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

We investigated the ability of LF 08--0299, a new immunosuppressive compound, to prevent murine graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). A short term LF 08--0299 treatment at optimal dosage protected more than 75% of recipient mice from lethal GVHD induced either across minor antigens alone or the full H2 barrier. Furthermore, LF 08--0299 still prevented lethal GVHD when treatment was delayed to 10 days post-BMT. Long-term LF 08--0299-treated survivors were free of clinical signs of GVHD, and histopathologic examination of liver, skin, and intestines was normal, demonstrating that recipient mice did not develop chronic GVHD. We assessed the immunocompetence of long-term surviving recipient mice. Results from MLR and CTL assays were weak whereas responses against unrelated H2 antigens were reduced but still preserved. Moreover, in vivo transfer experiments demonstrated that spleen cells from long-term survivors were unable to induce lethal GVHD in irradiated recipients of host origin, while spleen cells injected in irradiated recipients of a host-unrelated H2 were fully competent to induce a lethal GVHD. Together these results indicate that stable chimeric recipient mice were specifically tolerant to host antigens. We further showed that while LF 08--0299 can protect recipient mice from lethal GVHD, it also preserved a graft-versus-leukemia effect when mice were inoculated with P815 tumor cells. These data suggest that LF 08--0299 may be a novel pharmaceutical agent that would prevent GVHD in human unrelated bone marrow transplantation.
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PMID:Prevention of lethal graft-versus-host disease following allogeneic bone marrow transplantation in mice by short course administration of LF 08-0299. 882 67

Twenty to 25% of patients with chronic myelogenous leukemia (CML) treated with interferon-alpha (IFN-A) achieve a complete cytogenetic response (CCR). However, cells bearing rearrangement of BCR/ABL can still be detected many years after achieving a CCR despite the absence of clinical evidence of active disease. It has been suggested that the disease is kept in a dormant state by immune mechanisms. How this is achieved is not known, but it has been speculated that p210BCR/ABL might be presented by malignant cells through HLA molecules, thus making them the target for specific immune cell killing. Because specific peptides will be expressed in association with certain HLA molecules, different HLA phenotypes could be associated with different response rates to IFN-A. The response to IFN-A-based therapies in 239 patients with chronic phase CML was analyzed according to their HLA phenotype. One hundred and ninety-four (81%) achieved complete hematologic response, 142 (59%) had a cytogenetic response which was major (MCR) in 93 patients (39%): complete (CCR) in 71 (30%) and partial (PCR) in 22 (9%). Patients with an HLA-B27 phenotype had the best response rate to IFN-A: 10 of 14 (71%) had an MCR, including eight (57%) with a CCR (P=0.02). Patients with HLA-B35, -A3, and -A31 also showed a trend towards a higher response rate, whereas patients with HLA-B18 had the lowest response rate (MCR 17%). Patients with HLA-B27 and those with HLA-A31 showed a trend for better survival, whereas patients with HLA-A2, -B7, or -B18 had a trend for shorter survival. We conclude that response to IFN-A in patients with CML may be associated with the HLA phenotype. However, a much larger population would be required to determine if the impact of HLA phenotype on survival is independent of other clinical prognostic features. These findings could be relevant for the understanding of immune mechanisms of control of CML and possibly the design of immune therapy for this disease.
Leukemia 1998 Apr
PMID:Association of HLA phenotype and response to interferon-alpha in patients with chronic myelogenous leukemia. 955 1

Dendritic cells (DC) are potent antigen-presenting cells responsible for the initiation of primary antigen-specific immune responses. In chronic myeloid leukaemia DC have been generated from Ph+ cells and these Ph+ DC are capable of stimulating cytolytic T-cell responses against the parent leukaemia cells. The prevalence of this phenomenon in acute leukaemia (AL) is unknown and we have therefore studied a variety of acute leukaemias to determine their potential for DC development. Peripheral blood mononuclear cells (PBMC) from 21 cases of AL were cultured in GM-CSF + TNF alpha. Of these cases, 15 were viable in culture and cells with typical DC morphology were observed in 12 of these 15 cases. DC growing in culture expressed either CDla and/or CD83 and were HLA-DR+ CD40+ CD80+ CD86+ typical of mature DC. In 9/12 cases the cultured cells possessed potent antigen-presenting capacity as measured in the allo-MLR. The malignant origin of the cultured DC was confirmed by FISH analysis in two cases (one 5q- and one Ph+ AL) and by persistent aberrant expression of CD19 in two cases of biphenotypic leukaemia. Functional DC may be derived from AL blasts in a significant number of patients and such DC may be capable of inducing leukaemia-specific immune responses with potential for clinically beneficial effects.
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PMID:The in-vitro generation of dendritic cells from blast cells in acute leukaemia. 985 28

Donor leukocyte infusions after allogeneic bone marrow transplantation can provide a curative graft-vs-leukemia (GVL) effect, but there is a significant risk of graft-vs-host (GVH) disease. A simple and effective method for controlling the fate of naive or primed T-lymphocytes in vivo without eliminating their beneficial properties is needed. In this report, photochemical treatment (PCT) ex vivo with a synthetic psoralen (S-59) and UVA light was evaluated as a pharmacological approach to limiting the proliferation and GVH potential of naive and primed donor T cells in vivo. S-59 rapidly intercalates into and cross-links DNA on UVA illumination. The effects of PCT on T cells were found to be both S-59 and UVA dose dependent. With selected PCT regimens, treated T cells still expressed activation markers (CD25 and CD69) and secreted IL-2 on activation, but they showed limited proliferative capacity in vitro and in vivo. Clonal expansion of CTL in MLR was reduced after PCT, but short term lytic activity of primed CTL was not affected. In a murine model of MHC-mismatched bone marrow transplantation, the addition of PCT-treated T cells to T-depleted bone marrow facilitated donor engraftment and complete chimerism without causing acute or chronic graft-vs-host disease. Allospecific GVL reactivity was reduced but not eliminated after PCT treatment. In an MHC-matched model using host-presensitized donor T cells, PCT significantly reduced GVH-associated mortality without eliminating GVL reactivity. Thus, PCT ex vivo offers a simple, rapid, and inexpensive method by which to control the fate of naive and primed T cells in vivo.
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PMID:Photochemical treatment with S-59 psoralen and ultraviolet A light to control the fate of naive or primed T lymphocytes in vivo after allogeneic bone marrow transplantation. 1052 21

Pre-B cell acute lymphoblastic leukaemia (cALL) commonly occurs in young patients and although successful conventional therapies are available (such as cytotoxic drugs and bone marrow transplantation) for a proportion of patients (approximately 30%) these are ultimately unsuccessful. Recurrence of disease is a result of the failure of the immune system to recognize these abnormal cells and down-regulation of crucial molecules required for cognate CD4(+) T cell recognition has been postulated as a means of immune escape. In this study we show that an embryonic kidney cell line (293 cells) transfected with CD154 (40 L.1) are capable of not only maintaining the viability of primary ALL cells in culture but can also up-regulate the expression of a number of crucial molecules involved in antigen recognition. We show that 40 L.1 cell stimulation of primary ALL cell cultures can not only enhance the allogeneic and autologous MLR response to such cells but will also induce CTL effectors which are capable of lysing wild-type autologous ALL cells. It is therefore conceivable that such an approach could be used to generate an active anti-tumour response in patients, following conventional therapy, reducing the incidence of recurrence.
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PMID:Enhancement of cALL immunogenicity by co-culture with a CD154 expressing 293 cell line. 1147 95

The success of allogeneic hematopoietic stem cell transplantation from HLA-disparate donors depends on the development of new strategies for graft-versus-host disease prevention able to target specifically donor antihost alloreactivity, while preserving GVL and antiviral immune surveillance. Recent experimental and clinical work has shown the feasibility of an approach based on induction of anergy to host alloantigens through blockade of B7/CD28 costimulatory signal in donor T cells, but data on the impact of this strategy on the recovery of the immune system are still lacking. We devised an ex vivo method for induction of host alloantigen-specific unresponsiveness based on treatment with the B7/CD28 blocking agent CTLA4-Ig associated with CsA. We then proceeded to assess the maintenance of an effective immune response towards viral pathogens and tumor cells after CTLA4-Ig/CsA treatment, by measuring the frequency of CTL precursors directed against CMV- and EBV-infected targets, and against autologous leukemic blasts. We demonstrated that (1) CTLA4-Ig and CsA can act synergistically in inducing a state of unresponsiveness to alloantigens; (2) the number of leukemia-reactive, EBV-specific and CMV-specific CTLp is not impaired by CTLA4-Ig/CsA treatment. Our data provide the first direct in vitro evidence that it is possible to preserve antiviral and antileukemia effector cells after blockade of CD28/B7 interaction during MLR.
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PMID:Human alloantigen-specific anergic cells induced by a combination of CTLA4-Ig and CsA maintain anti-leukemia and anti-viral cytotoxic responses. 1154 44

Dendritic cell (DC) plays a key role in antitumor immune response. However, there is a deficiency of DC function in the majority of leukemia patients. It is a novel idea that expanding DC in vitro and enhancing their antitumor immune function and DC-based tumor vaccines may be used as an efficient immune therapy for leukemia. In the project, the condition to induce DC from myeloid leukemia cell lines and its anti-leukemia response were investigated. HL-60, K562 and THP-1 cells were cultured with various combinations of cytokines for inducing DC. The morphologic features were analyzed with optical and electron microscopy. The phenotype of DC was detected by FCM with CD1a, CD40, CD80, CD86, HLA-A, B, C and HLA-DR monoclonal antibodies. The ability of DC stimulating lymphocyte proliferation was observed by allo-mixed lymphocyte reaction using (3)H-TdR incorporation. Cytotoxicity assay was measured by (51)Cr-release method. The level of IL-12 and IFN-gamma in supernatant of DC culture was measured by ELISA. It was proved that the DCs derived from K562, HL-60 and THP-1 cells showed a typical morphology of dendritic cell. The induced cells expressed the surface differentiation antigens of DC. A high expression of phenotypes was found in HL-60-DC and THP-1-DC stimulated by GM-CSF + IL-4 + TNF-gamma and K562-DC with GM-CSF + IL-4 + IL-12. The DCs from the 3 leukemia cell lines stimulated allo-MLR and CTL reaction strongly. Different contents of IL-12 were detected in the supernatants of DC culture and IFN-gamma in the coculture of DC and blood mononuclear cells. It is concluded that the myeloid leukemia cells are able to be induced DCs by cytokines in vitro. The different leukemia cells need different cytokines and cultural conditions. DCs derived from leukemia cells express phenotype of antigen-presenting cells. They have the ability of stimulating T lymphocyte proliferation and inducing CTL reaction to clear leukemia cells, and the DCs secrete IL-12 and increase secretion of IFN-gamma by T cells.
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PMID:[Study on induction of dendritic cells from myeloid leukemia cell lines and their antitumor immune function]. 1251 92

The purpose of this study was to investigate the function of dendritic cells derived from chronic myeloid leukemia (CML-DC). Mononuclear cells were prepared from bone marrow and peripheral blood of 24 patients with CML, and the DCs were obtained by incubation of MNCs with media containing GM-CSF, IL-4 and TNF-alpha. The phenotype of CML-DCs was identified by flow cytometry. FITC-dextran uptake, (3)H-TdR incorporation or MTT assay and lactate dehydrogenase release assay were used to detect uptake of exogenous antigen in immature DCs, the antigen presenting ability in mature DCs and specific cytotoxicity of CTL to leukemic cells, respectively. The DCs with high expression of CD1a, CD86, CD80, HLA-DR, CD54 and CD4 were obtained from marrow and blood of patients with CML. The uptake of FITC-DX was observed in early DCs. There was a potent stimulation to allo-MLR in DCs cultured for 7 - 10 days, and a lightly lower stimulation to auto-MLR. CML-DCs can induce the generation of specific cytotoxic T cells. These results suggest that CML-DCs are functional DCs with the ability to induce anti-leukemia effect.
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PMID:[The Function of Dendritic Cells Derived from Chronic Myeloid Leukemia] 1257 75

Adoptive immunotherapy with CTL against minor histocompatibility Ags (mHA) provides a promising way to treat leukemia relapse in allogeneic chimeras. Here we describe the in vitro generation of CTL against mHA in the dog. We tested their inhibitory effect on the growth of hemopoietic progenitor cells stimulated by hemopoietic growth factors in a 4-day suspension culture. CTL were produced by coculture of donor PBMC with bone marrow-derived dendritic cells (DCs). These DCs were characterized by morphology, high expression of MHC class II and CD1a, and the absence of the monocyte-specific marker CD14. Characteristically these cells stimulated allogeneic lymphocytes (MLR) and, after pulsing with a foreign Ag (keyhole limpet hemocyanin), autologous T cells. CTL were generated either ex vivo by coculture with DCs of DLA-identical littermates or in vivo by immunization of the responder with DCs obtained from a DLA-identical littermate. In suspension culture assays the growth of hemopoietic progenitor cells was inhibited in 53% of DLA-identical littermate combinations. In canine families mHA segregated with DLA as restriction elements. One-way reactivity against mHA was found in five littermate combinations. In two cases mHA might be Y chromosome associated, in three cases autosomally inherited alleles were detected. We conclude that CTL can be produced in vitro and in vivo against mHA on canine hemopoietic progenitor cells using bone marrow-derived DCs.
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PMID:Minor histocompatibility antigens on canine hemopoietic progenitor cells. 1279 11

Dendritic cells (DC) play a pivotal role in linking innate and adaptive immunity. Only mature DC are able to initiate adaptive immune responses by sensitising naive antigen-specific T cells. For clinical immunotherapeutic applications, safe and efficient clinical grade maturation factors of DC are required. Here, we investigated the impact of OM-197-MP-AC (OM-197), a synthetic lipid A analogue pseudo-dipeptide derived from amino acids linked to three fatty acid chains, on the maturation of human monocyte-derived-DC (Mo-DC) and leukemia-derived DC generated in serum-free conditions. After culture with clinical grade GM-CSF and IL-13, OM-197 at 20 microg/ml efficiently induced CD83+ Mo-DC. In comparison to immature Mo-DC that were derived by culture with GM-CSF and IL-13 only, CD40, CD80, CD86, HLA-ABC and HLA-DR molecules were up-regulated upon OM-197 or LPS treatment similarly. In MLR, OM-197-matured Mo-DC were found to be as potent stimulators as LPS-matured Mo-DC for CD4+ T cell proliferation. No significant difference in IFN-gamma quantification was shown between naive CD4+ T cells stimulated by LPS- or OM-197-Mo-DC suggesting that OM-197-Mo-DC can drive naive T cells towards a Th1 response profile that was mainly independent of IL-12 secretion. Similarly, CD8+ T cells could be efficiently polarized into IFN-gamma-secreting-cells by OM-197-Mo-DC, and activated polyclonal pp65-cytomegalovirus-specific CD8+ T lymphocytes. Finally, myeloid leukemic blasts were able to differentiate in vitro into mature functional DC-like cells upon OM-197 treatment in our culture model. Overall, the in vitro effects of clinical grade adjuvant OM-197, showed that it represents a potent inducer of both normal and leukemic-DC maturation, and is likely a good candidate for adjuvant immunotherapy in DC-based vaccines.
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PMID:OM-197-MP-AC adjuvant properties: the in vitro maturation of normal and leukemic dendritic cells in a serum-free culture model. 1548 Nov 42


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