We present a case of complete deficiency of the interferon alpha/beta receptor alpha chain (IFNAR1) in a child with fatal systemic hyperinflammation, apparently provoked by live-attenuated viral vaccination. Such pathologic hyperinflammation, fulfilling criteria for hemophagocytic lymphohistiocytosis, is an emerging phenotype accompanying inborn errors of type I interferon immunity.
Deciphering the mechanisms that allow the induction of strong immune responses is crucial to developing efficient vaccines against infectious diseases and cancer. Based on the discovery that the adenylate cyclase from Bordetella pertussis binds to the CD11b/CD18 integrin, we developed a highly efficient detoxified adenylate cyclase-based vector (CyaA) capable of delivering a large variety of Ags to the APC. This vector allows the induction of protective and therapeutic immunity against viral and tumoral challenges as well as against transplanted tumors in the absence of any added adjuvant. Two therapeutic vaccine candidates against human papilloma viruses and melanoma have been developed recently, based on the CyaA vector, and are currently in clinical trials. We took advantage of one of these highly purified vaccines, produced under good manufacturing practice-like conditions, to decipher the mechanisms by which CyaA induces immune responses. In this study, we demonstrate that CyaA binds both human and mouse CD11b(+) dendritic cells (DCs) and induces their maturation, as shown by the upregulation of costimulatory and MHC molecules and the production of proinflammatory cytokines. Importantly, we show that DCs sense CyaA through the TLR4/Toll/IL-1R domain-containing adapter-inducing IFN-β pathway, independent of the presence of LPS. These findings show that CyaA possesses the intrinsic ability to not only target DCs but also to activate them, leading to the induction of strong immune responses. Overall, this study demonstrates that Ag delivery to CD11b(+) DCs in association with TLR4/Toll/IL-1R domain-containing adapter-inducing IFN-β activation is an efficient strategy to promote strong specific CD8(+) T cell responses.
- MeSH
- adaptorové proteiny vezikulární transportní imunologie MeSH
- adenylátcyklasový toxin imunologie MeSH
- antigeny CD11b imunologie MeSH
- antigeny CD80 biosyntéza MeSH
- antigeny CD86 biosyntéza MeSH
- Bordetella pertussis imunologie MeSH
- buněčná diferenciace imunologie MeSH
- cytotoxické T-lymfocyty imunologie MeSH
- dendritické buňky cytologie imunologie MeSH
- interferon beta imunologie MeSH
- interleukin-1beta biosyntéza MeSH
- interleukin-6 biosyntéza MeSH
- kultivované buňky MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- receptor interferonu alfa-beta genetika MeSH
- receptory interleukinu-1 imunologie MeSH
- signální transdukce imunologie MeSH
- TNF-alfa biosyntéza MeSH
- toll-like receptor 4 imunologie MeSH
- tyrosin genetika MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Interferon-alpha (IFN-alpha) is an important drug used in anti-melanoma therapy. However, metastases eventually reappear in almost 60% of melanoma patients, who have received adjuvant cytokine therapy suggesting that IFN-alpha can paradoxically promote disease progression in some cases, at least. In this study, we have investigated the possibility that a growth-promoting STAT3 protein might be activated by interferon-alpha in melanoma cells. We examined 24 primary cultures established from node metastases of melanoma patients who were monitored in a 5-year clinical follow-up. The patients differed in the course of disease and survival end-points. Using Western blot analyses, we show that interferon-alpha stimulated STAT3 phosphorylation at tyrosine (Y705) residue in 17% of cases. These over-reactive cell populations originated from patients who had the shortest disease-free intervals. A significant correlation was obtained between the length of survival end-points and a lack of STAT3 activation by IFN-alpha. No STAT3 induction was observed in normal melanocytes. The STAT1 activation at tyrosine (Y701) occurred at a similar frequency as that of STAT3 (17%) albeit in different patients, no clear correlation with the clinical status could be made. The interferon-alpha/beta receptors (IRFARs) were expressed irrespective to the signal transducers and activators of transcription (STATs) inducibility suggesting that signalling defects occur downstream from IRFAR. We propose that in some cases the application of IFN-alpha could increase the probability of disease progression via overactive STAT3. The tests for STAT3 inducibility prior to cytokine immunotherapy in the clinic are therefore warranted.
- MeSH
- dospělí MeSH
- financování organizované MeSH
- fosforylace MeSH
- imunohistochemie MeSH
- imunologické faktory škodlivé účinky MeSH
- interferon alfa škodlivé účinky MeSH
- Kaplanův-Meierův odhad MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfatické metastázy MeSH
- melanom farmakoterapie metabolismus MeSH
- messenger RNA analýza MeSH
- nádorové buňky kultivované MeSH
- nádory kůže farmakoterapie metabolismus MeSH
- přežití po terapii bez příznaků nemoci MeSH
- progrese nemoci MeSH
- proliferace buněk účinky léků MeSH
- receptor interferonu alfa-beta genetika MeSH
- senioři MeSH
- transkripční faktor STAT3 analýza metabolismus MeSH
- upregulace MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- western blotting metody MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
