induced arthritis is a commonly accepted model of rheumatoid arthritis (RA). However, it has been difficult to substantiate the involvement of autoimmunity to type II collagen (CII) in the pathogenesis of RA. The aim of this investigation was to determine if CII, modified by reactive oxidant species present within the inflamed joint, could generate neoantigenic epitopes.

Antibody response to the human stress protein BiP in rheumatoid arthritis.

Objectives: The human stress protein BiP (immunoglobulin binding protein) has been implicated in the pathogenesis of rheumatoid arthritis (RA) since BiP was found to stimulate synovial T-cell proliferation and anti-BiP antibodies are present in the serum of RA patients. The aim of this study was the development of a rapid and reproducible enzyme-linked immunosorbent assay (ELISA) to determine the specificity and sensitivity of anti-BiP antibodies in RA.

Methods: An ELISA was developed that detected antibodies to BiP.