Synovial Inflammatory Pathways Characterize Anti-TNF-Responsive Rheumatoid Arthritis Patients.

Objective: This study was undertaken to understand the mechanistic basis of response to anti-tumor necrosis factor (anti-TNF) therapies and to determine whether transcriptomic changes in the synovium are reflected in peripheral protein markers.

Methods: Synovial tissue from 46 rheumatoid arthritis (RA) patients was profiled with RNA sequencing before and 12 weeks after treatment with anti-TNF therapies. Pathway and gene signature analyses were performed on RNA expression profiles of synovial biopsies to identify mechanisms that could discriminate among patients with a good response, a moderate response, or no response, according to the American College of Rheumatology (ACR)/EULAR response criteria.

Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages.

The Krebs cycle-derived metabolite itaconate and its derivatives suppress the inflammatory response in pro-inflammatory "M1" macrophages. However, alternatively activated "M2" macrophages can take up itaconate. We therefore examined the effect of itaconate and 4-octyl itaconate (OI) on M2 macrophage activation.

Biomarkers for the clinical development of antiviral therapies.

With the morbidity and mortality associated with the COVID-19 pandemic that we are witnessing this year, the risks posed by emerging viral diseases to global health are all too obvious. This pandemic highlights the importance of antiviral drug discovery, which targets emerging viral pathogens, as well as existing pathogenic viruses that undergo continuous evolution. Drug discovery and development is a long and resource intensive process; however, the use of biomarkers can accelerate clinical development of antivirals by providing information regarding diagnosis of specific viral infections, status of infection, potential safety parameters, and antiviral responses.

The Immunomodulatory Metabolite Itaconate Modifies NLRP3 and Inhibits Inflammasome Activation.

The Krebs cycle-derived metabolite itaconate is highly upregulated in inflammatory macrophages and exerts immunomodulatory effects through cysteine modifications on target proteins. The NLRP3 inflammasome, which cleaves IL-1β, IL-18, and gasdermin D, must be tightly regulated to avoid excessive inflammation. Here we provide evidence that itaconate modifies NLRP3 and inhibits inflammasome activation.

Dual Blockade of Interleukin-1 and Interleukin-17A Reduces Murine Arthritis Pathogenesis but Also Leads to Spontaneous Skin Infections in Nonhuman Primates.

Despite the efficacy of biologics for treatment of rheumatoid arthritis (RA), many patients show inadequate responses and likely require neutralization of multiple mediators. Neutralization of both interleukin (IL)-1 and IL-17A with monoclonal antibodies showed greater efficacy than either agent alone in a mouse arthritis model with cooperative inhibition of key inflammatory factors, IL-6, granulocyte colony-stimulating factor (G-CSF), and CXC chemokine ligand (CXCL)1. Given the potential clinical benefit in RA, we generated a human dual variable domain antibody Ig, ABBV-615, capable of simultaneous binding and neutralization of IL-1 and IL-17A.

Murine antithymocyte globulin T-cell depletion is mediated predominantly by macrophages, but the Fas/FasL pathway selectively targets regulatory T cells.

Background: Thymoglobulin is a T-cell-depleting polyclonal rabbit anti-human thymocyte antibody used clinically for immunosuppression in solid organ and hematopoietic stem-cell transplantation. By using a surrogate rabbit anti-mouse thymocyte globulin (mATG), we previously demonstrated that murine regulatory and memory T cells are preferentially spared from mATG depletion in vivo. The current studies were designed to determine whether different effector mechanisms are involved in differential depletion of T-cell subsets by mATG.

In vivo characterization of rabbit anti-mouse thymocyte globulin: a surrogate for rabbit anti-human thymocyte globulin.

Background: Polyclonal rabbit anti-human thymocyte globulin (Thymoglobulin) is used clinically for immunosuppression in solid organ transplantation; however, it is difficult to fully characterize the effects of this agent in humans.

Methods: A surrogate rabbit anti-murine thymocyte globulin (mATG) was generated analogously to the commercial product Thymoglobulin and in vivo activities were evaluated, including pharmacokinetics, T-cell depletion, dose response and kinetics, depletion/sparing of T-cell subsets or other leukocyte populations, and depletion in different lymphoid organs.

Results: Within 1 day, T cells are depleted by mATG in the blood, spleen, lymph node, and bone marrow down to doses of 1 mg/kg.

Pharmacology of AMD3465: a small molecule antagonist of the chemokine receptor CXCR4.

CXCR4 is widely expressed in multiple cell types, and is involved in neonatal development, hematopoiesis, and lymphocyte trafficking and homing. Disruption of the CXCL12/CXCR4 interaction has been implicated in stem cell mobilization. Additionally CXCR4 is a co-receptor for HIV.

Homeostatic role of transforming growth factor-beta in the oral cavity and esophagus of mice and its expression by mast cells in these tissues.

Transforming growth factor-beta (TGF-beta) is a pleiotropic growth factor; its overexpression has been implicated in many diseases, making it a desirable target for therapeutic neutralization. In initial safety studies, mice were chronically treated (three times per week) with high doses (50 mg/kg) of a murine, pan-neutralizing, anti-TGF-beta antibody. Nine weeks after the initiation of treatment, a subset of mice exhibited weight loss that was concurrent with decreased food intake.

Ultrasound imaging accurately detects skin thickening in a mouse scleroderma model.

Systemic sclerosis (scleroderma) is characterized by initial thickening of the skin because of the accumulation of collagen within the dermis followed by progression of fibrosis to internal organs. Although ultrasound assessment of dermal thickening in scleroderma patients is well documented, whether this technique can accurately detect skin thickening in mice under similar disease conditions is not known. Unlike traditional histologic assessments performed for disease models, ultrasound does not require sacrifice of the animal, and assessments of the same individual mice can be made over time.

Characterization of in vitro antimurine thymocyte globulin-induced regulatory T cells that inhibit graft-versus-host disease in vivo.

Antithymocyte/antilymphocyte globulins are polyclonal antihuman T-cell antibodies used clinically to treat acute transplant rejection. These reagents deplete T cells, but a rabbit antihuman thymocyte globulin has also been shown to induce regulatory T cells in vitro. To examine whether antithymocyte globulin-induced regulatory cells might be functional in vivo, we generated a corresponding rabbit antimurine thymocyte globulin (mATG) and tested its ability to induce regulatory cells in vitro and whether those cells can inhibit acute graft-versus-host disease (GVHD) in vivo upon adoptive transfer.

A modified model of graft-versus-host-induced systemic sclerosis (scleroderma) exhibits all major aspects of the human disease.

Objective: Diffuse systemic sclerosis (SSc; scleroderma) is a debilitating disease characterized by excessive dermal fibrosis with later progression to internal organs. In addition to the fibrotic component, major aspects of the disease include vascular or circulatory involvement and immune dysregulation evidenced by inflammatory cells in affected tissues and production of autoantibodies. Many animal models resembling this disease have been studied, including genetic models in mice and chickens, challenge with chemicals such as bleomycin or vinyl chloride to induce fibrosis, and models of graft-versus-host (GVH)-induced disease using certain strains of mice with differences in minor histocompatibility loci.

Minimal effects on immune parameters following chronic anti-TGF-beta monoclonal antibody administration to normal mice.

Mice genetically deficient in TGF-beta1 or TGF-beta signaling capacity in T or B cells demonstrate profound immune dysregulation, as evidenced by increased lymph node size, expression of markers of memory/activation on T cells, inflammation in a variety of tissues and development of autoantibodies. However, this constant and complete lack of TGF-beta1 or TGF-betaR signaling may not reflect effects of TGF-beta neutralization using antibodies in mature animals. Thus, the present studies were designed to determine if administration of an anti-TGF-beta monoclonal antibody (neutralizes TGF-beta1, 2 and 3) to mature, normal mice results in evidence of immune dysregulation or immune-mediated pathology.

Adenoviral vectors stimulate murine natural killer cell responses and demonstrate antitumor activities in the absence of transgene expression.

Adenoviral vector-mediated gene delivery is currently the focus of many efforts to administer therapeutic gene products for the treatment of cancer. Although these vectors are replication deficient, they can induce specific immune responses against both vector- and transgene-encoded proteins. We have extended these findings to determine the level of innate natural killer (NK) cell responses to adenoviral vector administration in vivo.