Transforming growth factor-beta inhibits interferon-gamma-induced HLA-DR expression by cultured human fibroblasts

This study shows the induction of HLA-DR (DR) in fibroblasts by IFN-? and investigates the molecular mechanisms involved in the further DR down-regulation by TGF-?1. Kinetics of DR induction on human dermal fibroblasts by IFN-? showed that 1 hr of exposure was required to induce detectable levels of DR, and maximal DR expression was achieved only after 2 days of exposure to IFN-?. TGF-?1 inhibited DR induction by IFN-?, although complete inhibition never could be achieved, even with high concentrations of TGF-?1 and low concentrations of IFN-?. Inhibition was not accounted for by reduction in cell numbers, as TGF-?1 stimulated growth of the fibroblasts. Inhibition of DR induction was seen only if TGF-?1 was added during the first 24 hr of IFN-? treatment. TGF-?1 inhibited equally well if the cells were pretreated for as little as 1 hr and then washed before addition of IFN-?. TGF-?1 did not cause an overall suppression of protein synthesis. Northern blot analysis revealed that TGF-?1 greatly reduced the steady-state level of DR? mRNA induced by IFN-? at 24 hr, and then DR? transcripts became undetectable at later stages. It is concluded that early intracellular signals must build up to stimulate maximum DR synthesis, which, later on, are inactivated or degraded by the action of TGF-?1. We suggest that these mechanisms regulating DR gene transcription involve the action of genes coding for specific IFN-?-inducible transcriptional factors that are turned on and off in an expeditious manner

Safety and High Level Efficacy of the Combination Malaria Vaccine Regimen of RTS,S/AS01B With Chimpanzee Adenovirus 63 and Modified Vaccinia Ankara Vectored Vaccines Expressing ME-TRAP

Background. The need for a highly efficacious vaccine against Plasmodium falciparum remains pressing. In this controlled human malaria infection (CHMI) study, we assessed the safety, efficacy and immunogenicity of a schedule combining 2 distinct vaccine types in a staggered immunization regimen: one inducing high-titer antibodies to circumsporozoite protein (RTS,S/ AS01B) and the other inducing potent T-cell responses to thrombospondin-related adhesion protein (TRAP) by using a viral vector. Method. Thirty-seven healthy malaria-naive adults were vaccinated with either a chimpanzee adenovirus 63 and modified vaccinia virus Ankara–vectored vaccine expressing a multiepitope string fused to TRAP and 3 doses of RTS,S/AS01B (group 1; n = 20) or 3 doses of RTS,S/AS01B alone (group 2; n = 17). CHMI was delivered by mosquito bites to 33 vaccinated subjects at week 12 after the first vaccination and to 6 unvaccinated controls. Results. No suspected unexpected serious adverse reactions or severe adverse events related to vaccination were reported. Protective vaccine efficacy was observed in 14 of 17 subjects (82.4%) in group 1 and 12 of 16 subjects (75%) in group 2. All control subjects received a diagnosis of blood-stage malaria parasite infection. Both vaccination regimens were immunogenic. Fourteen protected subjects underwent repeat CHMI 6 months after initial CHMI; 7 of 8 (87.5%) in group 1 and 5 of 6 (83.3%) in group 2 remained protected. Conclusions. The high level of sterile efficacy observed in this trial is encouraging for further evaluation of combination approaches using these vaccine types