Search

Background: A vaccine (HB-101) consisting of 2 nonreplicating lymphocytic choriomeningitis virus (LCMV) vectors expressing the human cytomegalovirus antigens glycoprotein B (gB) and the 65-kD phosphoprotein (pp65), respectively, is in development to prevent cytomegalovirus infection., Methods: HB-101 was tested in cytomegalovirus-naive, healthy adults in a randomized, double-blind, placebo-controlled, dose-escalation Phase I trial. Fifty-four subjects received low, medium, or high dose of HB-101 or placebo by intramuscular administration at Month 0, 1, and 3. Safety and immunogenicity were the respective primary and secondary endpoints. Subjects were followed for 12 months after the initial immunization., Results: Vaccination was associated with transient mild to moderate adverse events. HB-101 administration induced dose-dependent gB- and pp65-specific cellular responses, dominated by pp65-specific CD8 T cells, a high fraction of which were polyfunctional. Two administrations were sufficient to elicit dose-dependent gB-binding and cytomegalovirus-neutralizing antibodies (Abs). Cytomegalovirus-specific immune responses were boosted after each administration. Only 1 of 42 vaccine recipients mounted a transient LCMV vector-neutralizing Ab response., Conclusions: HB-101 was well tolerated and induced cytomegalovirus-specific polyfunctional CD8 T-cell and neutralizing Ab responses in the majority of subjects. Lack of vector-neutralizing Ab responses should facilitate booster vaccinations. These results justify further clinical evaluation of this vaccine candidate., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

This review focuses on the biological functions and signalling pathways activated by Lymphotoxin α (LTα)/Lymphotoxin β (LTβ) and their receptor LTβR. Genetic mouse models shed light on crucial roles for LT/LTβR to build and to maintain the architecture of lymphoid organs and to ensure an adapted immune response against invading pathogens. However, chronic inflammation, autoimmunity, cell death or cancer development are disorders that occur when the LT/LTβR system is twisted. Biological inhibitors, such as antagonist antibodies or decoy receptors, have been developed and used in clinical trials for diseases associated to the LT/LTβR system. Recent progress in the understanding of cellular trafficking and NF-κB signalling pathways downstream of LTα/LTβ may bring new opportunities to develop therapeutics that target the pathological functions of these cytokines., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

As a wide variety of pro-inflammatory cytokines are involved in the development of rheumatoid arthritis (RA), there is an urgent need for the discovery of novel therapeutic strategies. Among these, the inhibition of the NF-kappaB inducing kinase (NIK), a key enzyme of the NF-kappaB alternative pathway activation, represents a potential interesting approach. In fact, NIK is involved downstream of many tumor necrosis factor receptors (TNFR) like CD40, RANK or LTbetaR, implicated in the pathogenesis of RA. But, up to now, the number of reported putative NIK inhibitors is extremely limited. In this work, we report a virtual screening (VS) study combining various filters including high-throughput docking using a 3D-homology model and ranking by using different scoring functions. This work led to the identification of two molecular fragments, 4H-isoquinoline-1,3-dione (5) and 2,7-naphthydrine-1,3,6,8-tetrone (6) which inhibit NIK with an IC(50) value of 51 and 90 microM, respectively. This study opens new perspectives in the field of the NF-kappaB alternative pathway inhibition., (Copyright 2010 Elsevier Ltd. All rights reserved.)

In this work, we aimed to build a 3D-model of NIK and to study the binding of pyrazolo[4,3-c]isoquinolines with a view to highlight the structural elements responsible for their inhibitory potency. However, in the course of this work, we unexpectedly found that the pyrazolo[4,3-c]isoquinolines initially reported as NIK inhibitors were neither inhibitors of this enzyme nor of the alternative NF-kappaB pathway, but were in fact inhibitors of another kinase, the TGF-beta activated kinase 1 (TAK1) which is involved in the classical NF-kappaB pathway., (2010 Elsevier Inc. All rights reserved.)

The Hedgehog (Hh) signaling pathway plays an important role in human development. Abnormal activation of this pathway has been observed in several types of human cancers, such as the upper gastro-intestinal tract cancers. However, activation of the Hh pathway in colorectal cancers is controversial. We analyzed the expression of the main key members of the Hh pathway in 7 colon cancer cell lines in order to discover whether the pathway is constitutively active in these cells. We estimated the expression of SHH, IHH, PTCH, SMO, GLI1, GLI2, GLI3, SUFU and HHIP genes by RT-PCR. Moreover, Hh ligand, Gli3 and Sufu protein levels were quantified by western blotting. None of the cell lines expressed the complete set of Hh pathway members. The ligands were absent from Colo320 and HCT116 cells, Smo from Colo205, HT29 and WiDr. GLI1 gene was not expressed in SW480 cells nor were GLI2/GLI3 in Colo205 or Caco-2 cells. Furthermore the repressive form of Gli3, characteristic of an inactive pathway, was detected in SW480 and Colo320 cells. Finally treatment of colon cancer cells with cyclopamine, a specific inhibitor of the Hh pathway, did not downregulate PTCH and GLI1 genes expression in the colorectal cells, whereas it did so in PANC1 control cells. Taken together, these results indicate that the aberrant activation of the Hh signaling pathway is not common in colorectal cancer cell lines., ((c) 2007 Wiley-Liss, Inc.)