Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In animal models and clinical trials, adoptive transfer of activated, antigen-specific CD8(+) T cells mediates tumor regression in a cell dose-dependent manner. The cytokine interleukin (IL)-12 promotes CD8(+) T-cell cytotoxicity and, with IL-18, synergistically up-regulates IFN-gamma release. We have shown that culturing CD8(+) T cells ex vivo with IL-12 and IL-18 enhanced antitumor responses in vivo and in vitro using a model of C1498/ovalbumin, a murine acute myeloid leukemia cell line expressing the antigen ovalbumin. Activated ovalbumin-specific CD8(+) T cells cultured with IL-12, IL-18, both, or neither were assayed for antigen-specific cytokine production and cytolytic activity and adoptively transferred to C57BL/6 mice with established tumors. Maximal IFN-gamma release occurred after T-cell culture with IL-12 and IL-18. Tumor-specific in vitro cytotoxicity was enhanced by IL-12, unaffected by addition of IL-18, and abrogated in perforin-deficient T cells irrespective of cytokine exposure. T cells cultured with IL-12 more effectively eliminated tumors, and addition of IL-18 did not further augment responses. IFN-gamma-deficient CD8(+) T cells showed effective antitumor activity that was enhanced by IL-12 with or without IL-18. Perforin-deficient CD8(+) T cells were poor mediators of antitumor activity, though, and showed no improvement after culture with IL-12 and/or IL-18. Thus, ex vivo culture with IL-12 was sufficient to augment antigen-specific in vitro cytotoxicity and antitumor activity in vivo in an IFN-gamma-independent but perforin-dependent manner. Ex vivo culture with IL-12 may improve CD8(+) T-cell immunotherapy of cancer in the absence of donor cell-derived IFN-gamma via perforin-mediated cytolysis.
 ...
PMID:Ex vivo culture with interleukin (IL)-12 improves CD8(+) T-cell adoptive immunotherapy for murine leukemia independent of IL-18 or IFN-gamma but requires perforin. 1665 48

In the present study, we analyzed the involvement of the BCR-ABL protein in the induction of antigen-specific CTL in order to develop an immunotherapeutic approach in patients with chronic myelogenous leukemia (CML). To accomplish this, we generated dendritic cells (DC) in vitro and electroporated them with various sources of RNA harboring the chimeric bcr-abl transcript. These genetically engineered DCs were used as antigen-presenting cells for the induction of CTLs. By applying this approach, we found that the CTLs induced by DCs transfected with RNA extracted from bcr-abl-positive K-562 cells or CML blasts lysed DCs transfected with the corresponding RNA, but failed to recognize epitopes derived from the chimeric BCR-ABL fusion protein in (51)Cr-release assays. In contrast, they were able to lyse autologous DCs electroporated with RNA isolated from patients with acute myeloid leukemia, indicating that antigens shared among these malignant cells are involved and recognized by these CTLs. In patients with CML in complete cytogenetic remission during IFN-alpha treatment, we detected some reactivity of CD8(+) T cells against BCR-ABL in IFN-gamma ELISPOT assays, which was weaker as compared with proteinase 3 (PR3)- or prame-directed responses, suggesting that the BCR-ABL protein is less immunogenic as compared with other CML-derived antigens.
 ...
PMID:BCR-ABL is not an immunodominant antigen in chronic myelogenous leukemia. 1674 Jul 29

Clinical application of immunotherapy for acute myeloid leukemia (AML) requires the efficient induction of dendritic cells (DCs) from AML blast cells using in vitro culture. We examined the effect of autologous serum on the properties of leukemic DCs derived from leukemic cells of AML patients by culture in AIM-V medium with GM-CSF, IL-4, TNF-alpha, and 0, 2, 5, or 10% human autologous serum. The expressions of CD80, CD83, CD86, and HLA-DR were upregulated under all culture conditions; however, 10% autologous serum induced the highest expression levels of several molecules. The capacity of leukemic DCs to stimulate allogeneic T cells increased with increasing serum concentration. Stimulation of autologous CD3(+) T cells with leukemic DCs grown in the presence of various concentrations of autologous serum resulted in induction of more IFN-gamma-secreting cells than was the case for unprimed CD3(+) T cells. Leukemic DCs cultured with 10% autologous serum induced the highest numbers of IFN-gamma-secreting cells and CD8(+)CD56(+) T cells from autologous T cells. These results suggest that culture of AML blast cells in the presence of autologous serum could be used to generate leukemic DCs for immunotherapy against AML. The highest serum concentration appeared optimal for generating the most potent leukemic DCs.
 ...
PMID:Optimization of the concentration of autologous serum for generation of leukemic dendritic cells from acute myeloid leukemic cells for clinical immunotherapy. 1712 Feb 32

The molecular pathogenesis of the myeloid leukemias that frequently occur in patients with Fanconi anemia (FA) is not well defined. Hematopoietic stem cells bearing inactivating mutations of FA complementation group C (FANCC) are genetically unstable and hypersensitive to apoptotic cytokine cues including IFN-gamma and TNF-alpha, but neoplastic stem cell clones that arise frequently in vivo are resistant to these cytokines. Reasoning that the combination of genetic instability and cytokine hypersensitivity might create an environment supporting the emergence of leukemic stem cells, we tested the leukemia-promoting effects of TNF-alpha in murine stem cells. TNF-alpha exposure initially profoundly inhibited the growth of Fancc-/- stem cells. However, longer-term exposure of these cells promoted the outgrowth of cytogenetically abnormal clones that, upon transplantation into congenic WT mice, led to acute myelogenous leukemia. TNF-alpha induced ROS-dependent genetic instability in Fancc-/- but not in WT cells. The leukemic clones were TNF-alpha resistant but retained their characteristic hypersensitivity to mitomycin C and exhibited high levels of chromosomal instability. Expression of FANCC cDNA in Fancc-/- stem cells protected them from TNF-alpha-induced clonal evolution. We conclude that TNF-alpha exposure creates an environment in which somatically mutated preleukemic stem cell clones are selected and from which unaltered TNF-alpha-hypersensitive Fancc-/- stem cells are purged.
 ...
PMID:TNF-alpha induces leukemic clonal evolution ex vivo in Fanconi anemia group C murine stem cells. 1796 Feb 49

Invasive fungal infection in severely immunosuppressed patients with acute myelogenous leukemia (AML) remains a serious challenge because (a) of the higher rates of non-drug susceptible fungal sinopulmonary disease; (b) despite advances in diagnostic fungal assays, the correct identification of causative organism(s) is difficult, and antifungal drug susceptibility data are seldom available during clinical decision making; and (c) the increasing frequencies of zygomycosis, scedosporiosis, and highly virulent Candida tropicalis infection have undermined the gains attributed to effective anti-Aspergillus drug therapy. Recombinant cytokines, such as recombinant human (rh)GM-CSF and interferon (IFN)-gamma, have been explored to augment host antifungal immune responses. These cytokines promote activation and recruitment of granulocyte and mononuclear phagocytic effector cells. Prophylaxis with rhGM-CSF was associated with significantly fewer life-threatening and serious (grade > or =3) infections, especially in older patients undergoing treatment for AML. The limited experience with rhGM-CSF for the treatment of invasive fungal infections in combination with antifungal drug(s) was associated with a favorable outcome, and in contrast to Escherichia coli-derived rhGM-CSF, the new preparation (sargramostim) was well tolerated and rarely associated with serious systemic toxicities. Similarly, IFN-gamma has been successfully used in patients with antimicrobial drug-refractory and/or disseminated fungal infection. Most patients tolerate the T-helper type 1 protagonist cytokine without serious adverse events. In difficult-to-treat fungal infections, the addition of cytokines appears to improve outcome and may be considered early in severely immunosuppressed patients with AML.
 ...
PMID:Difficulties with fungal infections in acute myelogenous leukemia patients: immune enhancement strategies. 1803 33

T lymphocytes are an integral part of the effective immune response against various tumors, but they are frequently functionally unresponsive in tumor-bearing patients. This study was aimed to investigate the T lymphocyte function of patients with acute myeloid leukemia (AML) in different status through analyzing intracellular cytokine characteristics of T lymphocytes in AML patients. The T lymphocytes from 18 de nuevo AML patients in different status and 10 healthy controls were stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin in the presence of monensin, and were stained with fluorescent McAbs CD4-PITC, CD8-FITC and IFNgamma-PE, ILA-PE, then their T lymphocytes were analyzed by flow cytometry. The results showed that IFN-gamma level in CD4+ and CD8+ T cells of de novo AML patients was significantly lower as compared with healthy controls (p<0.05), while IL-4 level in CD4+ and CD8+ T cells was low too, there was no significant difference between de novo AML patients and healthy controls. In AML patients in clinical remission, IFNgamma level in CD8+ T cells was significantly higher than that in de novo AML patients (p<0.05), but there was no significant difference as compared with healthy controls (p>0.05). In relapsed AML patients, IFNgamma level in CD4+ and CD8+ T cells was significantly lower than that in healthy controls and in AML patients with CR (p<0.05), while IL-4 level was significantly higher than that in healthy controls and de nuevo AML patients (p<0.05). It is concluded that the cytokine secretion in T cell subsets of AML patients in different status is changed. Correspondingly, the Th1/Tc1 level is low after stimulating CD4+ and CD8+ T cells in peripheral blood of de novo AML patients, but not different from healthy controls. Though the Th1 level in T cells of AML patients in complete remission is low, but Tc1 response is even enhanced as high as the healthy controls. The Th2/Tc2-like response of CD4+ and CD8+ T cells in relapsed AML patients obviously increases when compared with Th1/Tc1-like response.
 ...
PMID:[Intracellular cytokine expression characteristics of activated T lymphocytes in patients with acute myeloid leukemia]. 1808 57

A child with acute myeloid leukemia presented with multiple liver lesions mimicking hepatosplenic candidiasis during the neutropenic phase following the induction chemotherapy. All the available diagnostic tools showed repeatedly negative results, including galactomannan. An enzyme-linked immunospot (ELISPOT) assay showed a high number of Aspergillus-specific T cells producing interleukin-10 [TH2(IL-10)] and a low number of Aspergillus-specific T cells producing gamma interferon [TH1(IFN-gamma)], revealing invasive aspergillosis (IA) before the confirmatory biopsy. A progressive skewing from the predominance of TH2(IL-10) to a predominance of TH1(IFN-gamma) was observed close to the complete resolution of the infection and foreshadowed the outcome. The ELISPOT assay holds promise for diagnosing pediatric IA.
 ...
PMID:Assessment of Aspergillus-specific T cells for diagnosis of invasive aspergillosis in a leukemic child with liver lesions mimicking hepatosplenic candidiasis. 1866 32

Compelling evidences indicate a key role for regulatory T cells (T(reg)) on the host response to cancer. The Wilms' tumor antigen (WT1) is overexpressed in several human leukemias and thus considered as promising target for development of leukemia vaccine. However, recent studies indicated that the generation of effective WT1-specific cytotoxic T cells can be largely affected by the presence of T(regs). We have generated T-cell lines and clones that specifically recognized a WT1-84 (RYFKLSHLQMHSRKH) peptide in an HLA-DRB1*0402-restricted manner. Importantly, they recognized HLA-DRB1*04-matched fresh leukemic cells expressing the WT1 antigen. These clones exerted a T helper 2 cytokine profile, had a CD4(+)CD25(+)Foxp3(+)GITR(+)CD127(-) T(reg) phenotype, and significantly inhibited the proliferative activity of allogeneic T cells independently of cell contact. Priming of alloreactive T cells in the presence of T(regs) strongly inhibited the expansion of natural killer (NK), NK T, and CD8(+) T cells and had an inhibitory effect on NK/NK T cytotoxic activity but not on CD8(+) T cells. Furthermore, priming of T cells with the WT1-126 HLA-A0201-restricted peptide in the presence of T(regs) strongly inhibited the induction of anti-WT1-126 CD8(+) CTL responses as evidenced by both very low cytotoxic activity and IFN-gamma production. Moreover, these T(reg) clones specifically produced granzyme B and selectively induced apoptosis in WT1-84-pulsed autologous antigen-presenting cells but not in apoptotic-resistant DR4-matched leukemic cells. Importantly, we have also detected anti-WT1-84 interleukin-5(+)/granzyme B(+)/Foxp3(+) CD4(+) T(regs) in five of eight HLA-DR4(+) acute myeloid leukemia patients. Collectively, our in vitro and in vivo findings strongly suggest important implications for the clinical manipulation of T(regs) in cancer patients.
 ...
PMID:The Wilms' tumor antigen is a novel target for human CD4+ regulatory T cells: implications for immunotherapy. 1867 60

CD1d-restricted invariant NKT (iNKT) cells can enhance immunity to cancer or prevent autoimmunity, depending on the cytokine profile secreted. Antitumor effects of the iNKT cell ligand alpha-galactosylceramide (alphaGC) and iNKT cell adoptive transfer have been demonstrated in various tumor models. Together with reduced numbers of iNKT cells in cancer patients, which have been linked to poor clinical outcome, these data suggest that cancer patients may benefit from therapy aiming at iNKT cell proliferation and activation. Herein we present results of investigations on the effects of human iNKT cells on Ag-specific CTL responses. iNKT cells were expanded using alphaGC-pulsed allogeneic DC derived from the acute myeloid leukemia cell line MUTZ-3, transduced with CD1d to enhance iNKT cell stimulation, and with IL-12 to stimulate type 1 cytokine production. Enhanced activation and increased IFN-gamma production was observed in iNKT cells, irrespective of CD4 expression, upon stimulation with IL-12-overexpressing dendritic cells. IL-12-stimulated iNKT cells strongly enhanced the MART-1 (melanoma Ag recognized by T cell 1)-specific CD8(+) CTL response, which was dependent on iNKT cell-derived IFN-gamma. Furthermore, autologous IL-12-overexpressing dendritic cells, loaded with Ag as well as alphaGC, was superior in stimulating both iNKT cells and Ag-specific CTL. This study shows that IL-12-overexpressing allogeneic dendritic cells expand IFN-gamma-producing iNKT cells, which may be more effective against tumors in vivo. Furthermore, the efficacy of autologous Ag-loaded DC vaccines may well be enhanced by IL-12 overexpression and loading with alphaGC.
 ...
PMID:IFN-gamma-producing human invariant NKT cells promote tumor-associated antigen-specific cytotoxic T cell responses. 1868 35

Natural killer (NK) cells are key players of innate immunity. Besides their major cytotoxic function, NK cells can also produce inflammatory cytokines such as interferon (IFN)-gamma. In this way, NK cells can shape adaptive immune responses through activation of dendritic cells (DC), thereby promoting the bidirectional cross-talk between NK cells and DC. Including this helper function of NK cells in cancer vaccination might be important for the induction of effective T cell responses. Here, we explored the capacity of purified human NK cells to produce IFN-gamma upon two-signal stimulation using different types of acute myeloid leukemia (AML) cells and type I IFN. Based on our previous findings that AML cells produce IFN-alpha upon electroporation with the synthetic double-stranded (ds)RNA polyriboinosinic polyribocytidylic acid (poly(I:C)), we hypothesized that dsRNA-loaded tumor cells provide both signals to elicit an NK cell-driven IFN-gamma production. Our results show that in vitro, NK cells become strong IFN-gamma-secreting cells upon stimulation with specific AML cells and IFN-alpha, with a variable responsiveness against different AML cell lines. Importantly, loading of AML cells with poly(I:C) is an elegant method to provide NK cells with both signals, a feature that could have important clinical implications because it obviates the side effects of systemic cytokine administration. Moreover, in addition to our previous findings that DC become activated upon phagocytosis of poly(I:C)-electroporated AML cells, these data strongly encourage future research on the potential of dsRNA-transfected AML cells and their effect to favor NK-DC cross-talk for the design of leukemia vaccines.
 ...
PMID:Acute myeloid leukemic cell lines loaded with synthetic dsRNA trigger IFN-gamma secretion by human NK cells. 1884 37


<< Previous 1 2 3 4 5 Next >>