There is the first evidence of changes in the kinetics of B cell antigen receptor (BCR) internalisation of neoplastic cells in chronic lymphocytic leukemia (CLL) after the short-term and long-term administration of ibrutinib. We aimed to assess the influence of short-term and long-term ibrutinib treatment on the HLA-DR expression on CLL cells, T cells and monocytes. The immunophenotyping of CLL and immune cells in peripheral blood was performed on 16 high-risk CLL patients treated with ibrutinib. After early ibrutinib administration, the HLA-DR expression on CLL cells reduced (P = 0.032), accompanied by an increase in CLL cell counts in peripheral blood (P = 0.001). In vitro culturing of CLL cells with ibrutinib also revealed the reduction in the HLA-DR expression at protein and mRNA levels (P < 0.01). The decrease in HLA-DR on CLL cells after the first month was followed by the gradual increase of its expression by the 12th month (P = 0.001). A one-month follow-up resulted in elevated absolute counts of CD4+ (P = 0.002) and CD8+ (P < 0.001) T cells as well as CD4+ and CD8+ cells bearing HLA-DR (P < 0.01). The long-term administration of ibrutinib was associated with the increased numbers of CD4+ bearing HLA-DR (P = 0.006) and elevation of HLA-DR expression on all monocyte subsets (P ≤ 0.004). Our results provide the first evidence of the time-dependent immunomodulatory effect of ibrutinib on CLL and T cells and monocytes. The clinical consequences of time-dependent changes in HLA-DR expression in ibrutinib treated patients deserve further investigation.
- MeSH
- časové faktory MeSH
- CD4-pozitivní T-lymfocyty metabolismus patologie MeSH
- CD8-pozitivní T-lymfocyty metabolismus patologie MeSH
- chronická lymfatická leukemie * farmakoterapie metabolismus patologie MeSH
- HLA-DR antigeny biosyntéza MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové proteiny biosyntéza MeSH
- pyrazoly aplikace a dávkování MeSH
- pyrimidiny aplikace a dávkování MeSH
- regulace genové exprese u leukemie účinky léků MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Recent studies have identified molecular events characteristic of immunogenic cell death (ICD), including surface exposure of calreticulin (CRT), the heat shock proteins HSP70 and HSP90, the release of high-mobility group box protein 1 (HMGB1) and the release of ATP from dying cells. We investigated the potential of high hydrostatic pressure (HHP) to induce ICD in human tumor cells. HHP induced the rapid expression of HSP70, HSP90 and CRT on the cell surface. HHP also induced the release of HMGB1 and ATP. The interaction of dendritic cells (DCs) with HHP-treated tumor cells led to a more rapid rate of DC phagocytosis, upregulation of CD83, CD86 and HLA-DR and the release of interleukin IL-6, IL-12p70 and TNF-α. DCs pulsed with tumor cells killed by HHP induced high numbers of tumor-specific T cells. DCs pulsed with HHP-treated tumor cells also induced the lowest number of regulatory T cells. In addition, we found that the key features of the endoplasmic reticulum stress-mediated apoptotic pathway, such as reactive oxygen species production, phosphorylation of the translation initiation factor eIF2α and activation of caspase-8, were activated by HHP treatment. Therefore, HHP acts as a reliable and potent inducer of ICD in human tumor cells.
- MeSH
- adenosintrifosfát sekrece MeSH
- aktivace enzymů imunologie MeSH
- antigeny CD86 biosyntéza MeSH
- apoptóza imunologie MeSH
- CD antigeny biosyntéza MeSH
- dendritické buňky imunologie MeSH
- eukaryotický iniciační faktor 2 metabolismus MeSH
- fagocytóza imunologie MeSH
- fosforylace MeSH
- HLA-DR antigeny biosyntéza MeSH
- hydrostatický tlak MeSH
- imunoglobuliny biosyntéza MeSH
- interleukin-12 sekrece MeSH
- interleukin-6 sekrece MeSH
- kalretikulin biosyntéza imunologie MeSH
- kaspasa 8 metabolismus MeSH
- lidé MeSH
- membránové glykoproteiny biosyntéza MeSH
- membránové proteiny biosyntéza MeSH
- nádorové buněčné linie MeSH
- nádory imunologie MeSH
- protein HMGB1 imunologie sekrece MeSH
- proteiny tepelného šoku HSP70 biosyntéza imunologie MeSH
- proteiny tepelného šoku HSP90 biosyntéza imunologie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- regulační T-lymfocyty imunologie MeSH
- stres endoplazmatického retikula imunologie MeSH
- TNF-alfa sekrece MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
HIV-specific and non-specific immune responses are crucial in the immunopathogenesis of HIV infection. Therefore, the objective of our study was to analyse the frequency and functional status of HIV-specific CD8+ T cells and the expression of non-specific activation markers on CD8+ T cells in HIV+ patients, and to assess the effects of combined antiretroviral treatment (cART). We examined 28 HIV+ patients, including 13 patients not receiving therapy and 15 patients on cART therapy using ELISpot assay and flow cytometry with intracellular and MHC tetramer staining. MHC tetramers detected HIV-specific CD8+ T cells in 6 HIV+ patients on cART and in 7 untreated individuals; the ELISpot method detected these cells in 5 untreated HIV+ individuals only. Reduced intracellular IFN-γ and IL-2 production by HIV-specific CD8+ T cells was detected in both treated and untreated HIV+ patients, and multifunctional CD8+ T cells simultaneously producing these cytokines were not found in any patient. In contrary to these findings, the percentage of CD8+ T cells expressing CD38 and HLA-DR was significantly higher in untreated patients as compared to HIV+ patients on cART. Together, these results suggest that the alterations of HIV-specific immunity are not influenced by the therapy of HIV infection; whereas, the non-specific chronic immune activation is down-regulated by cART.
- MeSH
- antigeny CD38 biosyntéza MeSH
- CD8-pozitivní T-lymfocyty imunologie MeSH
- dospělí MeSH
- ELISPOT MeSH
- HIV infekce farmakoterapie imunologie MeSH
- HIV imunologie MeSH
- HLA-DR antigeny biosyntéza MeSH
- interferon gama biosyntéza MeSH
- interleukin-2 biosyntéza MeSH
- látky proti HIV aplikace a dávkování MeSH
- lidé středního věku MeSH
- lidé MeSH
- membránové glykoproteiny biosyntéza MeSH
- průtoková cytometrie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVES: The presence of MRI lesions at the first demyelinating event increases the risk of developing clinically definite multiple sclerosis (MS). The HLA DRB1*1501 genotype is linked to MS susceptibility but its relationship to quantitative MRI parameters at the first demyelinating event has not been assessed. The objectives were to assess the associations between HLA DRB1*1501 status and magnetic resonance imaging (MRI) measures in clinically isolated syndromes (CIS) at the first demyelinating event. METHODS: We genotyped 205 CIS patients (age: 29.0±7.7 years) enrolled in the Observational Study of Early Interferon beta 1-a Treatment in High Risk Subjects after CIS (SET study), a multi-center, clinical study of CIS for rs3135005, a single nucleotide polymorphism associated with HLA DRB1*1501 status. The inclusion criteria required 2 or more brain MRI lesions and the presence of two or more oligoclonal bands in cerebrospinal fluid. Clinical and MRI assessments were obtained within 4 months of the initial demyelinating event. RESULTS: The frequency of HLA DRB1*1501 positivity was 102/205 (49.7%). HLA DRB1*1501 positivity was associated with higher contrast-enhancing (CE) lesion number (p=0.002), higher CE-lesion volume (LV) (p<0.001) and exhibited a trend with higher T2-LV (p=0.012). There was no evidence for significant associations of HLA DRB1*1501 positivity with disability, symptoms at CIS presentation, whole brain, white and gray matter atrophy. CONCLUSIONS: HLA DRB1*1501 positivity is associated with increased brain inflammatory processes at first clinical onset. However, the effect sizes of the HLA DRB1*1501 associations with MRI are modest, which potentially limits the clinical usefulness.
- MeSH
- demyelinizační nemoci farmakoterapie imunologie patologie MeSH
- dospělí MeSH
- HLA-DR antigeny biosyntéza MeSH
- HLA-DRB1 řetězec MeSH
- interferon beta aplikace a dávkování terapeutické užití MeSH
- jednonukleotidový polymorfismus genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- longitudinální studie MeSH
- magnetická rezonanční tomografie MeSH
- mladiství MeSH
- mladý dospělý MeSH
- následné studie MeSH
- prospektivní studie MeSH
- roztroušená skleróza farmakoterapie imunologie patologie MeSH
- zánět farmakoterapie imunologie patologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- srovnávací studie MeSH
