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1.
HLA ; 2018 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-29943500

RESUMO

Natural killer cells are thought to influence the outcome of hematopoietic stem cell transplant (HSCT), impacting on relapse, overall survival, graft versus host disease and the control of infection, in part through the complex interplay between the large and genetically diverse killer immunoglobulin-like receptor (KIR) family and their ligands. This study examined the relationship between KIR gene content and clinical outcomes including the control of opportunistic infections such as cytomegalovirus in the setting of human leucocyte antigen (HLA)-matched sibling HSCT in an Australian cohort. The presence of the KIR B haplotype which contain more activating receptors in the donor, in particular centromeric B haplotype genes (Cen-B), was associated with improved overall survival of patients with acute myeloid leukemia (AML) undergoing sibling HSCT and receiving myeloablative conditioning. Donor Cen-B haplotype was also associated with reduced acute graft versus host disease grades II-IV whereas donor telomeric-B haplotype was associated with decreased incidence of CMV reactivation. In contrast, we were not able to demonstrate a reduced rate of relapse when the donor had KIR Cen-B, however relapse with a donor Cen-A haplotype was a competing risk factor to poor overall survival. Here we show that the presence of donor activating KIR led to improved outcome for the patient, potentially through reduced relapse rates and decreased incidence of acute GvHD translating to improved overall survival. This article is protected by copyright. All rights reserved.

2.
Br J Pharmacol ; 170(3): 532-45, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23826915

RESUMO

BACKGROUND AND PURPOSE: Paliperidone is an active metabolite of the second-generation atypical antipsychotic, risperidone recently approved for the treatment of schizophrenia and schizoaffective disorder. Because paliperidone differs from risperidone by only a single hydroxyl group, questions have been raised as to whether there are significant differences in the effects elicited between these two drugs. EXPERIMENTAL APPROACH: We compared the relative efficacies of paliperidone versus risperidone to regulate several cellular signalling pathways coupled to four selected GPCR targets that are important for either therapeutic or adverse effects: human dopamine D2 , human serotonin 2A receptor subtype (5-HT2A ), human serotonin 2C receptor subtype and human histamine H1 receptors. KEY RESULTS: Whereas the relative efficacies of paliperidone and risperidone were the same for some responses, significant differences were found for several receptor-signalling systems, with paliperidone having greater or less relative efficacy than risperidone depending upon the receptor-response pair. Interestingly, for 5-HT2A -mediated recruitment of ß-arrestin, 5-HT2A -mediated sensitization of ERK, and dopamine D2 -mediated sensitization of adenylyl cyclase signalling, both paliperidone and risperidone behaved as agonists. CONCLUSIONS AND IMPLICATIONS: These results suggest that the single hydroxyl group of paliperidone promotes receptor conformations that can differ from those of risperidone leading to differences in the spectrum of regulation of cellular signal transduction cascades. Such differences in signalling at the cellular level could lead to differences between paliperidone and risperidone in therapeutic efficacy or in the generation of adverse effects.


Assuntos
Antipsicóticos/farmacologia , Isoxazóis/farmacologia , Pirimidinas/farmacologia , Risperidona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Adenilil Ciclases/metabolismo , Animais , Antipsicóticos/química , Arrestinas/metabolismo , Células CHO , Cricetinae , Cricetulus , Agonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Agonismo Inverso de Drogas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Agonistas dos Receptores Histamínicos/farmacologia , Humanos , Isoxazóis/química , Estrutura Molecular , Palmitato de Paliperidona , Pirimidinas/química , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Receptor 5-HT2C de Serotonina/genética , Receptor 5-HT2C de Serotonina/metabolismo , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Receptores Histamínicos H1/efeitos dos fármacos , Receptores Histamínicos H1/genética , Receptores Histamínicos H1/metabolismo , Risperidona/química , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-Atividade , Transfecção , beta-Arrestinas
3.
Tissue Antigens ; 72(5): 415-24, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18946929

RESUMO

The non-classical major histocompatibility complex (MHC) class I molecule human leucocyte antigen (HLA)-E is the least polymorphic of all the MHC class I molecules and acts as a ligand for receptors of both the innate and the adaptive immune systems. The recognition of self-peptides complexed to HLA-E by the CD94-NKG2A receptor expressed by natural killer (NK) cells represents a crucial checkpoint for immune surveillance by NK cells. However, HLA-E can also be recognised by the T-cell receptor expressed by alphabeta CD8 T cells and therefore can play a role in the adaptive immune response to invading pathogens. The recent resolution of HLA-E in complex with both innate and adaptive ligands has provided insight into the dual role of this molecule in immunity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Antígenos HLA/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Células Matadoras Naturais/imunologia , Subfamília D de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Antígenos HLA/química , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunidade Ativa/imunologia , Imunidade Inata/imunologia , Células Matadoras Naturais/metabolismo , Subfamília D de Receptores Semelhantes a Lectina de Células NK/imunologia , Polimorfismo Genético , Domínios e Motivos de Interação entre Proteínas/fisiologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Células Matadoras Naturais/imunologia , Receptores de Células Matadoras Naturais/metabolismo , Antígenos HLA-E
4.
Am J Physiol Regul Integr Comp Physiol ; 281(3): R770-7, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11506991

RESUMO

Pulmonary surfactant (PS), a mixture of phospholipids and proteins secreted by alveolar type II cells, functions to reduce the surface tension in the lungs of all air-breathing vertebrates. Here we examine the control of PS during lung development in a homeothermic egg-laying vertebrate. In mammals, glucocorticoids and autonomic neurotransmitters contribute to the maturation of the surfactant system. We examined whether dexamethasone, epinephrine, and carbamylcholine hydrochloride (agonist for acetylcholine) increased the amount of PS secreted from cultured type II cells of the developing chicken lung. In particular, we wanted to establish whether dexamethasone would increase PS secretion through a process involving lung fibroblasts. We isolated and cocultured type II cells and lung fibroblasts from chickens after 16, 18, and 20 days of incubation and from hatchlings (day 21). Epinephrine stimulated phosphatidylcholine (PC) secretion at all stages, whereas dexamethasone stimulated secretion of PC at days 16 and 18. Carbamylcholine hydrochloride had no effect at any stage. This is the first study to establish the existence of similar cellular pathways regulating the development of surfactant in chickens and eutherian mammals, despite the vastly different birthing strategies and lung structure and function.


Assuntos
Dexametasona/farmacologia , Epinefrina/farmacologia , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/metabolismo , Surfactantes Pulmonares/metabolismo , Agonistas Adrenérgicos/farmacologia , Animais , Carbacol/farmacologia , Sobrevivência Celular , Células Cultivadas , Embrião de Galinha , Galinhas , Agonistas Colinérgicos/farmacologia , Técnicas de Cocultura , Meios de Cultivo Condicionados/química , Relação Dose-Resposta a Droga , Fibroblastos/metabolismo , Fibroblastos/ultraestrutura , Glucocorticoides/farmacologia , L-Lactato Desidrogenase/análise , Microscopia Eletrônica , Fosfatidilcolinas/análise , Fosfatidilcolinas/metabolismo , Alvéolos Pulmonares/ultraestrutura , Fatores de Tempo
5.
Physiol Biochem Zool ; 74(4): 493-501, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11436133

RESUMO

Pulmonary surfactant, consisting predominantly of phosphatidylcholine (PC), is secreted from Type II cells into the lungs of all air-breathing vertebrates, where it functions to reduce surface tension. In mammals, glucocorticoids and thyroid hormones contribute to the maturation of the surfactant system. It is possible that phylogeny, lung structure, and the environment may influence the development of the surfactant system. Here, we investigate the ontogeny of PC secretion from cocultured Type II cells and fibroblasts in the sea turtle, Chelonia mydas, following 58, 62, and 73 d of incubation and after hatching. The influence of glucocorticoids and thyroid hormones on PC secretion was also examined. Basal PC secretion was lowest at day 58 (3%) and reached a maximal secretion rate of 10% posthatch. Dexamethasone (Dex) alone stimulated PC secretion only at day 58. Triiodothyronine (T(3)) stimulated PC secretion in cells isolated from days 58 and 73 embryos and from hatchling turtles. A combination of Dex and T(3) stimulated PC secretion at all time points.


Assuntos
Pulmão/metabolismo , Fosfatidilcolinas/metabolismo , Surfactantes Pulmonares/metabolismo , Tartarugas/embriologia , Tartarugas/fisiologia , Animais , Peso Corporal , Técnicas de Cocultura , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Pulmão/citologia , Pulmão/embriologia , Masculino , Microscopia Eletrônica/veterinária , Tamanho do Órgão , Fosfatidilcolinas/análise , Surfactantes Pulmonares/análise , Tri-Iodotironina/farmacologia
7.
J Mol Evol ; 46(2): 131-8, 1998 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9452514

RESUMO

Surface tension is reduced at the air-liquid interface in the lung by a mixture of lipids and proteins termed pulmonary surfactant. This study is the first to provide evidence for the presence of a surfactant-specific protein (Surfactant Protein A-SP-A) in the gas-holding structures of representatives of all the major vertebrate groups. Western blot analysis demonstrated cross-reactivity between an antihuman SP-A antibody and material lavaged from lungs or swimbladders of members from all vertebrate groups. Immunocytochemistry localized this SP-A-like protein to the air spaces of lungs from the actinopterygiian fish and lungfish. Northern blot analysis indicated that regions of the mouse SP-A cDNA sequence are complementary to lung mRNA from all species examined. The presence of an SP-A-like protein and SP-A mRNA in members of all the major vertebrate groups implies that the surfactant system had a single evolutionary origin in the vertebrates. Moreover, the evolution of the surfactant system must have been a prerequisite for the evolution of airbreathing. The presence of SP-A in the goldfish swimbladder demonstrates a role for the surfactant system in an organ that is no longer used for airbreathing.


Assuntos
Evolução Molecular , Pulmão/metabolismo , Proteolipídeos/fisiologia , Surfactantes Pulmonares/fisiologia , Vertebrados , Animais , Northern Blotting , Western Blotting , Humanos , Imuno-Histoquímica , Proteína A Associada a Surfactante Pulmonar , Proteínas Associadas a Surfactantes Pulmonares
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