PD-L1- and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune disease.

Autoimmune diseases resulting from MHC class II-restricted autoantigen-specific T cell immunity include the systemic inflammatory autoimmune conditions rheumatoid arthritis and vasculitis. While currently treated with broad-acting immunosuppressive drugs, a preferable strategy is to regulate antigen-specific effector T cells (Teffs) to restore tolerance by exploiting DC antigen presentation. We targeted draining lymph node (dLN) phagocytic DCs using liposomes encapsulating 1α,25-dihydroxyvitamin D3 (calcitriol) and antigenic peptide to elucidate mechanisms of tolerance used by DCs and responding T cells under resting and immunized conditions.

Epithelial TNF Receptor Signaling Promotes Mucosal Repair in Inflammatory Bowel Disease.

TNF plays an integral role in inflammatory bowel disease (IBD), as evidenced by the dramatic therapeutic responses in Crohn's disease (CD) patients induced by chimeric anti-TNF mAbs. However, treatment of CD patients with etanercept, a decoy receptor that binds soluble TNF, fails to improve disease. To explore this discrepancy, we investigated the role of TNF signaling in Wnt/β-catenin-mediated intestinal stem cell and progenitor cell expansion in CD patients, human cells, and preclinical mouse models.

Role of the inflammatory response in the hemorrhagic syndrome induced by the hemolymph of the caterpillar Lonomia achelous.

Introduction: Contact with the caterpillar of Lonomia achelous causes a hemorrhagic syndrome in humans prompted by two processes, an initial mild DIC that is later masked by overwhelming fibrinolytic activity. Although the venom affects both the hemostatic and inflammatory systems separately, it is not clear whether the hematological and hemostatic disturbances may in part be due to an indirect effect via inflammatory mediators. Here we report results on the crosstalk between these systems, particularly the effect of the pro-inflammatory cytokine TNF-α on hemostatic parameters.

Divergent gene activation in peripheral blood and tissues of patients with rheumatoid arthritis, psoriatic arthritis and psoriasis following infliximab therapy.

Objective: The immune inflammatory disorders rheumatoid arthritis (RA), psoriatic arthritis (PsA) and psoriasis (Ps) share common pathologic features and show responsiveness to anti-tumor necrosis factor (TNF) agents yet they are phenotypically distinct. The aim of this study was to examine if anti-TNF therapy is associated with divergent gene expression profiles in circulating cells and target tissues of patients with these diseases.

Methods: Peripheral blood CD14+ and CD14- cells were isolated from 9 RA, 12 PsA and 10 Ps patients before and after infliximab (IFX) treatment.

Anti-tumor necrosis factor α prevents bowel fibrosis assessed by messenger RNA, histology, and magnetization transfer MRI in rats with Crohn's disease.

Objective: Treatment of Crohn's disease (CD) with anti-tumor necrosis factor α (TNFα) decreases intestinal inflammation, but the effect on fibrosis remains unclear. We hypothesized that treatment with rat-specific anti-TNFα will decrease the development of intestinal fibrosis in a rat model of CD. We further hypothesized that magnetization transfer magnetic resonance imaging (MT-MRI) will be sensitive in detecting these differences in collagen content.

Discovery and mechanism of ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders.

Monoclonal antibody (mAb) therapy was first established upon the approval of a mouse antibody for treatment of human acute organ rejection. However, the high incidence of immune response against the mouse mAb restricted therapeutic utility. Development of chimeric, "humanized" and human mAbs broadened therapeutic application to immune-mediated diseases requiring long-term treatment.

Refracting the k-function: Stavroudis's solution to the eikonal equation for multielement optical systems.

The k-function of Stavroudis describes a solution of the eikonal equation in a region of constant refractive index. Given the k-function describing the optical field in one region of space, and given a prescribed refractive or reflective boundary, we construct the k-function for the refracted or reflected field. This procedure, which Stavroudis calls refracting the k-function, can be repeated any number of times, and therefore extends the usefulness of the k-function formalism to multielement optical systems.

Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus.

An abnormal neutrophil subset has been identified in the PBMC fractions from lupus patients. We have proposed that these low-density granulocytes (LDGs) play an important role in lupus pathogenesis by damaging endothelial cells and synthesizing increased levels of proinflammatory cytokines and type I IFNs. To directly establish LDGs as a distinct neutrophil subset, their gene array profiles were compared with those of autologous normal-density neutrophils and control neutrophils.

Evaluation of an anti-tumor necrosis factor therapeutic in a mouse model of Niemann-Pick C liver disease.

Background: Niemann-Pick type C (NPC) disease is a lysosomal storage disease characterized by the accumulation of cholesterol and glycosphingolipids. The majority of NPC patients die in their teen years due to progressive neurodegeneration; however, half of NPC patients also suffer from cholestasis, prolonged jaundice, and hepatosplenomegaly. We previously showed that a key mediator of NPC liver disease is tumor necrosis factor (TNF) α, which is involved in both proinflammatory and apoptotic signaling cascades.

Characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis factor α.

We prepared and characterized golimumab (CNTO148), a human IgG1 tumor necrosis factor alpha (TNFα) antagonist monoclonal antibody chosen for clinical development based on its molecular properties. Golimumab was compared with infliximab, adalimumab and etanercept for affinity and in vitro TNFα neutralization. The affinity of golimumab for soluble human TNFα, as determined by surface plasmon resonance, was similar to that of etanercept (18 pM versus 11 pM), greater than that of infliximab (44 pM) and significantly greater than that of adalimumab (127 pM, p=0.

TNF-alpha drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice.

Inflammation is associated with blood vessel and lymphatic vessel proliferation and remodeling. The microvasculature of the mouse trachea provides an ideal opportunity to study this process, as Mycoplasma pulmonis infection of mouse airways induces widespread and sustained vessel remodeling, including enlargement of capillaries into venules and lymphangiogenesis. Although the mediators responsible for these vascular changes in mice have not been identified, VEGF-A is known not to be involved.

Tumor necrosis factor deficiency inhibits mammary tumorigenesis and a tumor necrosis factor neutralizing antibody decreases mammary tumor growth in neu/erbB2 transgenic mice.

Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine that is synthesized and secreted by cells of the immune system, as well as by certain epithelia and stroma. Based on our previous studies demonstrating TNF-stimulated proliferation of normal and malignant mammary epithelial cells, we hypothesized that TNF might promote the growth of breast cancer in vivo. To test this, we generated bigenic mice that overexpressed activated neu/erbB2 in the mammary epithelium and whose TNF status was wild-type, heterozygous, or null.

Evaluation of anti-IL-6 monoclonal antibody therapy using murine type II collagen-induced arthritis.

Interleukin-6 is a multifunctional cytokine that is critical for T/B-cell differentiation and maturation, immunoglobulin secretion, acute-phase protein production, and macrophage/monocyte functions. Extensive research into the biology of IL-6 has implicated IL-6 in the pathophysiology and pathogenesis of RA. An anti-murine IL-6 mAb that neutralizes mouse IL-6 activities was tested in animal model of collagen-induced arthritis.

Wavefront and caustics of a plane wave refracted by an arbitrary surface.

A simple expression is given for the k-function associated with the general solution of Stavroudis to the eikonal equation for refraction or reflection of a plane wave from an arbitrary surface. Using this result, we specialize the solution to derive analytic expressions for the wavefront and caustic surfaces after refraction of a plane wave from any rotationally symmetric surface. The method is applied to evaluating and comparing the wavefront and caustic surfaces formed both by a planospherical lens and a planoaspheric lens used for laser beam shaping, which provides understanding of how the irradiance is redistributed over a beam as the wavefront folds back on itself within the focal region.

Elucidating bone marrow edema and myelopoiesis in murine arthritis using contrast-enhanced magnetic resonance imaging.

Objective: While bone marrow edema (BME) detected by magnetic resonance imaging (MRI) is a biomarker of arthritis, its nature remains poorly understood due to the limitations of clinical studies. In this study, MRI of murine arthritis was used to elucidate its cellular composition and vascular involvement.

Methods: BME was quantified using normalized bone marrow intensity (NBMI) from precontrast MRI and normalized marrow contrast enhancement (NMCE) following intravenous administration of gadopentate dimeglumine.

Longitudinal assessment of synovial, lymph node, and bone volumes in inflammatory arthritis in mice by in vivo magnetic resonance imaging and microfocal computed tomography.

Objective: To develop longitudinal 3-dimensional (3-D) measures of outcomes of inflammation and bone erosion in murine arthritis using contrast-enhanced magnetic resonance imaging (CE-MRI) and in vivo microfocal computed tomography (micro-CT) and, in a pilot study, to determine the value of entry criteria based on age versus synovial volume in therapeutic intervention studies.

Methods: CE-MRI and in vivo micro-CT were performed on tumor necrosis factor-transgenic (TNF-Tg) mice and their wild-type littermates to quantify the synovial and popliteal lymph node volumes and the patella and talus bone volumes, respectively, which were validated histologically. These longitudinal outcome measures were used to assess the natural history of erosive inflammatory arthritis.

MRI and quantification of draining lymph node function in inflammatory arthritis.

While erosion and tissue necrosis are the end-stage result of inflammatory arthritis, factors that can predict their initiation and severity are unknown. In an effort to identify these prognostic factors we developed contrast-enhanced (CE)-magnetic resonance imaging (MRI) for the mouse knee to assess the pathogenesis of inflammatory arthritis. Using this approach to study synovitis and draining lymph node (LN) function we first demonstrated that the LNs of TNF-Tg mice at 5 months are significantly larger and have greater enhancement in comparison to wild-type (WT) mice.

Laser beam shaping profiles and propagation.

We consider four families of functions--the super-Gaussian, flattened Gaussian, Fermi-Dirac, and super-Lorentzian--that have been used to describe flattened irradiance profiles. We determine the shape and width parameters of the different distributions, when each flattened profile has the same radius and slope of the irradiance at its half-height point, and then we evaluate the implicit functional relationship between the shape and width parameters for matched profiles, which provides a quantitative way to compare profiles described by different families of functions. We conclude from an analysis of each profile with matched parameters using Kirchhoff-Fresnel diffraction theory and M2 analysis that the diffraction patterns as they propagate differ by small amounts, which may not be distinguished experimentally.

Induction of dendritic cell maturation by IL-18.

IL-18 is a pluripotent proinflammatory cytokine produced primarily by antigen presenting cells involved in numerous aspects of immune regulation most notably on lymphoid cells. The effect of IL-18 stimulation on cells in the myeloid compartment, however, has been poorly studied. Human monocytes did not respond to IL-18.

Coming of age: anti-cytokine therapies.

Although cytokines are critical in maintaining normal physiology, excessive production of these proteins can lead to pathological consequences. Inhibitors of cytokine production or action are therefore widely investigated as potential therapeutic agents in a variety of immune and inflammatory diseases. Indeed, the successful application of inhibitors of tumor necrosis factor-alpha in rheumatoid arthritis and Crohn's disease heralds the great therapeutic potential of biopharmaceutical agents to counteract cytokine activities.

An anti-tumor necrosis factor-alpha antibody inhibits the development of experimental skin tumors.

The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) was originally considered to have activity against malignant disease. However, recent studies suggest TNF-alpha may also act as an endogenous tumor promoter. In the present work, mice deficient in TNF-alpha either genetically (TNF-alpha(-/-)) or after blockade with a neutralizing antibody (cV1q) were used to investigate the role of TNF-alpha in skin tumor development.

Anti-TNF-alpha antibody allows healing of joint damage in polyarthritic transgenic mice.

Anti-tumor-necrosis-factor-alpha (TNF-alpha) monoclonal antibody was used to treat Tg197 transgenic mice, which constitutively produce human TNF-alpha (hTNF-alpha) and develop a progressive polyarthritic disease. Treatment of both young (7- or 8-week-old) and aged (27- or 28-week-old) mice commenced when at least two limbs showed signs of moderate to severe arthritis. The therapeutic efficacy of anti-TNF-alpha antibody was assessed using various pathological indicators of disease progression.

Binding and functional comparisons of two types of tumor necrosis factor antagonists.

Two tumor necrosis factor (TNF) antagonists infliximab (a chimeric monoclonal antibody) and etanercept (a p75 TNF receptor/Fc fusion protein) have been approved for treatment of rheumatoid arthritis. However, these agents have shown different degrees of clinical benefit in controlled clinical trials in other TNF-mediated diseases such as Crohn's disease (CD) and psoriasis. We investigated whether structural differences between these two antagonists translate into different binding and functional characteristics.

TNF receptor 1, IL-1 receptor, and iNOS genetic knockout mice are not protected from anthrax infection.

Anthrax produces at least two toxins that cause an intense systemic inflammatory response, edema, shock, and eventually death. The relative contributions of various elements of the immune response to mortality and course of disease progression are poorly understood. We hypothesized that knockout mice missing components of the immune system will have an altered response to infection.

Effects of 2 different anti-tumor necrosis factor-alpha agents in a primate model of subcutaneous abscess formation.

Tumor necrosis factor (TNF)-alpha exerts both physiologic and pathologic effects in response to infection, conferring the benefit of host defense against infection at the risk of eliciting severe pathology if the response is excessive or inappropriate. In the present study, the effects of an anti-TNF-alpha monoclonal antibody (MAb) and a TNF-alpha receptor construct (p75-Fc) were compared with that of saline in a primate model of subcutaneous abscess induced with Staphylococcus aureus. Intravenous administration of anti-TNF-alpha MAb delayed the onset and reduced the incidence and the severity of abscess formation in response to inoculation with S.