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1.
Expert Opin Ther Pat ; 30(3): 159-162, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31944149

RESUMO

Introduction: KIR is an inhibitory receptor expressed by natural killer cells that suppress the immune response against tumor cells. There is a great need to discover and develop new therapies focused on inhibiting the action of KIR and consequently improving the immune response in the various types of cancer. Authors of US9879082 and US2018208652 patents propose a method to eradicate cancer that utilizes anti-KIR antibody.Areas covered: US9879082 and US2018208652 patents describe an anti-KIR antibody, a pharmaceutical composition that contains it, and their application for cancer treatment, particularly, multiple myeloma and acute myeloid leukemia. Anti-KIR antibody is used to a dosage of 0.0003-3 mg antibody/kg patient weight, and is suspended in an isotonic solution consisting of sodium phosphate, sucrose, NaCl, and polysorbate 80.Expert opinion: The results of the clinical trials only support trials regarding the pharmacokinetic, pharmacodynamic, safety, and tolerability. In addition, these results demonstrate that treatment with the anti-KIR antibody can induce an antitumor response in cancer patients.


Assuntos
Anticorpos/administração & dosagem , Imunoterapia/métodos , Receptores KIR/antagonistas & inibidores , Animais , Anticorpos/imunologia , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/imunologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Patentes como Assunto , Receptores KIR/imunologia
2.
Immunogenetics ; 72(1-2): 37-47, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31781789

RESUMO

The Killer-cell Immunoglobulin-like Receptors (KIR) are encoded by a diverse group of genes, which are characterized by allelic polymorphism, gene duplications, and recombinations, which may generate recombinant entities. The number of reported macaque KIR sequences is steadily increasing, and these data illustrate a gene system that may match or exceed the complexity of the human KIR cluster. This report lists the names of quality controlled and annotated KIR genes/alleles with all the relevant references for two different macaque species: rhesus and cynomolgus macaques. Numerous recombinant KIR genes in these species necessitate a revision of some of the earlier-published nomenclature guidelines. In addition, this report summarizes the latest information on the Immuno Polymorphism Database (IPD)-NHKIR Database, which contains annotated KIR sequences from four non-human primate species.


Assuntos
Bases de Dados Factuais , Imunogenética , Macaca mulatta/genética , Polimorfismo Genético , Receptores KIR/genética , Receptores KIR/imunologia , Terminologia como Assunto , Animais
3.
Immunogenetics ; 71(10): 617-633, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31797008

RESUMO

The major histocompatibility complex (MHC) class I genes play a critical role within the immune system, both by the presentation of antigens from intracellular pathogens to immunocompetent cells and by the interaction with killer cell immunoglobulin-like receptors (KIR) on natural killer cells (NK cells). Genes of the MHC are highly diverse, and MHC variation can have effects on the immune functionality of individuals; hence, comparisons of MHC diversity among closely related phylogenetic taxa may give insight into the factors responsible for the shaping of its diversity. The four geographically separated chimpanzee subspecies differ in their overall genetic diversity, have different population histories, and are confronted with different pathogens in their natural habitat, all of which may affect MHC class I DNA sequence diversity. Here, we compare the MHC-B exon two DNA sequence diversity from 24 wild western and 46 wild eastern chimpanzees using necropsy and noninvasively collected fecal samples, respectively. We found a higher MHC-B exon two nucleotide diversity, in our western than eastern chimpanzees. The inclusion of previously published MHC-B exon two data from other western and eastern chimpanzees supported this finding. In addition, our results confirm and extend the finding of a very low C1 epitope frequency at eastern chimpanzee MHC-B molecules, which likely affects the ability of these molecules to interact with NK cells. While the understanding of the differing pathogen environments encountered by disparate populations of a species is a challenging endeavor, these findings highlight the potential for these pathogens to selectively shape immune system variation.


Assuntos
Variação Genética , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Receptores KIR/genética , Receptores KIR/imunologia , Animais , Frequência do Gene , Antígenos de Histocompatibilidade Classe I/classificação , Pan troglodytes , Filogenia , Receptores KIR/classificação
4.
S Afr Med J ; 109(8b): 29-34, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31662146

RESUMO

The major histocompatibility complex, known as the human leukocyte antigen (HLA) complex in humans, forms an integral component of adaptive T cell immunity by presenting self and non-self peptides to the T cell receptor, thereby allowing clonal expansion of responding peptide-specific CD4+ and CD8+ T cells. HLA likewise forms an integral part of the innate immune response through the binding of killer-cell immunoglobulin-like receptor (KIR) molecules, which regulate the response of natural killer (NK) cells. The HLA complex is found on the short arm of chromosome 6 and is the most polymorphic region in the human genome. Africans are genetically more diverse than other populations; however, information on HLA diversity among southern Africans, including South African populations, is limited. Paucity of African HLA data limits our understanding of disease associations, the ability to identify donor-recipient matches for transplantation and the development of disease-specific vaccines. This review discusses the importance of HLA in the clinical setting in South Africans and highlights how tools such as HLA imputation might augment standard HLA typing methods to increase our understanding of HLA diversity in our populations, which will better inform disease association studies, donor recruitment strategies into bone marrow registries and our understanding of human genetic diversity in South Africa.


Assuntos
Antígenos HLA/genética , Células Matadoras Naturais/imunologia , Receptores KIR/genética , Variação Genética , Antígenos HLA/imunologia , Humanos , Receptores KIR/imunologia , Sistema de Registros , África do Sul , Doadores de Tecidos
5.
Int J Mol Sci ; 20(14)2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31311121

RESUMO

Relapsed acute myeloid leukemia (AML) is a significant post-transplant complication lacking standard treatment and associated with a poor prognosis. Cellular therapy, which is already widely used as a treatment for several hematological malignancies, could be a potential treatment alternative. Natural killer (NK) cells play an important role in relapse control but can be inhibited by the leukemia cells highly positive for HLA class I. In order to restore NK cell activity after their ex vivo activation, NK cells can be combined with conditioning target cells. In this study, we tested NK cell activity against KG1a (AML cell line) with and without two types of pretreatment-Ara-C treatment that induced NKG2D ligands (increased activating signal) and/or blocking of HLA-KIR (killer-immunoglobulin-like receptors) interaction (decreased inhibitory signal). Both treatments improved NK cell killing activity. Compared with target cell killing of NK cells alone (38%), co-culture with Ara-C treated KG1a target cells increased the killing to 80%. Anti-HLA blocking antibody treatment increased the proportion of dead KG1a cells to 53%. Interestingly, the use of the combination treatment improved the killing potential to led to the death of 85% of KG1a cells. The combination of Ara-C and ex vivo activation of NK cells has the potential to be a feasible approach to treat relapsed AML after hematopoietic stem cell transplantation.


Assuntos
Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/terapia , Linhagem Celular Tumoral , Células Cultivadas , Ensaios Clínicos como Assunto , Citarabina/farmacologia , Humanos , Imunossupressores/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/transplante , Leucemia Mieloide Aguda/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptores KIR/imunologia , Transdução de Sinais
6.
Gastroenterology ; 157(4): 1067-1080.e9, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31229495

RESUMO

BACKGROUND & AIMS: Bile duct tumors are rare and have poor prognoses. Natural killer (NK) cells are frequent in human liver and infiltrate these tumors but do not control their progression. Responses of NK cells are regulated by NK immunoglobulin-like receptors (KIRs), which interact with HLA class I ligands. We aimed to characterize the features of the KIR gene loci and their ligands in patients with bile duct cancer (BDC). METHODS: We performed combined multidimensional characterization of genes that encode KIRs and their ligands in blood samples from patients with BDC from Sweden, followed for up to 8 years after diagnosis (n = 148), in 2 geographically matched cohorts of healthy individuals from Northern Europe (n = 204 and n = 900), and in healthy individuals from 6 geographically unrelated populations (n = 2917). We used real-time polymerase chain reaction, RNA sequencing, immunohistochemistry, and flow cytometry to evaluate NK-cell presence, as well as KIR and KIR-ligand expression in bile duct tumors and control tissues. RESULTS: Patients with bile duct tumors had multiple alterations at the KIR gene loci. KIR loci are grouped into genotypes that encode more inhibitory (group A) and more activating (group B) receptors, which can be subdivided into centromeric and telomeric fragments. Patients with BDC had a lower prevalence of KIR2DL3, which was linked to disequilibrium in centromeric A/B and B/B genotypes, compared with control individuals. The associations between KIRs and KIR ligands differed between patients with BDC and control individuals; patients had an altered balance between activating and inhibitory KIRs. KIR-positive NK cells infiltrated biliary tumors that expressed matched KIR ligands. CONCLUSIONS: In a multidimensional analysis of DNA from blood samples of patients with BDC in Europe, we found patients to have multiple alterations at the KIR and HLA gene loci compared with control individuals. These alterations might affect NK-cell tumor surveillance. NK cells from bile duct tumors expressed KIRs and were found in tumors that expressed cognate ligands. This should be considered in development of immune-based therapies for BDC.


Assuntos
Neoplasias dos Ductos Biliares/genética , Antígenos HLA/genética , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Receptores KIR/genética , Idoso , Idoso de 80 Anos ou mais , Ásia , Neoplasias dos Ductos Biliares/sangue , Neoplasias dos Ductos Biliares/imunologia , Neoplasias dos Ductos Biliares/patologia , Estudos de Casos e Controles , Europa (Continente) , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Antígenos HLA/sangue , Antígenos HLA/imunologia , Humanos , Células Matadoras Naturais/patologia , Ligantes , Desequilíbrio de Ligação , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , América do Norte , Fenótipo , Prognóstico , Receptores KIR/sangue , Receptores KIR/imunologia , Receptores KIR2DL3/genética , Receptores KIR2DL3/imunologia , Fatores de Risco , América do Sul , Fatores de Tempo
7.
Int J Immunogenet ; 46(4): 217-231, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31210416

RESUMO

Natural killer (NK) cells make vital contributions to the immune system and the reproductive system. Notably, NK cells of donor origin can recognize and kill residual leukaemic cells and cure malignant patients in hematopoietic stem cell (HSC) transplant setting. NK cell function is regulated by KIRs that recognize cognate HLA class I molecules on target cells, depending on their amino acid residues. In review, we addressed the question of binding capacity and avidity of HLA class I molecules to different killer cell immunoglobulin-like receptors (KIRs) depending on all interacting amino acid residues both on HLA and KIR side. We searched PubMed database and analysed available HLA:KIR crystallographic data for amino acid residues in HLA molecules, those physically involved in binding KIRs (termed here the "entire KIR interface"). Within entire KIR interface, we selected five functional sequence motifs (14-19, 66-76, 77-84, 88-92 and 142-151) and classified them according to the conservation of their amino acid sequences among 8,942 HLA class I molecules. Although some conserved amino acid motifs were shared by different groups of KIR ligands, the HLA motif combinations were exclusive for the ligand groups. In 135 common HLA class I molecules with known HLA:KIR recognition, we found 54 combinations of five motifs in each of the KIR-binding interfaces (C1, C2, Bw4, A3/11) and conserved non-KIR-binding interfaces. Based on the entire KIR interface, this analysis allowed to classify 8,942 HLA class I molecules into KIR specificity groups. This functional and evolutionary classification of entire KIR interfaces provides a tool for unambiguously predicting HLA:KIR interactions for common and those HLA molecules that have not yet been functionally tested. Considering the entire KIR interface in HLA class I molecules, functional interactions of HLA and KIR can be predicted in immune responses, reproduction and allotransplantation. Further functional studies are needed on the HLA:KIR interaction variations caused by the repertoires of peptides presented by HLA molecules and KIR polymorphisms at allelic level.


Assuntos
Motivos de Aminoácidos/genética , Células Matadoras Naturais/imunologia , Receptores KIR/genética , Motivos de Aminoácidos/imunologia , Sequência de Aminoácidos , Antígenos HLA-C/genética , Antígenos HLA-C/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Ligantes , Polimorfismo Genético , Receptores KIR/imunologia
8.
Pediatr Int ; 61(6): 566-571, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30974480

RESUMO

BACKGROUND: The prognosis of high-risk neuroblastoma stage 4 with bone marrow metastasis, MYCN amplified, or refractory neuroblastoma is poor. To date, no standard treatment has been established. In four selected cases, we challenged the killer-cell immunoglobulin-like receptor ligand mismatch cord blood transplantation in graft-versus-host disease (GVHD) with reduced-intensity conditioning. METHODS: Prior to this study, conventional chemotherapy, autologous peripheral blood stem cell transplantation with high-dose chemotherapy (busulfan and melphalan), surgery and radiation therapy were completed in every case. The status before cord blood transplantation in two cases was not complete remission (CR) and in the others it was CR. The primary site was the mediastinum, two adrenal glands and a retroperitoneum, respectively. Three patients had bone and bone marrow metastasis and one had MYCN amplification. In all cases, international neuroblastoma pathology classification was unfavorable histology. All patients were >2 years of age. RESULTS: Relapse occurred only in one patient 17 months after the last transplantation, and the other three patients maintained disease-free survival for 74, 36, and 24 months, respectively. In one case of relapse the disease could be controlled by conventional chemotherapy. Except one, all patients had no severe complications, such as acute or chronic GVHD. One patient had gastric antral vascular ectasia and hemorrhagic cystitis. CONCLUSION: This strategy might be feasible and should be investigated for efficacy in the future. No definite conclusion can be made, however, due to the very small number of patients. Further prospective studies are required to determine its efficacy.


Assuntos
Neoplasias das Glândulas Suprarrenais/terapia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Neoplasias do Mediastino/terapia , Neuroblastoma/terapia , Receptores KIR/imunologia , Neoplasias Retroperitoneais/terapia , Neoplasias das Glândulas Suprarrenais/imunologia , Neoplasias das Glândulas Suprarrenais/patologia , Biomarcadores , Pré-Escolar , Feminino , Humanos , Ligantes , Masculino , Neoplasias do Mediastino/imunologia , Neoplasias do Mediastino/patologia , Neuroblastoma/imunologia , Neuroblastoma/patologia , Neoplasias Retroperitoneais/imunologia , Neoplasias Retroperitoneais/patologia
9.
Oncol Rep ; 41(5): 2625-2635, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896812

RESUMO

The majority of natural killer (NK) cells serve an important role in eliminating malignant cells. The cytotoxic effects of NK cells were first identified against leukemia cells, and it is now hypothesized that they may have a critical role in leukemia therapy. The cellular functions of NK cells are mediated by their cell surface receptors, which recognize ligands on cancer cells. The role of NK cells is specifically regulated by the activating or inhibitory killer cell immunoglobulin­like receptors (KIRs) on their surface, which bind to the human leukocyte antigen (HLA) class I ligands present on the target cells. The association between KIR and HLA is derived from the diversity of KIR/HLA gene profiles present in different individuals, and this determines the cytotoxic effect of NK cells on cancer cells. Chronic myeloid leukemia (CML) is a hematological leukemia characterized by the hyper­proliferation of myeloid cells, with the majority of patients with CML presenting with abnormal immune cells. Tyrosine kinase inhibitors are the present standard therapy for CML, but are associated with numerous adverse side effects. Various studies have proposed CML therapy by immunotherapeutic approaches targeting the immune cells. This review summarizes the contents of NK cells and the association between KIR/HLA and leukemia, especially CML. This is followed by a discussion on the development of NK cell immunotherapy in hematological malignancies and research into strategies to enhance NK cell function for CML treatment.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Imunoterapia/métodos , Células Matadoras Naturais/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Receptores KIR/antagonistas & inibidores , Antineoplásicos Imunológicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Ensaios Clínicos como Assunto , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Receptores KIR/imunologia , Receptores KIR/metabolismo
10.
Nat Commun ; 10(1): 1065, 2019 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-30911002

RESUMO

The major cause of death after allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for acute myeloid leukemia (AML) is disease relapse. We investigated the expression of Inhibitory Receptors (IR; PD-1/CTLA-4/TIM-3/LAG-3/2B4/KLRG1/GITR) on T cells infiltrating the bone marrow (BM) of 32 AML patients relapsing (median 251 days) or maintaining complete remission (CR; median 1 year) after HSCT. A higher proportion of early-differentiated Memory Stem (TSCM) and Central Memory BM-T cells express multiple IR in relapsing patients than in CR patients. Exhausted BM-T cells at relapse display a restricted TCR repertoire, impaired effector functions and leukemia-reactive specificities. In 57 patients, early detection of severely exhausted (PD-1+Eomes+T-bet-) BM-TSCM predicts relapse. Accordingly, leukemia-specific T cells in patients prone to relapse display exhaustion markers, absent in patients maintaining long-term CR. These results highlight a wide, though reversible, immunological dysfunction in the BM of AML patients relapsing after HSCT and suggest new therapeutic opportunities for the disease.


Assuntos
Anergia Clonal , Regulação Leucêmica da Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Memória Imunológica/genética , Leucemia Mieloide Aguda/imunologia , Linfócitos T/imunologia , Adulto , Antígenos CD/genética , Antígenos CD/imunologia , Antineoplásicos/uso terapêutico , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Feminino , Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética , Proteína Relacionada a TNFR Induzida por Glucocorticoide/imunologia , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptores KIR/genética , Receptores KIR/imunologia , Recidiva , Indução de Remissão , Estudos Retrospectivos , Transdução de Sinais , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia , Linfócitos T/patologia , Transplante Homólogo
11.
J Assist Reprod Genet ; 36(5): 827-835, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30847698

RESUMO

Pregnancy is a unique immunological situation in which a fetus-bearing paternal histocompatibility antigens can survive in a maternal environment without apparent rejection. To face this challenge, cells of the uterine immune system show characteristic changes in absolute number and composition during pregnancy. Particularly relevant to this process are uterine natural killer (uNK) cells and their cell surface receptors, killer immunoglobulin-like receptors (KIRs). The main purpose of this review is to outline the current body of knowledge on the involvement of KIRs in the complications of pregnancy. Implantation depends on the invasion of embryonic trophoblast cells into maternal uterine tissue and remodeling of the uterine spiral arterioles, which is essential for placental perfusion and successful pregnancy. The proper interaction between maternal KIRs and their ligands human leukocyte antigen (HLA) class I molecules, expressed by the extravillous trophoblast cells, is crucial in this process. KIRs are a complex family that includes both activator and inhibitory receptors. The activation profile is genetically determined in each individual and leads to diverse levels of functionality for NK and T cells on engagement with specific HLA class I molecules. An association between different KIR alleles and HLA molecules has been reported in pregnancy complications, supporting the idea of a relevant role of these receptors in successful pregnancy.


Assuntos
Implantação do Embrião/imunologia , Antígenos HLA/imunologia , Células Matadoras Naturais/imunologia , Placentação/imunologia , Complicações na Gravidez/imunologia , Complicações na Gravidez/patologia , Receptores KIR/imunologia , Feminino , Antígenos HLA/metabolismo , Humanos , Células Matadoras Naturais/metabolismo , Gravidez , Receptores KIR/metabolismo
12.
Leukemia ; 33(1): 230-239, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29907809

RESUMO

Haploidentical stem cell transplantation with T cell-replete grafts and post-transplant cyclophosphamide (PTCy) is increasingly used with encouraging outcome. Natural killer (NK) cell alloreactivity, predicted by missing killer cell immunoglobulin-like receptor (KIR) ligands in the recipient that are present in their donor improves outcome of T cell-depleted haploidentical transplants. We explored the role of KIR ligand mismatching in 444 acute leukemia patients after T cell-replete transplants with PTCy. Thirty-seven percent of all patients had KIR ligand mismatching. Patients were in first remission (CR1) (39%), second remission (CR2) (26%), or active disease (35%). Stem cell source was peripheral blood (PBSC, 46%) or bone marrow (54%). The 2-year relapse, non-relapse mortality (NRM), and survival rates were 36.0% (95% confidence interval (CI), 31.4-40.7), 23.9% (20.0-28.0), and 45.9% (40.8-51.0), respectively. Multivariate analysis identified acute myeloid leukemia compared with acute lymphoblastic leukemia (hazard ratio (HR) 0.55, P = 0.002), female gender (HR 0.72, P = 0.04), and good performance status (HR 0.71, P = 0.04) as factors associated with better survival, while advanced age (HR 1.13, P = 0.04), active disease (HR 3.38, P < 0.0001), and KIR ligand mismatching (HR 1.41, P = 0.03) as associated with worse survival. KIR ligand mismatching was associated with a trend for higher relapse but not with graft-versus-host disease or NRM. The KIR ligand-mismatching effect was more prominent in patients given PBSC. In conclusion, there is no evidence that KIR ligand mismatching results in better outcome in the PTCy setting.


Assuntos
Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/mortalidade , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Receptores KIR/imunologia , Adulto , Idoso , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/terapia , Histocompatibilidade , Humanos , Imunossupressores/uso terapêutico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Receptores KIR/genética , Estudos Retrospectivos , Taxa de Sobrevida , Condicionamento Pré-Transplante , Transplante Haploidêntico , Adulto Jovem
14.
J Allergy Clin Immunol ; 143(1): 346-358.e6, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30096390

RESUMO

BACKGROUND: The mechanism by which natural killer (NK) cell education results in licensed NK cells with heightened effector function against missing self-targets is not known. OBJECTIVE: We sought to identify potential mechanisms of enhanced function in licensed human NK cells. METHODS: We used expanded human NK cells from killer immunoglobulin-like receptor (KIR)/HLA-genotyped donors sorted for single-KIR+ cells to generate pure populations of licensed and unlicensed NK cells. We performed proteomic and gene expression analysis of these cells before and after receptor cross-linking and performed functional and metabolic analysis before and after interference with selected metabolic pathways. We verified key findings using freshly isolated and sorted NK cells from peripheral blood. RESULTS: We confirmed that licensed human NK cells are greater in number in peripheral blood and proliferate more in vitro than unlicensed NK cells. Using high-throughput protein analysis, we found that unstimulated licensed NK cells have increased expression of the glycolytic enzyme pyruvate kinase muscle isozyme M2 and after KIR cross-linking have increased phosphorylation of the metabolic modulators p38-α and 5' adenosine monophosphate-activated protein kinase α. After cytokine expansion and activation, unlicensed NK cells depended solely on mitochondrial respiration for cytolytic function, whereas licensed NK cells demonstrated metabolic reprogramming toward glycolysis and mitochondrial-dependent glutaminolysis, leading to accumulation of glycolytic metabolites and depletion of glutamate. As such, blocking both glycolysis and mitochondrial-dependent respiration was required to suppress the cytotoxicity of licensed NK cells. CONCLUSIONS: Collectively, our data support an arming model of education in which enhanced glycolysis in licensed NK cells supports proliferative and cytotoxic capacity.


Assuntos
Glicólise/imunologia , Ativação Linfocitária/imunologia , Modelos Imunológicos , Regulação da Expressão Gênica/imunologia , Humanos , Proteômica , Receptores KIR/imunologia
15.
Transplant Proc ; 50(10): 3082-3087, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30577170

RESUMO

BACKGROUND: The selection of optimal donor is crucial for successful hematopoietic stem cell transplantation (HSCT). Thereby, it is appropriate to know, in addition to basic human leukocyte antigen (HLA) gene matches, other immunogenic or nonimmunogenic parameters predicting the outcome of transplant. OBJECTIVE: A unified approach is necessary to provide a comprehensive view of the patient-donor compatibility characterization outside of standard HLA genes. The approach should be applicable as a tool for optimizing procedures for extended donor typing and/or verification typing of a donor. METHODS: The study used the summary, unification, and innovation of existing practical knowledge and experience of the Czech National Marrow Donor Registry of various factors beyond HLA matching with impact on transplant outcome. RESULTS: An information technology system-implemented procedure (a verification algorithm) is presented as the decision support approach for prematurely discarding less suitable donors from the transplantation process. It is intended primarily for the transplant specialist to help establish optimal procedures for verifying and determining donor critical factors. CONCLUSIONS: A process defining HLAs, killer cell immunoglobulin-like receptors, and cytokine typing strategies was proposed to provide support to a transplant specialist in refining the choice of a suitable donor.


Assuntos
Algoritmos , Sistemas de Apoio a Decisões Clínicas , Seleção do Doador/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Tchecoslováquia , Antígenos HLA/imunologia , Teste de Histocompatibilidade/métodos , Humanos , Receptores KIR/imunologia , Sistema de Registros
16.
Front Immunol ; 9: 2848, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30564241

RESUMO

Natural killer (NK) cells are attractive candidates for allogeneic cell-based immunotherapy due to their potent antitumor effector function and good safety profile. NK cells express killer immunoglobulin-like receptors (KIRs) and the NKG2A receptor important for NK cells education as well as providing inhibitory signals upon encountering HLA-expressing target cells. Multiple myeloma (MM) is an example of a tumor expressing relatively high levels of HLA molecules. In this review, we discuss the functional relevance of inhibitory KIRs and NKG2A for NK cells anti-MM response and strategies to lower these inhibitory signaling to enhance clinical efficacy of allogeneic NK cells in MM.


Assuntos
Células Matadoras Naturais/imunologia , Mieloma Múltiplo/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptores KIR/imunologia , Animais , Humanos
17.
HLA ; 92(6): 384-391, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30468002

RESUMO

Killer cell immunoglobulin-like receptor (KIR) genes encode cell surface molecules that recognize HLA molecules and modulate the activity of natural killer (NK) cells. KIR genes exhibit presence and absence polymorphism, which generates a variety of gene-content haplotypes in worldwide populations. KIR gene-content variation is implicated in many diseases and is also important for placentation and transplantation. Because of the complexity of KIR polymorphism, variation in this family is still mostly studied at the gene-content level, even with the advent of next-generation sequencing (NGS) methods. Gene-content determination is generally expensive and/or time-consuming. To overcome these difficulties, we developed a method based on multiplex polymerase chain reaction with specific sequence primers (PCR-SSP) followed by melting curve analysis that allows cost-effective, precise and fast generation of results. Our method was 100% concordant with a gel-based method and 99.9% concordant with presence and absence determination by NGS. The limit of detection for accurate typing was 30 ng of DNA (0.42 µM) with 260/230 and 260/280 ratios as low as 0.19 and of 0.44. In addition, we developed a user-friendly Java-based computational application called killerPeak that interprets the raw data generated by Viia7 or QuantStudio 7 quantitative PCR machines and reliably exports the final genotyping results in spreadsheet file format. The combination of a reliable method that requires low amount of DNA with an automated interpretation of results allows scaling the KIR genotyping in large cohorts with reduced turnaround time.


Assuntos
Genótipo , Técnicas de Genotipagem/métodos , Reação em Cadeia da Polimerase Multiplex/métodos , Polimorfismo Genético , Receptores KIR/genética , Primers do DNA/química , Primers do DNA/metabolismo , Expressão Gênica , Técnicas de Genotipagem/economia , Técnicas de Genotipagem/instrumentação , Técnicas de Genotipagem/normas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Limite de Detecção , Reação em Cadeia da Polimerase Multiplex/economia , Reação em Cadeia da Polimerase Multiplex/instrumentação , Reação em Cadeia da Polimerase Multiplex/normas , Desnaturação de Ácido Nucleico , Receptores KIR/classificação , Receptores KIR/imunologia , Software
18.
Int J Rheum Dis ; 21(10): 1746-1755, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30398028

RESUMO

BACKGROUND: Several genetic studies have assessed the association between polymorphisms in killer immunoglobulin-like receptors (KIR) genes and susceptibility of individuals to ankylosing spondylitis (AS), but the findings have been inconclusive and incongruous. Therefore, we conducted this meta-analysis of all case-control studies meeting the inclusion criteria for obtaining an exact conclusion of the effect of KIR polymorphisms on the risk of AS. METHODS: A systematic literature search was conducted in electronic databases, including Scopus web of science, ScienceDirect, and PubMed to find all eligible studies exploring the association between KIR polymorphisms and the risk of AS, prior to June 2017. Pooled odds ratios (OR) and their corresponding 95% CIs were used to evaluate the strength of the association between KIR polymorphisms and the risk of AS. RESULTS: A total of 16 case-control studies, encompassed in 12 papers, with 1770 cases and 2907 healthy subjects were included in the meta-analysis. This meta-analysis revealed three significant positive associations of 2DS1, 2DS5, and 3DS1 with susceptibility to AS, while two significant negative associations of 2DL2 and 2DS2 with susceptibility to AS were identified. In the subgroup analysis based on human leukocyte antigen (HLA)-B*27 positive patients and healthy subjects, results indicated that there were four significant positive associations between 2DL5, 2DS4, 2DS5, 3DS1 polymorphisms and susceptibility to AS in HLA-B*27-positive patients; a significant negative association of 3DL1 in HLA-B*27-positive patients was found. CONCLUSIONS: While 2DS1, 2DS5, and 3DS1 polymorphisms increased AS risk, 2DL2 and 2DS2 polymorphisms were associated with reduced AS susceptibility.


Assuntos
Polimorfismo Genético , Receptores KIR/genética , Espondilite Anquilosante/genética , Estudos de Casos e Controles , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Fenótipo , Prognóstico , Fatores de Proteção , Receptores KIR/imunologia , Medição de Risco , Fatores de Risco , Espondilite Anquilosante/epidemiologia , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/prevenção & controle
19.
Sci Immunol ; 3(29)2018 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-30413420

RESUMO

Killer cell immunoglobulin-like receptors (KIRs) are expressed predominantly on natural killer cells, where they play a key role in the regulation of innate immune responses. Recent studies show that inhibitory KIRs can also affect adaptive T cell-mediated immunity. In mice and in human T cells in vitro, inhibitory KIR ligation enhanced CD8+ T cell survival. To investigate the clinical relevance of these observations, we conducted an extensive immunogenetic analysis of multiple independent cohorts of HIV-1-, hepatitis C virus (HCV)-, and human T cell leukemia virus type 1 (HTLV-1)-infected individuals in conjunction with in vitro assays of T cell survival, analysis of ex vivo KIR expression, and mathematical modeling of host-virus dynamics. Our data suggest that functional engagement of inhibitory KIRs enhances the CD8+ T cell response against HIV-1, HCV, and HTLV-1 and is a significant determinant of clinical outcome in all three viral infections.


Assuntos
Linfócitos T CD8-Positivos/imunologia , HIV-1/imunologia , Hepacivirus/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Receptores KIR/imunologia , Humanos
20.
HLA ; 92 Suppl 2: 42-46, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30168290

RESUMO

HLA are functional in cancer immunosurveillance in adaptive and innate immunity pathways. In unrelated hematopoietic stem cell transplantation (HSCT) in 688 patients with hematological malignancies we compared antitumor efficacy of transplant in three models including the level of: (a) donor-recipient HLA class I mismatch, (b) KIR-ligand mismatch, (c) post-transplant cognate HLA:KIR pairing. The effects were directly compared in multivariate models with backward elimination including all three effects in initial model. In final multivariate model HLA mismatch and KIR-ligand mismatch levels were eliminated and HLA:KIR-dependent NK cell licensing effect remained independent prognostic factor for DFS, relapse/progression incidence, and overall survival (OS). These results suggested that NK cell licensing via cognate HLA:KIR pairs is primarily functional in cancer immunosurveillance in HSCT.


Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Neoplasias Hematológicas/diagnóstico , Transplante de Células-Tronco Hematopoéticas/mortalidade , Antígenos de Histocompatibilidade Classe I/imunologia , Modelos Imunológicos , Receptores KIR/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Expressão Gênica , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/patologia , Antígenos de Histocompatibilidade Classe I/genética , Teste de Histocompatibilidade , Humanos , Lactente , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/uso terapêutico , Receptores KIR/genética , Recidiva , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Doadores não Relacionados
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