Biomedical subjects

R Gundel

Publications and source records attributed to R Gundel.

6 recordsLinked to original sources

PubMed2001

A murine IL-4 receptor antagonist that inhibits IL-4- and IL-13-induced responses prevents antigen-induced airway eosinophilia and airway hyperresponsiveness.

The closely related Th2 cytokines, IL-4 and IL-13, share many biological functions that are considered important in the development of allergic airway inflammation and airway hyperresponsiveness (AHR). The overlap of their functions results from the IL-4R alpha-chain forming an important functional signaling component of both the IL-4 and IL-13 receptors. Mutations in the C terminus region of the IL-4 protein produce IL-4 mutants that bind to the IL-4R alpha-chain with high affinity, but do not induce cellular responses. A murine IL-4 mutant (C118 deletion) protein (IL-4R antagonist) inhibited IL-4- and IL-13-induced STAT6 phosphorylation as well as IL-4- and IL-13-induced IgE production in vitro. Administration of murine IL-4R antagonist during allergen (OVA) challenge inhibited the development of allergic airway eosinophilia and AHR in mice previously sensitized with OVA. The inhibitory effect on airway eosinophilia and AHR was associated with reduced levels of IL-4, IL-5, and IL-13 in the bronchoalveolar lavage fluid as well as reduced serum levels of OVA-IGE: These observations demonstrate the therapeutic potential of IL-4 mutant protein receptor antagonists that inhibit both IL-4 and IL-13 in the treatment of allergic asthma.

Animals↗

PubMed2000

A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo.

Human interleukin 2 (IL-2; Proleukin) is an approved therapeutic for advanced-stage metastatic cancer; however, its use is restricted because of severe systemic toxicity. Its function as a central mediator of T-cell activation may contribute to its efficacy for cancer therapy. However, activation of natural killer (NK) cells by therapeutically administered IL-2 may mediate toxicity. Here we have used targeted mutagenesis of human IL-2 to generate a mutein with approximately 3,000-fold in vitro selectivity for T cells over NK cells relative to wild-type IL-2. We compared the variant, termed BAY 50-4798, with human IL-2 (Proleukin) in a therapeutic dosing regimen in chimpanzees, and found that although the T-cell mobilization and activation properties of BAY 50-4798 were comparable to human IL-2, BAY 50-4798 was better tolerated in the chimpanzee. BAY 50-4798 was also shown to inhibit metastasis in a mouse tumor model. These results indicate that BAY 50-4798 may exhibit a greater therapeutic index than IL-2 in humans in the treatment of cancer and AIDS.

Animals↗

PubMed1999

Empirical fitting with polycon II lenses.

Historically, rigid gas permeable (RGP) lens parameters have been determined through trial fitting. Nevertheless, practitioners would likely welcome the opportunity to empirically fit RGP lenses if they could be confident of the outcome. This clinical investigation sought to evaluate the potential success of empirically fitting 9.0 mm Polycon II lenses. Based on both objective and subjective outcomes, this study suggests that empirically fitting the larger 9.5 mm Polycon II design, in combination with a lid attachment approach, would yield greater initial patient satisfaction.

Journal Article↗

PubMed1998

An immune cell-selective interleukin 4 agonist.

Interleukin 4 (IL-4) is a pleiotropic cytokine. Of the cell types responsive to IL-4, T cells express one IL-4 receptor (IL-4R) type, IL-4Ralpha/IL-2Rgamma (class I IL-4R), whereas endothelial cells express another type, IL-4Ralpha/IL-13Ralpha (class II IL-4R). It was hypothesized that IL-4 variants could be generated that would be selective for cell types expressing the different IL-4Rs. A series of IL-4 muteins were generated that were substituted in the region of IL-4 implicated in interactions with IL-2Rgamma. These muteins were evaluated in T cell and endothelial cell assays. One of these muteins, containing the mutation Arg-121 to Glu (IL-4/R121E), exhibited complete biological selectivity for T cells, B cells, and monocytes, but showed no activity on endothelial cells. Receptor binding studies indicated that IL-4/R121E retained physical interaction with IL-2Rgamma but not IL-13Ralpha; consistent with this observation, IL-4/R121E was an antagonist of IL-4-induced activity on endothelial cells. IL-4/R121E exhibits a spectrum of activities in vitro that suggest utility in the treatment of certain autoimmune diseases.

B-Lymphocytes↗

PubMed1996

IL-4 induced leucocyte trafficking in cynomolgus monkeys: correlation with expression of adhesion molecules and chemokine generation.

BACKGROUND: Interleukin-4 (IL-4) is an immunoregulatory cytokine which has a wide variety of effects on immune cell function. In addition, recent studies suggest that IL-4 may have effects on other cells including endothelial cells in terms of the regulation of adhesion molecule expression and leucocyte extravasation from the vascular space to sites of tissue inflammation. Consequently, IL-4 may have an important role in the pathogenesis of allergic inflammation and disease. OBJECTIVE: The purpose of this study was to learn more about the potential role of IL-4 in inflammatory disease, specifically in regard to the potential of IL-4 to induce the expression of adhesion molecules on vascular endothelial cells and promote the adherence and transmigration of circulating leucocytes to sites of tissue inflammation. METHODS: Single subcutaneous injections of human IL-4 were administered to cynomolgus monkeys and tissue biopsy samples were obtained and analysed for adhesion molecule expression on vascular endothelium and inflammatory cell infiltrates. In another series of experiments, multiple subcutaneous injections of human IL-4 were administered (bid on four consecutive days) and the effects on peripheral blood leucocytes and plasma levels of various cytokines and chemokines were examined. RESULTS: Intradermal injection of IL-4 induced the expression of vascular cell adhesion molecule-1 (VCAM-1) on cutaneous vascular endothelium that was present at 8 hr and persisted out to 24 h post injection. The expression of VCAM-1 was associated with an inflammatory cell infiltrate comprised of granulocytes and mononuclear cells. Multiple injections of IL-4 resulted in a dose-related decrease in the relative percentage and total number of circulating lymphocytes and an increase in circulating neutrophils (4.6 +/- 1-2.1 +/- 0.2 x 10(6)/mL and 1.7 +/- 0.3-7.0 +/- 1 x 10(6)/mL, respectively). Analysis of cell surface markers by flow cytometry revealed a transient decrease in the number of CD4+T lymphocytes and a sustained decrease in CD16+ cells. In addition, IL-4 administration resulted in a large increase in plasma MCP-1 concentration. CONCLUSION: This is the first study to demonstrate an acute effect of IL-4 consistent with lymphocyte trafficking out of the vascular space, the induction of VCAM-1 expression on vascular endothelium and increases in plasma levels of MCP-1 in vivo. We suggest that IL-4 may be involved in the early recruitment of mononuclear cells to sites of tissue inflammation by the upregulation of VCAM-1 expression on vascular endothelium and the generation and release of potent chemoattractants.

Animals↗

PubMed1995

Thromboxane-blocked swine as an experimental model of severe intravascular inflammation and septic shock.

The cardiopulmonary response elicited by intravenous bacteria or endotoxin is well characterized in swine and has two major components. The first represents the acute pulmonary and broncho-constrictive phase (0-2 h) and the second phase (3-8 h) represents increased microvascular permeability, hypotension, and enhanced leukocyte-endothelial adhesion. The pulmonary vasoconstriction and bronchoconstriction of phase 1 results in acute pulmonary hypertension and airway dysfunction, which may result in rapid mortality. Because this acute pulmonary response may not mimic the development of human septic shock, we sought to block this early phase and examine the role of tumor necrosis factor in the latter septic phase (3-8 h). Employing a thromboxane A2 (TXA2) receptor antagonist (BAY U 3405) in the presence of LD100 Escherichia coli challenge, we blocked the acute pulmonary hypertensive phase and prevented early mortality, however, TXA2 blockade did not affect the latter development of septic shock and death. This latter lethal phase, characterized by prolonged leukopenia, was blocked in a dose-dependent manner by tumor necrosis factor monoclonal antibody. We conclude that the TXA2-blocked E. coli-challenged swine may provide a novel animal model in which to investigate the pathophysiology of acute septic shock.

Animals↗