NK cells, lymphocytes of the innate immune system, are important for defense against infectious pathogens and cancer. Classically, the CD56dim NK cell subset is thought to mediate antitumor ...responses, whereas the CD56bright subset is involved in immunomodulation. Here, we challenge this paradigm by demonstrating that brief priming with IL-15 markedly enhanced the antitumor response of CD56bright NK cells. Priming improved multiple CD56bright cell functions: degranulation, cytotoxicity, and cytokine production. Primed CD56bright cells from leukemia patients demonstrated enhanced responses to autologous blasts in vitro, and primed CD56bright cells controlled leukemia cells in vivo in a murine xenograft model. Primed CD56bright cells from multiple myeloma (MM) patients displayed superior responses to autologous myeloma targets, and furthermore, CD56bright NK cells from MM patients primed with the IL-15 receptor agonist ALT-803 in vivo displayed enhanced ex vivo functional responses to MM targets. Effector mechanisms contributing to IL-15-based priming included improved cytotoxic protein expression, target cell conjugation, and LFA-1-, CD2-, and NKG2D-dependent activation of NK cells. Finally, IL-15 robustly stimulated the PI3K/Akt/mTOR and MEK/ERK pathways in CD56bright compared with CD56dim NK cells, and blockade of these pathways attenuated antitumor responses. These findings identify CD56bright NK cells as potent antitumor effectors that warrant further investigation as a cancer immunotherapy.
Cyanoformaldehyde (CNCHO) has been detected toward the star-forming region Sagittarius B2(N) with the 100 m Green Bank Telescope (GBT) by means of four P-branch rotational transitions in emission, ...the 7(0, 7)-6(1, 6) at 8.6 GHz, the 8(0, 8)-7(1, 7) at 19.4 GHz, the 9(0, 9)-8(1, 8) at 30.3 GHz, and the 10(0, 10)-9(1, 9) at 41.3 GHz, and one P-branch transition in absorption, the 5(1, 5)-6(0, 6) at 2.1 GHz. The five b-type transitions have favorable transition line strengths (S unk mu super(2) > 10 D super(2)) and occur in spectral regions that have little possibility of confusion with other molecular species. The transition line strengths and energy levels involved in the four cyanoformaldehyde transitions in emission are similar; however, transitions with larger beam sizes give systematically higher column densities, suggesting that CNCHO is spatially extended and not concentrated toward the Sgr B2(N-LMH) position. Moreover, with a GBT beamwidth of similar to 350 unk, the 5(1, 5)-6(0, 6) transition of CNCHO was detected in absorption, confirming the widespread spatial extent of this molecule. We suggest that cyanoformaldehyde is likely formed in a neutral-radical reaction of two other interstellar molecules known for widespread spatial distributions: formaldehyde (H sub(2)CO) and the cyanide (CN) radical.
In 2003, Kuan and coworkers reported the detection of interstellar glycine (NH sub(2)CH sub(2)COOH) based on observations of 27 lines in 19 different spectral bands in one or more of the sources Sgr ...B2(N-LMH), Orion KL, and W51 e1/e2. They supported their detection report with rotational temperature diagrams for all three sources. In this paper we present essential criteria that can be used in a straightforward analysis technique to confirm the identity of an interstellar asymmetric rotor such as glycine. We use new laboratory measurements of glycine as a basis for applying this analysis technique, both to our previously unpublished 12 m telescope data and to the previously published Swedish-ESO Submillimetre Telescope (SEST) data of Nummelin and colleagues. We conclude that key lines necessary for an interstellar glycine identification have not yet been found. We identify some common molecular candidates that should be examined further as more likely carriers of several of the lines reported as glycine. Finally, we illustrate that a rotational temperature diagram used without the support of correct spectroscopic assignments is not a reliable tool for the identification of interstellar molecules.
Background: Current understanding of T cell epitopes in coeliac disease (CD) largely derives from intestinal T cell clones in vitro. T cell clones allow identification of gluten peptides that ...stimulate T cells but do not quantify their contribution to the overall gluten specific T cell response in individuals with CD when exposed to gluten in vivo. Aims: To determine the contribution of a putative dominant T cell epitope to the overall gliadin T cell response in HLA-DQ2 CD in vivo. Patients: HLA-DQ2+ individuals with CD and healthy controls. Methods: Subjects consumed 20 g of gluten daily for three days. Interferon γ (IFN-γ) ELISPOT was performed using peripheral blood mononuclear cells (PBMC) to enumerate and characterise peptide and gliadin specific T cells before and after gluten challenge. Results: In 50/59 CD subjects, irrespective of homo- or heterozygosity for HLA-DQ2, IFN-γ ELISPOT responses for an optimal concentration of A-gliadin 57–73 Q-E65 were between 10 and 1500 per million PBMC, equivalent to a median 51% of the response for a “near optimal” concentration of deamidated gliadin. Whole deamidated gliadin and gliadin epitope specific T cells induced in peripheral blood expressed an intestinal homing integrin (α4β7) and were HLA-DQ2 restricted. Peripheral blood T cells specific for A-gliadin 57–73 Q-E65 are rare in untreated CD but can be predictably induced two weeks after gluten exclusion. Conclusion: In vivo gluten challenge is a simple safe method that allows relevant T cells to be analysed and quantified in peripheral blood by ELISPOT, and should permit comprehensive high throughput mapping of gluten T cell epitopes in large numbers of individuals with CD.
Celiac disease (CD) is an increasingly diagnosed enteropathy (prevalence, 1:200-1:300) that is induced by dietary exposure to wheat gliadins (as well as related proteins in rye and barley) and is ...strongly associated with HLA-DQ2 (alpha1*0501, beta1*0201), which is present in over 90% of CD patients. Because a variety of gliadin peptides have been identified as epitopes for gliadin-specific T-cell clones and as bioactive sequences in feeding studies and in ex vivo CD intestinal biopsy challenge, it has been unclear whether a 'dominant' T-cell epitope is associated with CD. Here, we used fresh peripheral blood lymphocytes from individual subjects undergoing short-term antigen challenge and tissue transglutaminase-treated, overlapping synthetic peptides spanning A-gliadin to demonstrate a transient, disease-specific, DQ2-restricted, CD4 T-cell response to a single dominant epitope. Optimal gamma interferon release in an ELISPOT assay was elicited by a 17-amino-acid peptide corresponding to the partially deamidated peptide of A-gliadin amino acids 57-73 (Q65E). Consistent with earlier reports indicating that host tissue transglutaminase modification of gliadin enhances gliadin-specific CD T-cell responses, tissue transglutaminase specifically deamidated Q65 in the peptide of A-gliadin amino acids 56-75. Discovery of this dominant epitope may allow development of antigen-specific immunotherapy for CD.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We present strong detections of methyl cyanide (CH sub(3)CN), vinyl cyanide (CH sub(2)CHCN), ethyl cyanide (CH sub(3)CH sub(2)CN), and cyanodiacetylene (HC sub(4)CN) molecules with the Green Bank ...Telescope (GBT) toward the Sgr B2(N) molecular cloud. Attempts to detect the corresponding isocyanide isomers were only successful in the case of methyl isocyanide (CH sub(3)NC) for its J sub(K) = 1 sub(0)-0 sub(0) transition, which is the first interstellar report of this line. To determine the spatial distribution of CH sub(3)NC, we used archival Berkeley-Illinois-Maryland Association (BIMA) array data for the J sub(K) = 4 sub(K)-3 sub(K) (K = 0-3) transitions, but no emission was detected. From ab initio calculations, the bonding energy difference between the cyanide and isocyanide molecules is >8500 cm super(-1) (>12,000 K). Thus, cyanides are the more stable isomers and would likely be formed more preferentially over their isocyanide counterparts. That we detect CH sub(3)NC emission with a single antenna (Gaussian beam size sub(B) = 1723 arcsec super(2)) but not with an interferometer ( sub(B) = 192 arcsec super(2)) strongly suggests that CH sub(3)NC has a widespread spatial distribution toward the Sgr B2(N) region. Other investigators have shown that CH sub(3)CN is present both in the LMH hot core of Sgr B2(N) and in the surrounding medium, while we have shown that CH sub(3)NC appears to be deficient in the LMH hot core. Thus, large-scale, nonthermal processes in the surrounding medium may account for the conversion of CH sub(3)CN to CH sub(3)NC, while the LMH hot core, which is dominated by thermal processes, does not produce a significant amount of CH sub(3)NC. Ice analog experiments by other investigators have shown that radiation bombardment of CH sub(3)CN can produce CH sub(3)NC, thus supporting our observations. We conclude that isomers separated by such large bonding energy differences are distributed in different interstellar environments, making the evaluation of column density ratios between such isomers irrelevant unless it can be independently shown that these species are cospatial.
PDF
