37 research outputs found
Preclinical and early clinical development of GNbAC1, a humanized IgG4 monoclonal antibody targeting endogenous retroviral MSRV-Env protein
Monoclonal antibodies (mAbs) play an increasing important role in the therapeutic armamentarium against multiple
sclerosis (MS), an inflammatory and degenerative disorder of the central nervous system. Most of the mAbs currently
developed for MS are immunomodulators blocking the inflammatory immune process. In contrast with mAbs targeting
immune function, GNbAC1, a humanized IgG4 mAb, targets the multiple sclerosis associated retrovirus envelope (MSRVEnv)
protein, an upstream factor in the pathophysiology of MS. MSRV-Env protein is of endogenous retroviral origin,
expressed in MS brain lesions, and it is pro-inflammatory and toxic to the remyelination process, by preventing the
differentiation of oligodendrocyte precursor cells. We present the preclinical and early clinical development results of
GNbAC1. The specificity of GNbAC1 for its endogenous retroviral target is described. Efficacy of different mAb versions of
GNbAC1 were assessed in MSRV-Env induced experimental allergic encephalitis (EAE), an animal model of MS. Because
the target MSRV-Env is not expressed in animals, no relevant animal model exists for a proper in vivo toxicological
program. An off-target 2-week toxicity study in mice was thus performed, and it showed an absence of safety risk.
Additional in vitro analyses showed an absence of complement or antibody-dependent cytotoxicity as well as a low level
of cross-reactivity to human tissues. The first-in-man clinical study in 33 healthy subjects and a long-term clinical study in
10 MS patients showed that GNbAC1 is well tolerated in humans without induction of immunogenicity and that it
induces a pharmacodynamic response on MSRV biomarkers. These initial results suggest that the mAb GNbAC1 could be
a safe long-term treatment for patients with MS with a unique therapeutic mechanism of action.GeNeuro SA, Geneva, Switzerlandhttp://www.tandfonline.com/loi/kmab202016-01-31hb201
Autoantikörpernachweis mittels indirekter Immunfluoreszenz an HEp-2-Zellen
Systemic autoimmune diseases are characterized by the presence of antinuclear autoantibodies (ANAs). Diluted patient sera are typically used to screen for the presence of ANAs by immunofluorescence microscopy with fixed HEp-2 cells. Despite high quality test kits, reports of different laboratories frequently present controversial results. This study presents a recommendation for a unified processing and interpretation of HEp-2 based screening for autoantibodies. We provide suggestions for selection of high quality test kits, optimized processing, and diagnostic procedures. For good laboratory practice, in addition to a relevant clinical diagnosis and an experienced laboratory specialist, the following procedure is highly recommended: initial HEp-2 based screening by indirect immunofluorescence, starting with a 1:80 serum dilution and evaluation in a bright fluorescence microscope, pathological values from a titer of 1:160, internal quality checks, and unified interpretation. We aim to improve diagnostics and care for patients with autoimmune diseases as a central focus of the European Autoimmunity Standardization Initiative (EASI)
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Does erythropoietin modulate human hair follicle melanocyte activities in situ?
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Human hair follicles are an extrarenal source and a nonhematopoietic target of erythropoietin
ABSTRACT
Erythropoietin primarily serves as an essential growth factor for erythrocyte precursor cells. However, there is increasing evidence that erythropoietin (EPO)/EPO receptor (EPO‐R) signaling operates as a potential tissue‐protective system outside the bone marrow. Arguing that growing hair follicles (HF) are among the most rapidly proliferating tissues, we have here explored whether human HFs are sources of EPO and targets of EPO‐R‐mediated signaling. Human scalp skin and microdissected HFs were assessed for EPO and EPO‐R expression, and the effects of EPO on organ‐cultured HFs were assessed in the presence/ absence of a classical apoptosis‐inducing chemothera‐peutic agent. Here, we show that human scalp HFs express EPO on the mRNA and protein level in situ, up‐regulate EPO transcription under hypoxic conditions, and express transcripts for EPO‐R and the EPO‐stimulatory transcriptional cofactor hypoxia‐inducible factor‐1α. Although EPO does not significantly alter human hair growth in vitro, it significantly down‐regulates chemotherapy‐induced intrafollicular apoptosis and changes the gene expression program of the HFs. The current study points to intriguing targets of EPO beyond the erythropoietic system: human HFs are an extrarenal site of EPO production and an extrahema‐topoietic site of EPO‐R expression. They may recruit EPO/EPO‐R signaling e.g., for modulating HF apopto‐sis under conditions of hypoxia and chemotherapy‐induced stress.—Bodó, E., Kromminga, A., Funk, W., Laugsch, M., Duske, U., Jelkmann, W., Paus, R. Human hair follicles are an extrarenal source and a non‐hematopoietic target of erythropoietin. FASEB J. 21, 3346–3354 (2007
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Thyrotropin releasing hormone (TRH): A new player in human hair-growth control
Thyrotropin‐releasing hormone (TRH) is the most proximal component of the hypothalamic‐pituitary‐thyroid axis that regulates thyroid hormone synthesis. Since transcripts for members of this axis were detected in cultured normal human skin cells and since human hair follicles (HFs) respond to stimulation with thyrotropin we now have studied whether human HF functions are also modulated by TRH. Here we report that the epithelium of normal human scalp HFs expresses not only TRH receptors (TRH‐R) but also TRH itself at the gene and protein level. Stimulation of microdissected organ‐cultured HFs with TRH promotes hair‐shaft elongation prolongs the hair cycle growth phase (anagen) and antagonizes its termination by TGF‐β2. It also increases proliferation and inhibits apoptosis of hair matrix keratinocytes. These TRH effects may be mediated in part by reducing the ATM/Atr‐dependent phosphorylation of p53. By microarray analysis several differentially up‐ or down‐regulated TRH‐target genes were detected (e.g., selected keratins). Thus human scalp HFs are both a source and a target of TRH which operates as a potent hair‐growth stimulator. Human HFs provide an excellent discovery tool for identifying and dissecting nonclassical functions of TRH and TRH‐mediated signaling in situ, which emerge as novel players in human epithelial biology.—Gáspár, E., Hardenbicker, C., Bodó, E., Wenzel B. Ramot Y. Funk W. Kromminga A. Paus R. Thyrotropin releasing hormone (TRH): a new player in human hair‐growth control. FASEB J. 24, 393–403 (2010). www.fasebj.or