Center for Biologics Evaluation and Research

About: Center for Biologics Evaluation and Research is a facility organization based out in Silver Spring, Maryland, United States. It is known for research contribution in the topics: Virus & Vaccination. The organization has 3024 authors who have published 4648 publications receiving 228078 citations. The organization is also known as: CBER.

Stat6-deficient mice develop airway hyperresponsiveness and peribronchial fibrosis during chronic fungal asthma

Abstract: Signal transducer and activator of transcription 6 (Stat6) is critical for Th2-mediated responses during allergic airway disease. To investigate the role of Stat6 in fungus-induced airway hyperresponsiveness and remodeling, Stat6-deficient (Stat6-/-) and Stat6-wildtype (Stat6+/+) mice were sensitized to Aspergillus fumigatus and airway disease was subsequently assessed in both groups at days 21, 30, 38, and 44 after an intratracheal challenge with live A. fumigatus conidia. At all times after conidia, histological analysis revealed an absence of goblet cell hyperplasia and markedly diminished peribronchial inflammation in Stat6-/- mice in contrast to Stat6+/+ mice. Airway hyperresponsiveness and peribronchial fibrosis in Stat6-/- mice were significantly reduced at day 21 after conidia compared with Stat6+/+ mice, but both groups exhibited significant, similar increases in these parameters at all subsequent times after conidia. In separate experiments, IL-13-responsive cells in Stat6-/- mice were targeted via the daily intranasal administration of 200 ng of IL-13-PE38QQR (IL13-PE), comprised of human IL-13 and a derivative of Pseudomonas exotoxin, from days 38 to 44 after the conidia challenge. IL13-PE treatment abolished airway hyperresponsiveness, but not peribronchial fibrosis in Stat6-/- mice. Taken together, these data demonstrate that the chronic development of airway hyperresponsiveness during fungal asthma is IL-13-dependent but Stat6-independent.

Nanoparticle-based immunoassays for sensitive and early detection of HIV-1 capsid (p24) antigen

Abstract: We evaluated the feasibility of using nanoparticle (NP)-based assays for improving detection sensitivity of human immunodeficiency virus type 1 (HIV-1) p24 antigen. One assay that was evaluated is a gold NP-based biobarcode amplification (BCA) assay, which can detect HIV-1 p24 antigen at levels as low as 0.1 pg/mL. The lower limit of detection for an enzyme-linked immunosorbent assay (ELISA) is 10-15 pg/mL. These results demonstrate that the HIV-1 p24 BCA assay offers 100-150-fold enhancement in the detection limit over the traditional colorimetric ELISA. Furthermore, the BCA assay detected HIV-1 infection 3 days earlier than did ELISA in samples from patients who had experienced seroconversion. The other assay that we tested is the europium NP-based immunoassay, which uses europium NPs to replace gold NPs in the BCA assay to further simplify the detection method and decrease the incubation time. For detection of HIV-1 p24, the lower limit of detection for the europium NP-based immunoassay was 0.5 pg/mL. These results indicate that the universal labeling technology based on NPs and its application may provide a rapid and sensitive testing platform for clinical diagnosis and laboratory research.

Synthetic CpG oligodeoxynucleotides augment BAFF- and APRIL-mediated immunoglobulin secretion

Abstract: The B lymphocyte-activating factor belonging to TNF superfamily (BAFF) acts on B lymphocytes through BAFF receptor (BAFF-R), the transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI), and the B cell maturation antigen (BCMA). Another cytokine, a proliferation-inducing ligand (APRIL), only binds to TACI and BCMA. In this study, we sought to determine the effect of Toll-like receptor agonists (TLR-A) on the expression of BAFF/APRIL receptors by murine splenic B lymphocytes. CpG oligodeoxynucleotides (ODN) and LPS strongly up-regulated TACI expression, while BAFF-R was only up-regulated by CpG ODN. CpG ODN pretreatment up-regulated TACI expression on follicular and marginal zone B lymphocytes and increased their responses to BAFF- and APRIL-mediated Ig secretion. TACI seemed to be playing a pivotal role in BAFF- or APRIL-induced Ig secretion because B lymphocytes from TACI-knockout mouse or the blocking of TACI with a neutralizing antibody resulted in total inhibition of IgA and IgG secretion in CpG ODN-pretreated and BAFF- or APRIL-stimulated B cells. Thus, CpG ODN-induced increase in TACI expression is likely to play an important role in Ig secretion following activation of B lymphocytes through TLR9.

Two different IL-13 receptor chains are expressed in normal human skin fibroblasts, and IL-4 and IL-13 mediate signal transduction through a common pathway.

Abstract: IL-13 and IL-4, pleiotropic immune regulatory cytokines, have been shown to mediate similar prominent effects in human fibroblast cell lines. However, molecular mechanisms for their redundant effects are not known. Here, we have investigated the structure of IL-13 receptors (IL-13R) and molecular mechanisms of signal transduction through IL-13 and IL-4 receptors in non-transformed normal skin fibroblast cell lines. We demonstrate that high-affinity IL-13R is expressed in normal skin fibroblast cell lines. Upon [ 125 I]IL-13 cross-linking, a ~60‐70 kDa band was observed in sk559 and sk574 fibroblast cell lines. By RT-PCR analysis, mRNA for IL-13Ra, IL-13Ra9 and IL-4Rb chains were expressed; however, the IL-2Rg chain, shown to participate and modulate IL-4 and IL-13 binding, was not expressed in any of the cell lines examined. The Janus kinase (JAK)2 and Tyk2 were phosphorylated in response to IL-4 or IL-13 in sk559 and sk574 cell lines. JAK1 was also phosphorylated in one of two cell lines while JAK3 was present but not phosphorylated in any of the cell lines studied. A signal transduction and activator of transcription (STAT)6 was also activated in response to both IL. An insulin receptor substrate (IRS)-1 was constitutively phosphorylated and its phosphorylation level was augmented in response to both IL. These results suggest that the mechanism of signal transduction through IL-13 and IL-4 receptors in human fibroblast cell lines is similar, and this may, at least in part, be responsible for the redundant effects of these two cytokines. In addition, JAK2 tyrosine kinase instead of JAK3 appears to play a major role in IL-4- and IL-13-induced signal transduction in human fibroblasts.