Immunogenicity of Structurally Perturbed Hen Egg Lysozyme Adsorbed to Silicone Oil Microdroplets in Wild-Type and Transgenic Mouse Models.

Silicone oil microdroplets may act as adjuvants, promoting unwanted immune responses against both foreign and self-proteins. Proteins often unfold upon adsorption to silicone oil microdroplets, but it is unclear how such unfolding might affect the immune response. In this study, we found that hen egg lysozyme (HEL) readily adsorbed to silicone oil microdroplets and perturbed the conformation of HEL.

Subvisible Particle Content, Formulation, and Dose of an Erythropoietin Peptide Mimetic Product Are Associated With Severe Adverse Postmarketing Events.

Peginesatide (Omontys(®); Affymax, Inc., Cupertino, CA) was voluntarily withdrawn from the market less than a year after the product launch. Although clinical trials had demonstrated the drug to be safe and efficacious, 49 cases of anaphylaxis, including 7 fatalities, were reported not long after market introduction.

Lack of Evidence for Molecular Mimicry in HIV-Infected Subjects.

Previous studies in HIV patients have reported autoantibodies to several human proteins, including erythropoietin (EPO), interferon-α (IFN-α), interleukin-2 (IL-2), and HLA-DR, as potential mediators of anemia or immunosuppression. The etiology of these autoantibodies has been attributed to molecular mimicry between HIV epitopes and self-proteins. Here, the Luciferase Immunoprecipitation System (LIPS) was used to investigate the presence of such autoantibodies in HIV-infected adults.

The serological evidence in humans supports a negligible risk of zoonotic infection from porcine circovirus type 2.

There are two porcine circovirus (PCV) genotypes, PCV-1 and PCV-2. In pigs, PCV-1 infection is asymptomatic but PCV-2 infection can cause severe respiratory disease and other pathology. Although humans ingest PCV-contaminated foods and are exposed to PCV through other sources, the potential of PCV-2 as a zoonotic agent in humans and other species has not been fully explored.

The future of protein particle characterization and understanding its potential to diminish the immunogenicity of biopharmaceuticals: a shared perspective.

Biopharmaceuticals represent an important and growing class of medicines. Immunogenic responses to biopharmaceuticals in patients can sometimes result in reduced safety and efficacy. Although multiple factors are known to influence immunogenicity, our understanding of the complex underlying mechanisms remains imperfect.

IL-2 regulates expression of C-MAF in human CD4 T cells.

Blockade of IL-2R with humanized anti-CD25 Abs, such as daclizumab, inhibits Th2 responses in human T cells. Recent murine studies have shown that IL-2 also plays a significant role in regulating Th2 cell differentiation by activated STAT5. To explore the role of activated STAT5 in the Th2 differentiation of primary human T cells, we studied the mechanisms underlying IL-2 regulation of C-MAF expression.

Human CD14hi monocytes and myeloid dendritic cells provide a cell contact-dependent costimulatory signal for early CD40 ligand expression.

CD40L on CD4(+) T cells plays a vital role in the activation of antigen-presenting cells, thus catalyzing a positive feedback loop for T-cell activation. Despite the pivotal juxtaposition of CD40L between antigen-presenting cells and T-cell activation, only a T-cell receptor stimulus is thought to be required for early CD40L surface expression. We show, for the first time, that CD40L expression on peripheral blood CD4(+) T cells is highly dependent on a cell-cell interaction with CD14(hi)CD16(-) monocytes.

High-dose humanized anti-IL-2 receptor alpha antibody (daclizumab) for the treatment of active, non-infectious uveitis.

Purpose: This study was designed to provide preliminary data regarding the safety and efficacy of high-dose humanized anti-IL-2 receptor (daclizumab) therapy for the treatment of active intermediate, posterior or panuveitis.

Methods: Five patients were recruited into this non-randomized, prospective pilot study of high-dose intravenous induction daclizumab therapy given at doses of 8mg/kg at day 0 and 4mg/kg at day 14. Patients who did not meet a safety endpoint at the 3-week follow-up evaluation were given the option of continuing therapy with subcutaneous daclizumab at 2mg/kg every 4 weeks for 52 weeks.

Direct inhibition of CD40L expression can contribute to the clinical efficacy of daclizumab independently of its effects on cell division and Th1/Th2 cytokine production.

Humanized anti-CD25 antibodies (eg, daclizumab) have been successfully used to treat several autoimmune diseases. Paradoxically, IL-2 blockade in mice can induce autoimmunity. An interspecies difference in the relative contribution of IL-2 to CD25(+) T regulatory cell (CD25(+)Treg) versus CD25(+) effector cell function might explain this conundrum.

The role of cytokine mRNA stability in the pathogenesis of autoimmune disease.

Inflammatory cytokines such as interferon (IFN)-gamma, interleukin (IL)-2, tumor-necrosis factor (TNF)-alpha and IL-17 play an important role in the pathogenesis of cell-mediated autoimmune diseases. Cytokine gene expression is tightly regulated at the post-transcriptional level. Cytokine mRNA decay is dependent not only upon cis-elements in the RNA but also upon trans-acting factors such as the RNA binding proteins TTP, HuR, AUF-1, Nucleolin and YB-1.

Targeted infection of HIV-1 Env expressing cells by HIV(CD4/CXCR4) vectors reveals a potential new rationale for HIV-1 mediated down-modulation of CD4.

Background: Efficient targeted gene transfer and cell type specific transgene expression are important for the safe and effective expression of transgenes in vivo. Enveloped viral vectors allow insertion of exogenous membrane proteins into their envelopes, which could potentially aid in the targeted transduction of specific cell types. Our goal was to specifically target cells that express the T cell tropic HIV-1 envelope protein (Env) using the highly specific interaction of Env with its cellular receptor (CD4) inserted into the envelope of an HIV-1-based viral vector.

Selective cytoplasmic translocation of HuR and site-specific binding to the interleukin-2 mRNA are not sufficient for CD28-mediated stabilization of the mRNA.

The interleukin-2 mRNA is a labile transcript containing AU-rich elements that is transiently stabilized by CD28 receptor signaling. For a number of proto-oncogenes and cytokines, the HuR protein has been shown to avidly bind the AU-rich elements that confer instability upon their mRNAs. HuR was originally thought to participate in mRNA degradation but subsequent studies indicated that it actually functions to stabilize mRNA.

IL-2 receptor blockade inhibits late, but not early, IFN-gamma and CD40 ligand expression in human T cells: disruption of both IL-12-dependent and -independent pathways of IFN-gamma production.

mAbs directed against the alpha-chain (Tac/CD25) of the IL-2R are an emerging therapy in both transplantation and autoimmune disease. However, the mechanisms underlying their therapeutic efficacy have not been fully elucidated. Therefore, we examined the effect of IL-2R blockade on Th1 and Th2 cytokine production from human PBMC.