GLPG1205 for idiopathic pulmonary fibrosis: a phase 2 randomised placebo-controlled trial.

Background: GLPG1205 is a selective functional antagonist of G-protein-coupled receptor 84, which plays an important role in fibrotic processes. This study assessed the efficacy, safety and tolerability of GLPG1205 for treatment of idiopathic pulmonary fibrosis (IPF).

Methods: PINTA (ClinicalTrials.

Macroautophagy in Dendritic Cells Controls the Homeostasis and Stability of Regulatory T Cells.

Regulatory T cells (Tregs) play a crucial role in controlling autoimmune and inflammatory responses. Recent studies have demonstrated that dendritic cells (DCs) contribute to the homeostasis of peripheral Tregs. Autophagy, a critical pathway for cellular homeostasis, is active in DCs and is upregulated in different inflammatory conditions.

Nanocrystals of a potent p38 MAPK inhibitor embedded in microparticles: Therapeutic effects in inflammatory and mechanistic murine models of osteoarthritis.

This study aimed to formulate nanocrystal-polymer particles (NPPs) containing the potent p38α/β MAPK inhibitor PH-797804 (PH-NPPs) and to test their extended-release properties over months in comparison to those of conventional PH microparticles for the intra-articular treatment of inflammatory and mechanistic murine models mirroring aspects of human osteoarthritis (OA). The steps of the study were (i) to formulate PH nanocrystals (wet milling), (ii) to encapsulate a high payload of PH nanocrystals in fluorescent particles (spray drying), (iii) to assess in vitro drug release, (iv) to evaluate PH-NPP toxicity to human OA synoviocytes (MTT test), (v) to investigate the in vivo bioactivity of the particles in mice in an inflammatory antigen-induced arthritis (AIA) model (using histology and RT-qPCR) and (vi) to investigate the in vivo bioactivity of the particles in the OA model obtained by mechanistic surgical destabilization of the medial meniscus (DMM) (using histology, micro-CT, and multiplex ELISA). The PH nanocrystals stabilized with vitamin E TPGS had a monomodal size distribution.

Nanocrystal-Polymer Particles: Extended Delivery Carriers for Osteoarthritis Treatment.

An efficient treatment for osteoarthritis (OA) can benefit from the local release of a high therapeutic dose over an extended period of time. Such a treatment will minimize systemic side effects and avoid the inconvenience of frequent injections. To this aim, nanocrystal-polymer particles (NPPs) are developed by combining the advantages of nanotechnology and microparticles.

Self-assembled thermoresponsive nanostructures of hyaluronic acid conjugates for osteoarthritis therapy.

Under pathological conditions, joints and skin are often affected by an imbalance in the breakdown and production of hyaluronic acid (HA). The unique biochemical and biomechanical properties provided by HA must be restored for the long-term lubrication and cushioning effects. To overcome the inconvenience of repeated injections and the rapid degradation of exogenous HA treatments, HA is conjugated to a thermosensitive polymer, enabling the spontaneous formation of nanoparticles (HA Nano) at body temperature.

Deficiency in IL-1 Receptor Type 2 Aggravates K/BxN Serum Transfer-Induced Arthritis in Mice but Has No Impact on Systemic Inflammatory Responses.

The biological activity of IL-1 is tightly regulated by the specific receptor antagonist (IL-1Ra) and the decoy receptor IL-1 receptor type 2 (IL-1R2). The role of IL-1Ra has been well demonstrated in IL-1Ra-deficient mice. In contrast, the role of endogenous IL-1R2 remains widely unknown.

Modeling the Effect of the Selective S1P Receptor Modulator Ponesimod on Subsets of Blood Lymphocytes.

Purpose: This analysis aimed at describing the effect of the selective sphingosine-1-phosphate receptor 1 modulator ponesimod on lymphocyte subsets in peripheral blood. As the involvement of different lymphocyte subsets varies among different autoimmune diseases, characterizing the effect of ponesimod on these may be beneficial in better understanding treatment effects.

Methods: Three phase 1 clinical studies in healthy human subjects were pooled.

Effect of particle size on the biodistribution of nano- and microparticles following intra-articular injection in mice.

Intra-articular (IA) injection of extended drug release forms based on biodegradable microparticles holds promise for the treatment of joint diseases. However, the fate of microparticles following intra-articular injection is controversial and has not been thoroughly investigated. The aim of this work was therefore to evaluate the biodistribution of fluorescent poly(lactic acid) particles of different sizes after IA injection in arthritic or healthy mice.

Intra-articular bioactivity of a p38 MAPK inhibitor and development of an extended-release system.

In the treatment of arthritic diseases, oral or systemic administration of anti-inflammatory substances, such as p38 MAPK inhibitors, is hampered by numerous side effects. To overcome them, formulations of rapid and extended drug delivery systems were studied in intra-articular administration. For the first time, VX-745, a highly selective p38 MAPK inhibitor, demonstrated in vivo bioactivity, similar to dexamethasone activity, following intra-articular administration in an antigen-induced arthritic (AIA) mouse model.

Severe neutrophil-dominated inflammation and enhanced myelopoiesis in IL-33-overexpressing CMV/IL33 mice.

IL-33 is a cytokine of the IL-1 family, which signals through the ST2 receptor. Previous studies emphasized a role for IL-33 in shaping innate and adaptive immune responses. IL-33 was also reported to modulate myelopoiesis and myeloid cell activity.

The severity of experimental arthritis is independent of IL-36 receptor signaling.

Introduction: Interleukin (IL)-36 refers to three related IL-1 family cytokines, IL-36α, IL-36β, and IL-36γ, that bind to the IL-36 receptor (IL-36R). IL-36 exerts proinflammatory effects in skin and lung and stimulates T cell responses. In the present study, we examined the expression and function of IL-36R and its ligands in experimental arthritis.

Disease severity in K/BxN serum transfer-induced arthritis is not affected by IL-33 deficiency.

Introduction: Interleukin (IL)-33 is a cytokine of the IL-1 family, which signals through the ST2 receptor. Previous work suggested implication of the IL-33/ST2 axis in the pathogenesis of human and mouse arthritis. Here, we directly investigated the role of endogenous IL-33 in K/BxN serum transfer-induced arthritis by using IL-33 knockout (KO) mice.

Mice deficient in hepatocyte-specific IL-1Ra show delayed resolution of concanavalin A-induced hepatitis.

Interleukin-1 receptor antagonist (IL-1Ra) is a specific IL-1 inhibitor that possesses anti-inflammatory activities. Several studies in human and mouse suggested a protective role for IL-1Ra in liver inflammation, and we previously demonstrated that hepatocytes produce high levels of IL-1Ra in response to inflammatory challenge in vitro and in vivo. In the present study, we investigated the production and the biological function of hepatocyte-derived IL-1Ra in concanavalin A (ConA)-induced hepatitis in mice.

Articular inflammation is controlled by myeloid cell-derived interleukin 1 receptor antagonist during the acute phase of arthritis in mice.

Objectives: To define the cell type (myeloid vs other cells) specific effect of interleukin 1 (IL-1) receptor antagonist (IL-1Ra) deficiency on the acute inflammatory phase of arthritis.

Methods: Arthritis was induced by K/BxN serum transfer in wild-type (WT), IL-1Ra-deficient (IL-1Ra(-/-)) and conditional knockout mice. In the latter, IL-1Ra production was specifically targeted in myeloid cells (IL-1Ra(ΔM)) or in both hepatocytes and myeloid cells (IL-1Ra(ΔH+M)).

Adeno-associated virus type 5-mediated intraarticular administration of tumor necrosis factor small interfering RNA improves collagen-induced arthritis.

Objective: RNA interference (RNAi) is a powerful tool for sequence-specific gene silencing, and interest in its application in human diseases is growing. Given the success of recent strategies for administering gene therapy in rheumatoid arthritis using recombinant vectors such as adeno-associated virus type 5 (rAAV5) for optimized intraarticular gene transfer, we undertook the present study to determine the feasibility of using rAAV5-mediated RNAi-based therapy in arthritis.

Methods: We developed rAAV5 vectors expressing short hairpin small interfering RNA (shRNA) against tumor necrosis factor alpha (TNFalpha) under H1 promoter, and carrying the enhanced green fluorescent protein (eGFP) reporter gene under cytomegalovirus promoter (rAAV5-shTNF).

Enhanced Th1 and Th17 responses and arthritis severity in mice with a deficiency of myeloid cell-specific interleukin-1 receptor antagonist.

Objective: The balance between interleukin-1 (IL-1) and its specific inhibitor, the IL-1 receptor antagonist (IL-1Ra), plays a major role in the development of arthritis. The purpose of this study was to investigate the role of IL-1Ra produced specifically by myeloid cells in the control of collagen-induced arthritis (CIA) by using myeloid cell-specific IL-1Ra-deficient mice (IL-1Ra(DeltaM)).

Methods: IL-1Ra(DeltaM) mice were generated by using the loxP/Cre recombinase system.

Magnetically retainable microparticles for drug delivery to the joint: efficacy studies in an antigen-induced arthritis model in mice.

Introduction: Conventional corticosteroid suspensions for the intra-articular treatment of arthritis suffer from limitations such as crystal formation or rapid clearance from the joint. The purpose of this study was to investigate an innovative alternative consisting of corticosteroid encapsulation into magnetically retainable microparticles.

Methods: Microparticles (1 or 10 microm) containing both superparamagnetic iron oxide nanoparticles (SPIONs) and dexamethasone 21-acetate (DXM) were prepared.

Inhibition of interleukin-33 signaling attenuates the severity of experimental arthritis.

Objective: Interleukin-33 (IL-33; or, IL-1F11) was recently identified as the ligand of the IL-1 family receptor T1/ST2. The aim of this study was to examine IL-33 production in human and mouse joints and to investigate the role of IL-33 and T1/ST2 in experimental arthritis.

Methods: IL-33 expression was examined in human synovial tissue, rheumatoid arthritis (RA) synovial fibroblasts, and arthritic mouse joints.

Dexamethasone-containing PLGA superparamagnetic microparticles as carriers for the local treatment of arthritis.

Superparamagnetic iron oxide nanoparticles (SPIONs) are attractive materials that have been widely used in medicine for diagnostic imaging and therapeutic applications. In our study, SPIONs and the corticosteroid dexamethasone acetate (DXM) are co-encapsulated into PLGA microparticles for the aim of locally treating inflammatory conditions such as arthritis. The magnetic properties conferred by the SPIONs could help to maintain the microparticles in the joint with an external magnet.

BK virus large T and VP-1 expression in infected human renal allografts.

Objective: We investigated the expression of early and late phase BK virus (BKV) proteins and their interactions with host cell proteins in renal allografts, with ongoing polyomavirus associated nephropathy (PVAN), and correlated this with the nuclear and cell morphology.

Methods: Frozen sections from three patients with renal allografts (two biopsies, one explant) with PVAN were analysed by indirect immunofluorescence using BKV specific anti-polyoma large T-antigen and anti-VP-1 antibodies, as well as anti-p53, anti-Ki67, anti-caspase-3, anti-bcl2 and anti-cytokeratin 22 antibodies. Nuclear morphology and size were estimated by DNA Hoechst staining.

Lack of protein expression of the Simian virus 40 large T antigen in human lymphomas.

Several studies have detected Simian virus 40 (SV40) deoxyribonucleic acid sequences in human tumor tissues, including lymphomas, mainly by the polymerase chain reaction, but these data were not confirmed by subsequent investigations. Regional differences in the distribution of the SV40 and/or technical difficulties have been taken into account to explain these divergent results, but because only a few such studies dealt with the expression of SV40 proteins in tumor tissues, we investigated the expression of the SV40 large T antigen in human lymphomas by immunohistochemistry. Tissue microarrays containing Non-Hodgkin's-lymphomas and Hodgkin's-lymphomas were constructed utilizing archival samples encompassing the years 1974--2001 from Italian, Swiss and Austrian patients.

In situ hybridization of synovial tissue.

The chapter focuses on the detection of specific mRNA by in situ hybridization (ISH) in synovial tissue specimens. This technique is widely applied, reliable, specific, and sensitive, because even small quantities of mRNA can be detected. Presented here contemporary protocols for ISH using a combined nonradioactive immunohistochemical detection system.

Low prevalence of SV40 in Swiss mesothelioma patients after elimination of false-positive PCR results.

The association of simian virus 40 (SV40) with malignant pleural mesothelioma is currently under debate. In some malignancies of viral aetiology, viral DNA can be detected in the patients' serum or plasma. To characterize the prevalence of SV40 in Swiss mesothelioma patients, we optimized a real-time PCR for quantitative detection of SV40 DNA in plasma, and used a monoclonal antibody for immunohistochemical detection of SV40 in mesothelioma tissue microarrays.