Browsing by Subject "NK cells"
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- PublicationOpen AccessActivating Killer-cell Immunoglobulin-like Receptors are associated with the severity of COVID-19(Oxford University Press, 2021-04-30) Bernal, Enrique; Alcaraz, María J.; Quadee, Ahmed A.; Moreno, Marta; Martínez-Sánchez, María V.; Campillo, José A.; Gómez, Jose M.; Peláez, Ana; García-Vázquez, Elisa; Herranz, Maite; Hernández-Olivo, Marta; Martínez-Alfaro, Elisa; Alcaraz, Antonia; Muñoz, Ángeles; Cano, Alfredo; McKay, Matthew R.; Muro, Manuel; Minguela, Alfredo; Murcian COVID19 Study group; Gimeno Arias, Lourdes; MedicinaBackground: Etiopathogenesis of the clinical variability of the coronavirus disease 2019 (COVID-19) remains mostly unknown. Here we investigate the role of Killer-cell Immunoglobulin-like receptor (KIR)/Human Leukocyte Antigen Class-I (HLA-I) interactions in the susceptibility and severity of COVID-19. Methods: KIR and HLA-I genotyping and NK cell (NKc) receptors immunophenotyping in 201 symptomatic patients and 210 non-infected controls. Results: NKcs with a distinctive immunophenotype, suggestive of recent activation (KIR2DS4low CD16low CD226low CD56high TIGIThigh NKG2Ahigh), expanded in patients with severe COVID-19. This was associated with a higher frequency of the functional A-telomeric activating KIR2DS4 in severe than mild/moderate patients and controls (83.7%, 55.7% and 36.2%, p<7.7x10-9). In mild/moderate patients HLA-B*15:01 was associated with higher frequencies of activating B-telomeric KIR3DS1 compared to patients with other HLA-B*15 subtypes and non-infected controls (90.9%, 42.9% and 47.3%, p<0.002, Pc=0.022). This strongly suggests that HLA-B*15:01 specifically presenting SARS-CoV-2 peptides could form a neo-ligand interacting with KIR3DS1. Similarly, a putative neo-ligand for KIR2DS4 could arise from other HLA-I molecules presenting SARS-CoV-2 peptides expressed on infected/activated lung antigen presenting cells. Conclusions: Our results support a crucial role of NKcs in the clinical variability of COVID-19 with specific KIR/Ligand interactions associated to disease severity.
- PublicationOpen AccessAdoptive cellular immunotherapy. NK cells and bone marrow transplantation(Murcia : F. Hernández, 2000) Koh, C.Y.; Welniak, L.A.; Murphy, W.J.Allogeneic bone marrow transplantation (BMT) has been increasingly used for the treatment of both neoplastic and non-neoplastic disorders. However, serious obstacles currently limit the efficacy and thus more extensive use of BMT. These obstacles include: graft-versus-host disease (GVHD), relapse from the original tumor, and susceptibility of patients to opportunistic infections due to the immunosuppressive effects of the conditioning regimen.Overcoming these obstacles is complicated by dual outcome of existing regimens; attempts to reduce GVHD by depleting T cells from the graft, result in increased rates of tumor relapse and failure of engraftment. On the other hand, efforts to increase graft-versus-tumor (GVT) effects of the transplant also promote GVHD. In this review, the use of natural killer (NK) cells to overcome some of these obstacles of allogeneic BMT is evaluated. Adoptive immunotherapy using NK cells after allogeneic BMT has several potential advantages. First, NK cells can promote hematopoiesis and therefore engraftment by production of hematopoietic growth factors. Second, NK cells have been shown to prevent the incidence and severity of GVHD. This has been shown to be at least partially due to TGF-B, an immunosuppressive cytokine. Third, NK cells have been shown to augment numerous anti-tumor effects in animals after BMT suggesting a vital role of NK cells in mediating GVT effects. Finally, NK cells have been demonstrated to affect B cell recovery and function in mice. Therefore, understanding the mechanisms of beneficial effects of NK cells after BMT may lead to significant increases in the efficacy of this procedure.
- PublicationOpen AccessBiomarkers of innate immunity and immunological susceptibility to viral Infection in patients with alcoholic cirrhosis(MDPI, 2024-02-01) Navarro Noguera, Elena; Collados Ros, Aurelia; Miguel Bolarín, Jose; Muro, Manuel; Legaz Pérez, Isabel; Ciencias SociosanitariasBackground: The harmful effect of alcohol on the immune system may be due to both a direct action of the alcohol or its metabolites on immune cells as an indirect action modifying the different mechanisms of intercellular interaction. The interplay between stimulatory (aKIR) and inhibitory (iKIR) natural killer (NK) cell receptors and their corresponding human leukocyte antigen (HLA) ligands influences the outcome of virus infection. The aim was to analyze the influence of the KIR/HLA pair genetic profile in male alcoholic cirrhosis (AC) patients with and without viral infections to find susceptibility biomarkers that can help establish the risks and prevent viral infections. Methods: A total of 281 male AC patients were analyzed. The sociodemographic characteristics, viral hepatitis C (HCV), hepatitis B (HBV), and cytomegalovirus (CMV) infections were analyzed. Genomic DNA was extracted, and genetic the KIR/HLA profiles were investigated. A total of 6 KIR genes and their corresponding ligands (HLA-C) were analyzed. Patients were grouped into two groups: with and without associated viral infection. Results: A statistically significant increase in the combination of KIR2DL2+/C1C1 was observed in male AC patients with viral infection compared to those without viral infection (45.9% vs. 24.5%, p = 0.021). The analysis of KIR2DL3+/C1+ showed a high frequency comparing healthy controls and male AC patients without virus infection (85% vs. 76.4%; p = 0.026). The analysis of KIR2DL3+/C2C2 frequency showed a statistically significant increase comparing male AC patients without viral infection and healthy controls (23.6% vs. 15%; p = 0.026). Conclusions: The genetic KIR2DL2+/C2C2 profiles may play a significant role in determining the vulnerability of male AC patients to viral infections, providing valuable insights for future research and potential therapeutic interventions.
- PublicationOpen AccessCD33 (Siglec-3) Inhibitory Function: Role in the NKG2D/DAP10 Activating Pathway.(Hindawi, 2019) Corral-San Miguel, Rubén; García-Peñarrubia, Pilar; Hernández Caselles, Trinidad; Ruiz Alcaraz, Antonio José; Bioquímica y Biología Molecular B e InmunologíaCD33 (siglec-3), a well-known target in leukemia therapy, is an inhibitory sialoadhesin expressed in human leukocytes of the myeloid lineage and some lymphoid subsets, including NK cells. It may constitute a control mechanism of the innate immune system; nevertheless, its role as an inhibitory receptor remains elusive. Using human NK cells as a cellular model, we analyzed CD33 inhibitory function upon different activating receptors. In high-cytotoxicity NKL cells, CD33 displayed a prominent inhibition on cytotoxicity triggered by the activating receptors NKG2D and, in a lower extent, 2B4, whereas it did not inhibit NKp46-induced cytotoxicity. NKp46 was partially inhibited by CD33 only when low-cytotoxicity NKL cells were tested. CD33 triggering did not inhibit IFN-γ secretion, contrasting with ILT-2 and CD94/NKG2A inhibitory receptors that inhibited cytotoxicity and IFN-γ secretion induced by all activating receptors tested. CD33-mediated inhibition of NKG2D-induced triggering involved Vav1 dephosphorylation. Our results support the role of CD33 as an inhibitory receptor preferentially regulating the NKG2D/DAP10 cytotoxic signaling pathway, which could be involved in self-tolerance and tumor and infected cell recognition.
- PublicationRestrictedDivergences in KIR2D+ natural killer and KIR2D+CD8+ T-cell reconstitution following liver transplantation(Elsevier, 2011-03) López Álvarez, M.R.; Campillo, J.A.; Blanco García, R.M.; Salgado Cecilia, G.; Bolarín, J.M.; Gil, J.; García Alonso, A.M.; Muro, M.; Álvarez López, M.R.; Miras, M.; Minguela, A.; Gimeno Arias, Lourdes; Legaz Pérez, Isabel; Ciencias SociosanitariasNatural killer (NK) and CD8+ T cells may be active elements in the allograft response, but little is known about their role in liver transplantation. Some of these cells express killer immunoglobulin-like receptors (KIRs), which after binding specific ligands may transmit inhibitory/activating signals. In this study, circulating NK and CD8+ T cells expressing CD158a/h (KIR2DL1/S1) or CD158b/j (KIR2DL2/3/S2) receptors were analyzed in 142 liver recipients by flow cytometry. They were underrepresented in patients before transplantation, but following transplantation, whereas the KIR2D+ NK subsets experienced a late recuperation (day 365) mainly in C2-homozygous patients developing early acute rejection, recovery of the 2 CD8+KIR2D+ T cells started earlier, showing significant differences on day 365 between patients without acute rejection and those suffering from it (p = 0.004 and p < 0.0001, respectively). These differences were also evident when the human leukocute antigen-C genotypes of the recipient were considered. In conclusion, whereas the late recovery of KIR2D+ NK cells in C2/C2 patients appears to be linked to acute rejection, the increase in early CD8+KIR2D+ T cells in overall liver recipients correlates with a most successful early graft outcome. Therefore, monitoring of KIR2D+ cells appears to be a useful tool for liver transplant follow-up.
- PublicationOpen AccessImmunohistochemical study of immunological markers: HLAG, CD16, CD25, CD56 and CD68 in placenta tissues in recurrent pregnancy loss(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2014) Papamitsou, Theodora; Toskas, Alexandros; Papadopoulou, Kyriaki; Sioga, Antonia; Lakis, Sotirios; Chatzistamatiou, Maria; Economou, Zinon; Adriopoulou, LuisaIntroduction: Recurrent pregnancy loss (RPL) of unknown etiology is correlated with immunological alterations during pregnancy. Normally, changes in leukocyte subpopulations and HLA expression take place in pregnant uterus in order to tolerate the semi-allogenic embryo. Objective: Our research tries to enlighten the immunological changes that take place in the uterus of women with recurrent abortions of unknown etiology during first trimester of pregnancy. Materials and methods: The miscarriage group was obtained from 25 women who miscarried between the ages of 35 to 42 years and controls consisted of 25 healthy women between the ages of 27 to 39 years, who had electively terminated their pregnancies during the first trimester of pregnancy. The abortion was processed and specimens taken were studied using immunohistochemical methods. Specimens were taken from decidua basalis and decidua parietalis. Monoclonal antibodies were used against HLAG (Human Leukocyte Antigen G), CD68( Cluster of Differentiation 68), CD56, CD16 and CD25. The results were statistically analysed with Mann-Whitney test. Results: HLA-G expression in decidua basalis from miscarriage group was found to be decreased. CD25+ cell expression was found to be invariable in deciduas from both groups. CD16+ cell and CD68 + cell expression was found to be increased in deciduas from the miscarriage group. CD56+ cell expression was found to be increased in decidua parietalis from miscarriage group. Conclusion : Several differences in the immunological profile of deciduas from RPL group were observed. Changes in feto-protective HLA-G expression and a possible implication of macrophages and NK cells were found.
- PublicationEmbargoNatural killer (NK) cells play a critical role in the early innate immune response to Chlamydophila abortus infection in mice(Elsevier, 2004-01) Río, L. del; Caro, M. R.; Gallego, M. C.; Sánchez, J.; Cuello, F.; Salinas, J.; Martínez Cáceres, Carlos Manuel; Navarro Cámara, José Antonio; Ortega Hernández, Nieves; Buendía Marín, Antonio Julián; Anatomía y Anatomía Patológica ComparadasChlamydophila abortus, the aetiological agent of ovine enzootic abortion, induces a strong inflammatory reaction that leads to the T helper cell (Th1) specific immune response necessary for the clearance of infection. Because the role of natural killer (NK) cells during the first stages of this response has received little attention, this study focused on determining the function of these cells in a mouse model of infection. The location of NK cells in the liver and spleen of infected mice was examined immunohistochemically with an anti-Ly49G monoclonal antibody. The number of NK cells increased during the infection both in spleen and liver. In subsequent experiments, an anti-asialo GM1 polyclonal antibody was injected to deplete the NK cells. NK-depleted mice showed a substantial increase in their susceptibility to C. abortus infection, with high mortality rates and an increased burden of bacteria in the liver. Histopathological studies showed that inflammatory foci, composed mainly of neutrophils, were greater in size and number in depleted mice, while numerous chlamydial inclusions were associated with the foci. Serum concentrations of IFN-gamma, a key cytokine in the control of C. abortus infection, were substantially reduced in the NK-depleted mice. To establish the relationship between NK cells and other components of the innate immune response, neutrophils were depleted with the RB6-8C5 antibody. These cells were shown to be crucial in the recruitment of NK cells to the inflammatory foci.
- PublicationOpen AccessTumoricidal potential of binary therapy in lymphoma: Role of DC-NK cross-talk and checkpoint inhibitors(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Chaudhary, Pratima; Yadav, Pragya; Manna, Partha Pratim; Biología Celular e HistologíaLymphoma is a common type of cancer that occurs in humans. Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL) subtype and is characterized by high clinical and biological heterogeneity. The tumor microenvironment (TME) in lymphoma is critical for the initiation, progression, and metastasis of tumors and influences the therapeutic efficiency of chemotherapy or immuno-therapy, including cell therapy or appropriate combinations of therapeutics. The role of effector immune cells in the development and progression of DLBCL is complex and involves reciprocal interactions between tumor cells, adaptive and innate immune cells, their soluble mediators, and structural components present in the TME. Recruitment of immune cells in the TME and their distinct effects on tumor progression and therapeutic outcomes in the presence of therapy have decisive effects on the outcome of therapy. In this review, we discuss the application and implications of binary therapy involving suboptimal-dose chemotherapy and adoptive cell therapy on the basis of our recent findings on γc cytokine-aided cross-talk between dendritic cells and natural killer cells in therapy against experimental murine lymphoma. This novel therapeutic protocol induces a healing response in experimental lymphoma by downregulating FOXP3 and programmed cell death protein 1. We discuss the various aspects of binary therapy covering multiple issues, including the participation of cell subsets and checkpoint inhibitors in the treatment of malignant lymphoma. These new therapies involve the induction of adoptive cell therapy through the passive transfer of immunologic effectors in addition to a suboptimal dose of adriamycin (doxorubicin hydrochloride) to increase the ability of the immune system to react against tumor antigens, inducing the destruction of tumor cells.