BACKGROUND: Teplizumab, a humanized monoclonal antibody to CD3 on T cells, is approved by the Food and Drug Administration to delay the onset of clinical type 1 diabetes (stage 3) in patients 8 years of age or older with preclinical (stage 2) disease. Whether treatment with intravenous teplizumab in patients with newly diagnosed type 1 diabetes can prevent disease progression is unknown. METHODS: In this phase 3, randomized, placebo-controlled trial, we assessed β-cell preservation, clinical end points, and safety in children and adolescents who were assigned to receive teplizumab or placebo for two 12-day courses. The primary end point was the change from baseline in β-cell function, as measured by stimulated C-peptide levels at week 78. The key secondary end points were the insulin doses that were required to meet glycemic goals, glycated hemoglobin levels, time in the target glucose range, and clinically important hypoglycemic events. RESULTS: Patients treated with teplizumab (217 patients) had significantly higher stimulated C-peptide levels than patients receiving placebo (111 patients) at week 78 (least-squares mean difference, 0.13 pmol per milliliter; 95% confidence interval [CI], 0.09 to 0.17; P<0.001), and 94.9% (95% CI, 89.5 to 97.6) of patients treated with teplizumab maintained a clinically meaningful peak C-peptide level of 0.2 pmol per milliliter or greater, as compared with 79.2% (95% CI, 67.7 to 87.4) of those receiving placebo. The groups did not differ significantly with regard to the key secondary end points. Adverse events occurred primarily in association with administration of teplizumab or placebo and included headache, gastrointestinal symptoms, rash, lymphopenia, and mild cytokine release syndrome. CONCLUSIONS: Two 12-day courses of teplizumab in children and adolescents with newly diagnosed type 1 diabetes showed benefit with respect to the primary end point of preservation of β-cell function, but no significant differences between the groups were observed with respect to the secondary end points. (Funded by Provention Bio and Sanofi; PROTECT ClinicalTrials.gov number, NCT03875729.).
- MeSH
- antigeny CD3 antagonisté a inhibitory imunologie MeSH
- beta-buňky účinky léků imunologie MeSH
- C-peptid analýza MeSH
- diabetes mellitus 1. typu * diagnóza imunologie terapie MeSH
- dítě MeSH
- dvojitá slepá metoda MeSH
- humanizované monoklonální protilátky * škodlivé účinky farmakologie terapeutické užití MeSH
- hypoglykemika aplikace a dávkování terapeutické užití MeSH
- inzulin aplikace a dávkování terapeutické užití MeSH
- lidé MeSH
- mladiství MeSH
- progrese nemoci MeSH
- T-lymfocyty účinky léků imunologie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie MeSH
- Klíčová slova
- autoimunitní regulátor,
- MeSH
- antigen prezentující buňky imunologie MeSH
- antigeny imunologie klasifikace MeSH
- autoimunitní polyglandulární syndromy genetika imunologie klasifikace MeSH
- dendritické buňky imunologie MeSH
- imunologická tolerance * imunologie MeSH
- lidé MeSH
- specificita protilátek imunologie MeSH
- T-lymfocyty imunologie klasifikace MeSH
- thymus imunologie růst a vývoj MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND: KMT2A-rearranged acute lymphoblastic leukemia (ALL) in infants is an aggressive disease with 3-year event-free survival below 40%. Most relapses occur during treatment, with two thirds occurring within 1 year and 90% within 2 years after diagnosis. Outcomes have not improved in recent decades despite intensification of chemotherapy. METHODS: We studied the safety and efficacy of blinatumomab, a bispecific T-cell engager molecule targeting CD19, in infants with KMT2A-rearranged ALL. Thirty patients younger than 1 year of age with newly diagnosed KMT2A-rearranged ALL were given the chemotherapy used in the Interfant-06 trial with the addition of one postinduction course of blinatumomab (15 μg per square meter of body-surface area per day; 28-day continuous infusion). The primary end point was clinically relevant toxic effects, defined as any toxic effect that was possibly or definitely attributable to blinatumomab and resulted in permanent discontinuation of blinatumomab or death. Minimal residual disease (MRD) was measured by polymerase chain reaction. Data on adverse events were collected. Outcome data were compared with historical control data from the Interfant-06 trial. RESULTS: The median follow-up was 26.3 months (range, 3.9 to 48.2). All 30 patients received the full course of blinatumomab. No toxic effects meeting the definition of the primary end point occurred. Ten serious adverse events were reported (fever [4 events], infection [4], hypertension [1], and vomiting [1]). The toxic-effects profile was consistent with that reported in older patients. A total of 28 patients (93%) either were MRD-negative (16 patients) or had low levels of MRD (<5×10-4 [i.e., <5 leukemic cells per 10,000 normal cells], 12 patients) after the blinatumomab infusion. All the patients who continued chemotherapy became MRD-negative during further treatment. Two-year disease-free survival was 81.6% in our study (95% confidence interval [CI], 60.8 to 92.0), as compared with 49.4% (95% CI, 42.5 to 56.0) in the Interfant-06 trial; the corresponding values for overall survival were 93.3% (95% CI, 75.9 to 98.3) and 65.8% (95% CI, 58.9 to 71.8). CONCLUSIONS: Blinatumomab added to Interfant-06 chemotherapy appeared to be safe and had a high level of efficacy in infants with newly diagnosed KMT2A-rearranged ALL as compared with historical controls from the Interfant-06 trial. (Funded by the Princess Máxima Center Foundation and others; EudraCT number, 2016-004674-17.).
- MeSH
- akutní lymfatická leukemie * farmakoterapie imunologie MeSH
- antitumorózní látky * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- kojenec MeSH
- lidé MeSH
- pre-B-buněčná leukemie farmakoterapie MeSH
- přežití po terapii bez příznaků nemoci MeSH
- protilátky bispecifické * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- reziduální nádor diagnóza MeSH
- T-lymfocyty imunologie MeSH
- výsledek terapie MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
Achieving fast immunosuppression blood exposure after kidney transplantation is key to abrogating both preformed and de novo anti-donor humoral and cellular alloresponses. However, while tacrolimus (TAC) is the cornerstone immunosuppressant inhibiting adaptive alloimmunity, its blood exposure is directly impacted by different single-nucleotide polymorphisms (SNPs) in CYP3A TAC-metabolizing enzymes. Here, we investigated how functional TAC-CYP3A genetic variants (CYP3A4*22/CYP3A5*3) influence the main baseline clinical and immunological risk factors of biopsy-proven acute rejection (BPAR) by means of preformed donor-specific antibodies (DSAs) and donor-specific alloreactive T cells (DSTs) in a large European cohort of 447 kidney transplants receiving TAC-based immunosuppression. A total of 70 (15.7%) patients developed BPAR. Preformed DSAs and DSTs were observed in 12 (2.7%) and 227 (50.8%) patients, respectively. According to the different CYP3A4*22 and CYP3A5*3 functional allele variants, we found 4 differential new clusters impacting fasting TAC exposure after transplantation; 7 (1.6%) were classified as high metabolizers 1 (HM1), 71 (15.9%) as HM2, 324 (72.5%) as intermediate (IM), and 45 (10.1%) as poor metabolizers (PM1). HM1/2 showed significantly lower TAC trough levels and higher dose requirements than IM and PM (p < 0.001) and more frequently showed TAC underexposure (<5 ng/ml). Multivariate Cox regression analyses revealed that CYP3A HM1 and IM pharmacogenetic phenotypes (hazard ratio (HR) 12.566, 95% CI 1.99-79.36, p = 0.007, and HR 4.532, 95% CI 1.10-18.60, p = 0.036, respectively), preformed DSTs (HR 3.482, 95% CI 1.99-6.08, p < 0.001), DSAs (HR 4.421, 95% CI 1.63-11.98, p = 0.003), and delayed graft function (DGF) (HR 2.023, 95% CI 1.22-3.36, p = 0.006) independently predicted BPAR. Notably, a significant interaction between T-cell depletion and TAC underexposure was observed, showing a reduction of the BPAR risk (HR 0.264, 95% CI 0.08-0.92, p = 0.037). Such variables except for DSAs displayed a higher predictive risk for the development of T cell-mediated rejection (TCMR). Refinement of pretransplant monitoring by incorporating TAC CYP3A SNPs with preformed DSAs as well as DSTs may improve current rejection-risk stratification and help induction treatment decision-making.
- MeSH
- cytochrom P-450 CYP3A * genetika imunologie metabolismus MeSH
- hodnocení rizik MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- paměťové B-buňky * imunologie MeSH
- T-lymfocyty * imunologie MeSH
- takrolimus * farmakologie terapeutické užití MeSH
- transplantace ledvin * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- buněčná imunita * MeSH
- COVID-19 MeSH
- lidé MeSH
- T-lymfocyty imunologie MeSH
- thymus imunologie MeSH
- Check Tag
- lidé MeSH
- Klíčová slova
- cytopenie,
- MeSH
- analýza přežití MeSH
- chimerické antigenní receptory * imunologie terapeutické užití MeSH
- difúzní velkobuněčný B-lymfom terapie MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- nežádoucí účinky léčiv * MeSH
- statistika jako téma MeSH
- T-lymfocyty imunologie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
- MeSH
- chimerické antigenní receptory * imunologie terapeutické užití MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- mnohočetný myelom * mortalita terapie MeSH
- senioři MeSH
- statistika jako téma MeSH
- T-lymfocyty imunologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- dopisy MeSH
- MeSH
- akutní lymfatická leukemie * terapie MeSH
- analýza přežití MeSH
- antigeny CD19 * imunologie škodlivé účinky terapeutické užití MeSH
- chimerické antigenní receptory imunologie terapeutické užití MeSH
- lidé MeSH
- průtoková cytometrie MeSH
- recidiva MeSH
- statistika jako téma MeSH
- T-lymfocyty imunologie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- multicentrická studie MeSH
- MeSH
- analýza genové exprese jednotlivých buněk metody přístrojové vybavení MeSH
- analýza přežití MeSH
- chimerické antigenní receptory * imunologie terapeutické užití MeSH
- doba přežití bez progrese choroby MeSH
- lidé MeSH
- maturační antigen B-buněk imunologie účinky léků MeSH
- mnohočetný myelom * terapie MeSH
- nežádoucí účinky léčiv epidemiologie MeSH
- syndrom uvolnění cytokinů chemicky indukované epidemiologie MeSH
- T-lymfocyty imunologie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- klinická studie MeSH
- práce podpořená grantem MeSH
Nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic NDD. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.
- MeSH
- chromatin chemie imunologie MeSH
- dítě MeSH
- faktor C1 hostitelské buňky genetika imunologie MeSH
- heterozygot MeSH
- histony genetika imunologie MeSH
- kojenec MeSH
- lidé MeSH
- missense mutace * MeSH
- mladiství MeSH
- mutace ztráty funkce * MeSH
- nádorové supresorové proteiny nedostatek genetika imunologie MeSH
- neurovývojové poruchy genetika imunologie patologie MeSH
- předškolní dítě MeSH
- proteasomový endopeptidasový komplex genetika imunologie MeSH
- protein BRCA1 genetika imunologie MeSH
- regulace genové exprese MeSH
- restrukturace chromatinu genetika imunologie MeSH
- rodina MeSH
- T-lymfocyty imunologie patologie MeSH
- thiolesterasa ubikvitinu nedostatek genetika imunologie MeSH
- ubikvitin genetika imunologie MeSH
- ubikvitinace MeSH
- ubikvitinligasy genetika imunologie MeSH
- zárodečné mutace * MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH