Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activation of natural killer (NK) cells leads to degranulation and secretion of cytotoxic granula. During this process, the lytic granule membrane protein CD107a becomes detectable at the cell surface. Based on this phenomenon, we have analyzed by a novel flow cytometry-based assay, the number and phenotype of NK cells responding to tumor targets. Using human leukemia and lymphoma cell lines, we observed a close correlation between CD107a surface expression and target cell lysis, indicating that NK cell cytotoxicity can be assessed by this method. The number of degranulating NK cells was closely related to the ratio of effector and target cells and showed a maximum at a ratio of 1:1. Moreover, we were able to show that the population of CD56(dim)/CD16(neg) NK cells is primarily responsible for the cytotoxic activity against tumor targets whereas neither CD56(dim)/CD16(pos) nor CD56(bright) NK cells degranulated in response to the cell lines. Our results indicate that the CD107a assay represents a promising new method for the quantification and characterization of cells exhibiting natural cytotoxicity.
Leukemia 2005 May
PMID:CD56dimCD16neg cells are responsible for natural cytotoxicity against tumor targets. 1725 1

The aim of this study was to investigate the in vitro immunomodulatory effects of zoledronic acid (Zol) on peripheral blood Vgamma9/Vdelta2 (gammadelta) T cells of normal donors and multiple myeloma (MM) patients. gammadelta T cells were stimulated with Zol and low doses of interleukin-2 (IL-2), and then analyzed for proliferation, cytokine production, and generation of effector activity against myeloma cell lines and primary myeloma cells. Proliferation of gammadelta T cells was observed in 100% of normal donors and 50% of MM patients. gammadelta T cells produced IFN-gamma, surface mobilized the CD107a and CD107b antigens, and exerted direct cell-to-cell antimyeloma activity irrespective of the ability to proliferate to Zol and IL-2. The memory phenotype was predominant in the MM gammadelta T cells that proliferated in response to Zol (responders), whereas effector cells were predominant in those that did not (nonresponders). Zol induced antimyeloma activity through the monocyte-dependent activation of gammadelta T cells and by enhancing the immunosensitivity of myeloma cells to gammadelta T cells. Mevastatin, a specific inhibitor of hydroxy-methylglutaryl-CoA reductase, completely abrogated this antimyeloma activity.
Leukemia 2005 Apr
PMID:Effector gammadelta T cells and tumor cells as immune targets of zoledronic acid in multiple myeloma. 1574 46

We have analyzed the clonotype composition of CD8+ T cells following nonmyeloablative (NMA) conditioning and hematopoietic cell transplantation (HCT), of patients with chronic lymphocytic leukemia (CLL). Consecutive analyses of blood samples taken up to 2 years following HCT, demonstrated that CD8+ T-cell clonality was highly dynamic in the early phases after HCT, but became more stable after 4-5 months. Moreover, donor lymphocyte infusion (DLI) given for disease progression in one of the patients led to establishment of recurrent as well as new T-cell clonotypes. This coincided with disease remission, strongly suggesting that these T cells were engaged with anti-CLL cytotoxicity. To examine the functional capacity of stable clonally expanded T cells after HCT, CD8+ T cells isolated post-transplant from the recipients were stimulated ex vivo with CLL cells and subsequently analyzed by FACS for surface expression of the marker for cytotoxic activity, CD107a. Stimulation with CLL cells indeed led to surface expression of CD107a, and clonotype analyses of sorted cells demonstrated that CD107a positive T cells were stably expanded following HCT. Our data suggest that clonally expanded CD8+ T-cell clones participate in the ongoing T-cell response against CLL cells following HCT with NMA conditioning.
Leukemia 2005 Dec
PMID:Evidence for involvement of clonally expanded CD8+ T cells in anticancer immune responses in CLL patients following nonmyeloablative conditioning and hematopoietic cell transplantation. 1630 75

Expression of UL16-binding proteins (ULBPs) has been reported in various cancers, such as leukemia and melanoma, and also in some other cancer cell lines. However, the factors that modulate the expression of ULBPs are not well defined. In this study, we investigated the effects of IL-18 on the expression of NKG2D ligands in leukemia cells. IL-18 treatment increased ULBP2 expression in leukemia cells at the mRNA and protein levels. In addition, PD98059 (an ERK1/2 MAPK inhibitor) and SP600125 (a JNK inhibitor) attenuated IL-18-induced ULBP2 expression in a dose-dependent manner. We observed that ERK1/2 and JNK MAPK phosphorylation increased upon treatment with IL-18. IL-18 elevated CD107a expression in cancer cells and increased the cytotoxic activity of NK cells; therefore, we propose that IL-18 increases the susceptibility of target cells by inducing surface expression of ULBP2. Taken together, these findings suggest that IL-18 may play a critical role in regulating ULBP2 expression via the ERK1/2 and JNK MAPK pathways in leukemia cells.
 ...
PMID:IL-18 enhances ULBP2 expression through the MAPK pathway in leukemia cells. 1870 45

Engagement of NKG2D by their ligands (NKG2D-L), as the human major histocompatibility complex class I-related molecules MIC-A and the UL16-binding proteins, on cytolytic lymphocytes leads to the enhancement of antitumour effector functions. These ligands are missing or expressed at very low levels on leukaemic cells; furthermore, they can be shed by tumour cells and inhibit cytolytic activity of lymphocytes. Herein, we show that in vivo administration of all-trans-retinoic acid (ATRA) or the histone deacetylase inhibitor sodium valproate (VPA) to patients affected with acute myeloid leukaemia (AML) M3 or M1 respectively, leads to the induction of transcription and expression of NKG2D-L at the surface of leukaemic cells. Apparently, no detectable shedding of the soluble form of these molecules was found in patients' sera. Conversely, AML blasts from patients treated with chemotherapy not including ATRA or VPA did not show any induction of NKG2D-L transcription. Furthermore, upon therapy with ATRA or VPA, leukaemic blasts become able to trigger lytic granule exocytosis by autologous CD8(+) T and natural killer lymphocytes, as shown by CD107a mobilization assay, followed by leukaemic cell lysis. These findings indicate that ATRA and VPA may contribute to the activation of cytolytic effector lymphocytes in vivo, possibly enhancing their anti-leukaemic effect.
Leukemia 2009 Apr
PMID:Effective in vivo induction of NKG2D ligands in acute myeloid leukaemias by all-trans-retinoic acid or sodium valproate. 1915 70

Immunotherapeutic strategies are increasingly being explored as a method of enhancing anti-tumour immune responses in patients with acute myeloid leukaemia (AML). Regulatory CD4(+) T cells (Tregs) suppress effector T and natural killer (NK) cells and therefore pose a potential challenge to the efficacy of immunotherapy. AML cells transduced with a lentivirus expressing CD80 (B7.1) and IL2 (LV-CD80/IL2) are capable of stimulating T and NK cell cytotoxicity in vitro. This study examines the effect of CD80/IL2 modified AML cells on Treg number and function. We report a significant increase in the number of CD8(+) T cells (P = 0.046) CD3(-)CD56(+) NK cells (P = 0.028) and CD3(+)CD4(+)CD25(high)Foxp3(+) Tregs (P = 0.043) following stimulation for 7 days with allogeneic LV-CD80/IL2 AMLs. In contrast, autologous LV-CD80/IL2 AML cell cultures provide a weaker stimulation with a lower number of CD8(+) T cells (P = 0.011) and no change in NK cell or Treg numbers. However, an increase in cytotoxic CD8(+) T cells and NK cells are detected following both allogeneic and autologous LV-CD80/IL2 stimulation as demonstrated by an increase in IFN-gamma and CD107a expression. Despite the presence of increased numbers of Tregs with suppressive activity in a subset of cultures, increased lysis of unmodified AMLs was still achieved following allogeneic (day 0, 2.2%; day 7, 20.4%) and more importantly, autologous LV-CD80/IL2 culture in which AML patients had recently received intensive chemotherapy (day 0, 0%; day 7, 16%). Vaccination with LV-CD80/IL2 therefore provides a potential strategy to enhance anti-leukaemia immune responses without a concomitant stimulation of Treg-mediated inhibition of cytotoxic immunological responses.
 ...
PMID:Human CD80/IL2 lentivirus transduced acute myeloid leukaemia cells enhance cytolytic activity in vitro in spite of an increase in regulatory CD4+ T cells in a subset of cultures. 1928 81

Immunotherapeutic strategies may promote T and/or natural killer (NK) cell cytotoxicity. NK cells have the potential to exert a powerful anti-leukaemia effect, as demonstrated by studies of allogeneic transplantation. We have previously shown that CD80/interleukin 2 (IL2) lentivirus (LV)-transduced AML cells stimulate in-vitro T cell activation. The present study demonstrated that allogeneic and autologous culture of peripheral blood mononuclear cells with CD80/IL2-expressing AML cells also promoted NK cell cytotoxicity. Expression of the activation receptors NKp30, NKp44, CD244, CD25, CD69 and HLA-DR significantly increased following allogeneic culture and a consistent increased expression of NKp30, NKp44, NKp46, NKG2D, NKG2C and CD69, and up-regulation of the cytolytic marker CD107a was detected following autologous culture with LV-CD80/IL2 AML cells. Furthermore, increased NK cell lysis of K562 and primary AML blasts was detected. The lytic activity increased by twofold against K562 (from 46.6% to 90.4%) and allogeneic AML cells (from 11.8% to 20.1%) following in-vitro stimulation by CD80/IL2-expressing AML cells. More importantly for potential therapeutic applications, lysis of primary AML cells by autologous NK cells increased by more than 40-fold (from 0.4% to 22.5%). These studies demonstrated that vaccination of patients with CD80/IL2-transduced AML cells could provide a powerful strategy for T/NK cell-mediated stimulation of anti-leukaemic immunological responses.
 ...
PMID:Human CD80/IL2 lentivirus-transduced acute myeloid leukaemia (AML) cells promote natural killer (NK) cell activation and cytolytic activity: implications for a phase I clinical study. 1938 35

The prognosis after hematopoietic cell transplantation (HCT) for the treatment of leukemia or lymphoma in humans is influenced by donor-derived natural killer (NK) cells, which enhance the graft-versus-leukemia (GVL) effect. Such alloreactive killer cells can be generated in vivo after HCT if the donor expresses killer cell immunoglobulin-like receptors (KIRs), such as KIR2DL1, KIR2DL2/3, or KIR3DL1, for which the recipient lacks HLA class I ligands. We studied effector cells from 22 KIR/HLA-ligand mismatched and 14 KIR/HLA-ligand matched, primarily HLA-matched patient-donor pairs after allogeneic HCT. A novel 8-color flow cytometry panel allowed us to characterize effector-cell populations without "broadly reactive" inhibitory receptors such as CD94/NKG2A or LIR1. The numbers of such NKG2A(-) LIR1(-) NK cells increased following HCT in patients transplanted by KIR/HLA-ligand mismatched grafts, compared to KIR/HLA-ligand matched grafts, and in patients transplanted from donors of the A/B, compared to A/A, KIR haplotypes. NKG2A(-)LIR1(-) NK cells expressing only those inhibitory KIRs for which the patient had no HLA class I ligands could be stimulated by HLA class I-deficient cells to express CD107a. Thus, NKG2A(-)LIR1(-) NK cells may be important GVL effector cells following HCT, even in patients transplanted from HLA-matched donors.
 ...
PMID:Expansion of NKG2A-LIR1- natural killer cells in HLA-matched, killer cell immunoglobulin-like receptors/HLA-ligand mismatched patients following hematopoietic cell transplantation. 2004 12

The receptor for hyaluronic acid-mediated motility (RHAMM) is a tumor-associated antigen in chronic lymphocytic leukemia (CLL). CD8(+) T cells primed with the RHAMM-derived epitope R3, which is restricted by human leukocyte antigen (HLA)-A2, effectively lyse RHAMM(+) CLL cells. Therefore, we initiated a phase I clinical trial of R3 peptide vaccination. Six HLA-A2(+) CLL patients were vaccinated four times at biweekly intervals with the R3 peptide (ILSLELMKL; 300 microg per dose) emulsified in incomplete Freund's adjuvant; granulocyte-macrophage colony stimulating factor (100 microg per dose) was administered concomitantly. Detailed immunological analyses were conducted throughout the course of peptide vaccination. No severe adverse events greater than CTC I degrees skin toxicity were observed. Four patients exhibited reduced white blood cell counts during vaccination. In five of six patients, R3-specific CD8(+) T cells were detected with the corresponding peptide/HLA-A2 tetrameric complex; these populations were verified functionally in four of five patients using enzyme-linked immunosorbent spot (ELISpot) assays. In patients with clinical responses, we found increased frequencies of R3-specific CD8(+) T cells that expressed high levels of CD107a and produced both interferon-gamma and granzyme B in response to antigen challenge. Interestingly, vaccination was also associated with the induction of regulatory T cells in four patients. Thus peptide vaccination in six CLL patients was safe and could elicit to some extent specific CD8(+) T-cell responses against the tumor antigen RHAMM.
Leukemia 2010 Apr
PMID:Peptide vaccination elicits leukemia-associated antigen-specific cytotoxic CD8+ T-cell responses in patients with chronic lymphocytic leukemia. 2022 Jul 77

Natural killer (NK) cell alloreactivity can be exploited in haploidentical (one haplotype mismatched) haematopoietic stem cell transplantation (HSCT) to prevent leukaemia relapse, rejection, and graft-vs-host disease (GVHD) (Blood 94:333-339; Science 295:2097-2100). If NK cell alloreactivity is to be exploited in HSCT, it is important to be able to reliably select donors who have NK alloreactivity towards the patient. The detection of donor NK alloreactivity towards patient target cells has traditionally been evaluated by NK cell cloning and (51)Cr-release cytotoxicity assay. This approach is complex and time consuming with results taking up to 6 weeks. Here, we detail a novel flow cytometric CD107a-based assay capable of detecting NK cell alloreactivity in 14 days.
 ...
PMID:The detection of NK cell alloreactivity by flow cytometric CD107a assay. 2266 51


1 2 3 Next >>