ABSTRACT
We have recently described a specialized subset of human natural killer (NK) cells with a CD56(dim)CD57(+)NKG2C(+) phenotype that expand specifically in response to cytomegalovirus (CMV) reactivation in hematopoietic cell transplant (HCT) recipients and exhibit properties characteristic of adaptive immunity. We hypothesize that these cells mediate relapse protection and improve post-HCT outcomes. In 674 allogeneic HCT recipients, we found that those who reactivated CMV had lower leukemia relapse (26% (17-35%), P=0.05) and superior disease-free survival (DFS) (55% (45-65%) P=0.04) 1 year after reduced intensity conditioning (RIC) compared with CMV seronegative recipients who experienced higher relapse rates (35% (27-43%)) and lower DFS (46% (38-54%)). This protective effect was independent of age and graft-vs-host disease and was not observed in recipients who received myeloablative regimens. Analysis of the reconstituting NK cells demonstrated that CMV reactivation is associated with both higher frequencies and greater absolute numbers of CD56(dim)CD57(+)NKG2C(+) NK cells, particularly after RIC HCT. Furthermore, expansion of these cells at 6 months posttransplant independently trended toward a lower 2-year relapse risk. Together, our data suggest that the protective effect of CMV reactivation on posttransplant relapse is in part driven by adaptive NK cell responses.
Subject(s)
CD56 Antigen/analysis , CD57 Antigens/analysis , Hematopoietic Stem Cell Transplantation , Killer Cells, Natural/immunology , Leukemia/therapy , NK Cell Lectin-Like Receptor Subfamily C/analysis , Adolescent , Adult , Cell Line, Tumor , Cytomegalovirus/physiology , Female , Humans , Leukemia/immunology , Leukemia/virology , Male , Middle Aged , Monocytes/physiology , Recurrence , Virus ActivationABSTRACT
Human NK cells express cell surface class I MHC receptors (killer cell immunoglobulin-like receptor, KIR) in a probabilistic manner. Previous studies have shown that a distal promoter acts in conjunction with a proximal bidirectional promoter to control the selective activation of KIR genes. We report here the presence of an intron 2 promoter in several KIR genes that produce a spliced antisense transcript. This long noncoding RNA (lncRNA) transcript contains antisense sequence complementary to KIR-coding exons 1 and 2 as well as the proximal promoter region of the KIR genes. The antisense promoter contains myeloid zinc finger 1 (MZF-1)-binding sites, a transcription factor found in hematopoietic progenitors and myeloid precursors. The KIR antisense lncRNA was detected only in progenitor cells or pluripotent cell lines, suggesting a function that is specific for stem cells. Overexpression of MZF-1 in developing NK cells led to decreased KIR expression, consistent with a role for the KIR antisense lncRNA in silencing KIR gene expression early in development.
Subject(s)
Embryonic Stem Cells/metabolism , Pluripotent Stem Cells/metabolism , RNA, Long Noncoding/genetics , Receptors, KIR/genetics , Binding Sites , Exons , Gene Silencing , HEK293 Cells , HeLa Cells , Humans , Introns , Kruppel-Like Transcription Factors/chemistry , Kruppel-Like Transcription Factors/metabolism , Promoter Regions, Genetic , RNA, Antisense/chemistry , RNA, Antisense/genetics , RNA, Antisense/metabolism , RNA, Long Noncoding/chemistry , RNA, Long Noncoding/metabolism , Receptors, KIR/metabolismSubject(s)
Infant, Low Birth Weight , Maternal Exposure/adverse effects , Pregnancy Trimester, First , Radiation Injuries/etiology , Thyroid Gland/radiation effects , X-Rays/adverse effects , Adult , Birth Weight , Dose-Response Relationship, Radiation , Female , Humans , Infant, Newborn , Male , Pregnancy , Radiation Injuries/epidemiologyABSTRACT
The effective dose (ED) and the organ dose given with Computer Tomography (CT) scanners can be determined by means of a computing method suggested by the English National Radiological Protection Board (NRPB). This method uses the integral air-dose profile as input. Due to the non-rectangular shape of the CT profiles, a Computer Tomography Dose Index (CTDI) has been defined, as the integral dose profile divided by nominal slice thickness. The experimental determination of the CTDI can be carried out with thermoluminescent dosimeters. However, the measurement can be simplified by using a cylindrical ion chamber. This paper reports the calibration of a PMO5 ion chamber (5 cm3 in volume and 5 cm in length) in terms of sensitivity value (4.45 pC mGy-1 mm-1). CTDI measurements by means of a PMO5 ion chamber were used to determine the effective doses and lung doses for the CT scanners used at the Institute of Radiology of the Catholic University in Rome. The dose levels thus obtained are in agreement with other national and international data. Moreover, the method allows the differences in the doses absorbed by the patients submitted to CT with different technical approaches to be calculated.
Subject(s)
Radiation Dosage , Radiometry/instrumentation , Tomography, X-Ray Computed , Humans , Lung/radiation effects , Models, Theoretical , Radiation Monitoring , Thermoluminescent DosimetryABSTRACT
Tomographic images with electronic density can be obtained by irradiation with a monoenergetic beam and detection of the scattered Compton photons. The results of a dosimetric study on the beam of an irradiating Compton unit (equipped with two 192Ir 277.5 GBq sources) are here presented. Doses along the central axis of the beam were measured using thermoluminescent LIF-100 dosimeters. Measurements were taken both in water (RFA-3 Therados) and in cork phantoms. Isodose distributions were estimated by reading the automatic photo-densitometry of radiographic films. A simple algorithm for calculating depth dose values was obtained by analyzing experimental data. The mean absorbed dose (mad) in soft tissues (up to 25 cm deep) was 2.81 mGy for a work load of 7.4 X 10(11) Bq min. The mad in standard thorax was calculated also, which amounted to 3.78 mGy.
