Medicine (Austin & Northern Health) - Research Publications

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    Fas transduces activation signals in normal human T lymphocytes.
    Alderson, MR ; Armitage, RJ ; Maraskovsky, E ; Tough, TW ; Roux, E ; Schooley, K ; Ramsdell, F ; Lynch, DH (Rockefeller University Press, 1993-12-01)
    The Fas gene encodes a cell surface molecule that is a member of the the nerve growth factor/tumor necrosis factor receptor family of proteins and can mediate programmed cell death (apoptosis) in certain transformed cell lines. To characterize further the biological function of Fas, particularly with regard to its function in normal cells, a panel of monoclonal antibodies (mAbs) was generated against the extracellular portion of human Fas. Some of these mAbs induced apoptosis in transformed cell lines expressing Fas, but only when immobilized on the culture vessel. One of the new Fas mAbs (M38) was used for studies on normal lymphoid cells and found to stimulate the proliferation of purified human T cells and thymocytes when immobilized on culture wells along with CD3 antibody. T cell proliferation induced by Fas mAb was largely interleukin 2 independent and was demonstrated to be due to a direct effect on the precursor T cell. Thus, the data demonstrate that in addition to a role in the induction of apoptosis in certain transformed cell lines, the Fas protein may also play an important role in the activation and proliferation of normal T cells.
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    Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice.
    Peschon, JJ ; Morrissey, PJ ; Grabstein, KH ; Ramsdell, FJ ; Maraskovsky, E ; Gliniak, BC ; Park, LS ; Ziegler, SF ; Williams, DE ; Ware, CB ; Meyer, JD ; Davison, BL (Rockefeller University Press, 1994-11-01)
    Interleukin 7 (IL-7) stimulates the proliferation of B cell progenitors, thymocytes, and mature T cells through an interaction with a high affinity receptor (IL-7R) belonging to the hematopoietin receptor superfamily. We have further addressed the role of IL-7 and its receptor during B and T cell development by generating mice genetically deficient in IL-7R. Mutant mice display a profound reduction in thymic and peripheral lymphoid cellularity. Analyses of lymphoid progenitor populations in IL-7R-deficient mice define precisely those developmental stages affected by the mutation and reveal a critical role for IL-7R during early lymphoid development. Significantly, these studies indicate that the phase of thymocyte expansion occurring before the onset of T cell receptor gene rearrangement is critically dependent upon, and mediated by the high affinity receptor for IL-7.
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    Prevention of peripheral tolerance by a dendritic cell growth factor: flt3 ligand as an adjuvant.
    Pulendran, B ; Smith, JL ; Jenkins, M ; Schoenborn, M ; Maraskovsky, E ; Maliszewski, CR (Rockefeller University Press, 1998-12-07)
    Injections of soluble proteins are poorly immunogenic, and often elicit antigen-specific tolerance. The mechanism of this phenomenon has been an enduring puzzle, but it has been speculated that tolerance induction may be due to antigen presentation by poorly stimulatory, resting B cells, which lack specific immunoglobulin receptors for the protein. In contrast, adjuvants, or infectious agents, which cause the release of proinflammatory cytokines such as tumor necrosis factor alpha and interleukin 1beta in vivo are believed to recruit and activate professional antigen-presenting cells to the site(s) of infection, thereby eliciting immunity. Here we show that administration of Flt3 ligand (FL), a cytokine capable of inducing large numbers of dendritic cells (DCs) in vivo, (a) dramatically enhances the sensitivity of antigen-specific B and T cell responses to systemic injection of a soluble protein, through a CD40-CD40 ligand-dependent mechanism; (b) influences the class of antibody produced; and (c) enables productive immune responses to otherwise tolerogenic protocols. These data support the hypothesis that the delicate balance between immunity and tolerance in vivo is pivotally controlled by DCs, and underscore the potential of FL as a vaccine adjuvant for immunotherapy in infectious disease and other clinical settings.
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    Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified.
    Maraskovsky, E ; Brasel, K ; Teepe, M ; Roux, ER ; Lyman, SD ; Shortman, K ; McKenna, HJ (Rockefeller University Press, 1996-11-01)
    Dendritic cells (DC) are the most efficient APC for T cells. The clinical use of DC as vectors for anti-tumor and infectious disease immunotherapy has been limited by their trace levels and accessibility in normal tissue and terminal state of differentiation. In the present study, daily injection of human Flt3 ligand (Flt3L) into mice results in a dramatic numerical increase in cells co-expressing the characteristic DC markers-class II MHC, CD11c, DEC205, and CD86. In contrast, in mice treated with either GM-CSF, GM-CSF plus IL-4, c-kit ligand (c-kitL), or G-CSF, class II+ CD11c+ cells were not significantly increased. Five distinct DC subpopulations were identified in the spleen of Flt3L-treated mice using CD8 alpha and CD11b expression. These cells exhibited veiled and dendritic processes and were as efficient as rare, mature DC isolated from the spleens of untreated mice at presenting allo-Ag or soluble Ag to T cells, or in priming an Ag-specific T cell response in vivo. Dramatic numerical increases in DC were detected in the bone marrow, gastro-intestinal lymphoid tissue (GALT), liver, lymph nodes, lung, peripheral blood, peritoneal cavity, spleen, and thymus. These results suggest that Flt3L could be used to expand the numbers of functionally mature DC in vivo for use in clinical immunotherapy.
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    Dendritic cell development in culture from thymic precursor cells in the absence of granulocyte/macrophage colony-stimulating factor.
    Saunders, D ; Lucas, K ; Ismaili, J ; Wu, L ; Maraskovsky, E ; Dunn, A ; Shortman, K (Rockefeller University Press, 1996-12-01)
    The earliest lymphoid precursor population in the adult mouse thymus had previously been shown to produce not only T cells, but also dendritic cell (DC) progeny on transfer to irradiated recipients. In this study, culture of these isolated thymic precursors with a mixture of cytokines induced them to proliferate and to differentiate to DC, but not to T lineage cells. At least 70% of the individual precursors had the capacity to form DC. The resultant DC were as effective as normal thymic DC in the functional test of T cell stimulation in mixed leukocyte cultures. The cultured DC also expressed high levels of class I and class II major histocompatibility complex, together with CD11c, DEC-205, CD80, and CD86, markers characteristic of mature DC in general. However, they did not express CD8 alpha or BP-1, markers characteristic of normal thymic DC. The optimized mixture of five to seven cytokines required for DC development from these thymic precursors did not include granulocyte/macrophage colony stimulating factor (GM-CSF), usually required for DC development in culture. The addition of anti-GM-CSF antibody or the use of precursors from GM-CSF-deficient mice did not prevent DC development. Addition of GM-CSF was without effect on DC yield when interleukin (IL) 3 and IL-7 were present, although some stimulation by GM-CSF was noted in their absence. In contrast, DC development was enhanced by addition of the Flt3/Flk2 ligand, in line with the effects of the administration of this cytokine in vivo. The results indicate that the development of a particular lineage of DC, probably those of lymphoid precursor origin, may be independent of the myeloid hormone GM-CSF.
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    Reduction of carboplatin induced emesis by ondansetron.
    Harvey, VJ ; Evans, BD ; Mitchell, PL ; Mak, D ; Neave, LM ; Langley, GB ; Dickson, DS (Springer Science and Business Media LLC, 1991-06)
    Ondansetron is a selective 5-HT3 antagonist with significant antiemetic properties in patients receiving cytotoxic chemotherapy. Patients who had suffered severe vomiting on carboplatin alone (23 patients with ovarian carcinoma) or in combination (two patients with testicular cancer) despite intensive antiemetic regimens were treated with ondansetron, given as 8 mg immediately prior to carboplatin followed by 8 mg orally, 8 hourly for 5 days. Twenty-five patients received 58 courses of ondansetron. In the first 24 h after the first course of chemotherapy with ondansetron, 17 patients (68%) experienced no vomiting, five patients (20%) had almost complete control and the other three patients had partial control. During the subsequent 4 days slightly lesser control was achieved. Nausea was similarly controlled in most patients. Twenty-two patients stated a preference for ondansetron with future chemotherapy. Fourteen patients received additional chemotherapy with ondansetron and in only three patients did the efficacy of therapy lessen. Toxicity was mild and transient with headache and constipation predominant. No extrapyramidal reaction was seen. Sedation was absent. Ondansetron is highly effective in refractory vomiting associated with carboplatin chemotherapy. It may be particularly beneficial when an extrapyramidal reaction has occurred on previous antiemetics and when sedation is unacceptable.
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    Platinum-Taxol non-cross resistance in epithelial ovarian cancer.
    Gore, ME ; Preston, N ; A'Hern, RP ; Hill, C ; Mitchell, P ; Chang, J ; Nicolson, M (Springer Science and Business Media LLC, 1995-06)
    The aim of this study was to assess the clinical evidence for platinum-Taxol non-cross-resistance in patients with epithelial ovarian cancer. Unlike other studies, only patients who had demonstrably progressive disease on platinum therapy were analysed. Patients received 135-200 mg m-2 of Taxol over 3 or 24 h and all patients were assessed for response by computerised axial tomography. The overall response rate was 22.2% (8/36 patients, 95% CI 10-39%). Only patients who received > or = 175 mg m-2 of Taxol responded (26.7%; 8/30 patients, 95% CI 12-46%). No complete responses were seen and the duration of response was short, median 7 months (range 5-9+). Response was associated with a short treatment-free interval (P = 0.02); only those who were treated immediately after they had progressed on their previous platinum therapy responded. Response duration was associated with a good performance status (P < 0.05). Platinum and Taxol are non-cross-resistant in a proportion of patients and therefore patients who are resistant to platinum compounds may benefit from Taxol although the duration of any response is short. These data support current strategies that involve combining Taxol with platinum compounds as first-line therapy in advanced epithelial ovarian cancer.
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    Dose-intense weekly cyclophosphamide, methotrexate, 5-fluorouracil, vincristine and prednisolone (CMFP) in advanced breast cancer.
    Cebon, JS ; Bishop, JF ; Harvey, V ; Mason, B ; Jeal, PN (Springer Science and Business Media LLC, 1990-01)
    Weekly chemotherapy with cyclophosphamide 80 mg m-2 day-1 p.o. continuously, methotrexate 35 mg m-2 week-1 i.v., 5-fluorouracil 500 mg m-2 week-1 i.v., vincristine 1.4 mg m-2 i.v. every two weeks and prednisolone 20 mg m-2 day-1 p.o. continuously (CMFVP) was prospectively studied in 45 previously untreated outpatients with advanced breast cancer to determine the feasibility of delivering a dose-intense regimen. Of 40 evaluable patients, complete response (CR) occurred in one patient, partial response (PR) in 20 (CR + PR 53%), stable in eight, progression in 11 and five were unevaluable for response. The median relapse-free survival for responders was 25 weeks and median survival for all patients was 31 weeks. The mean dose intensity relative to the Cooper regimen fell from 1.02 to 0.6 within the first 4 weeks of treatment and the median dose intensity achieved for all patients on study was only 0.52. Eighty-seven per cent of patients had treatment delays with a mean of 3.9 delays per patient and 71% had dose reductions. Neutropenia was the major toxicity with WHO grade 3 or 4 neutropenia (less than 1.0 x 10(9) l-1) in 62% of patients and three septic deaths while neutropenic. Dose-intense weekly CMFVP in this schedule cannot be delivered to previously untreated outpatients with advanced breast cancer.
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    Abnormal phosphomonoester signals in 31P MR spectra from patients with hepatic lymphoma. A possible marker of liver infiltration and response to chemotherapy.
    Dixon, RM ; Angus, PW ; Rajagopalan, B ; Radda, GK (Springer Science and Business Media LLC, 1991-06)
    Hepatic infiltration by lymphoma can be difficult to detect by conventional methods. We have studied 22 patients in vivo 31P magnetic resonance spectroscopy of the liver and compared the results with the clinical staging and assessment of liver involvement by computed tomography (CT), ultrasound (US), and liver function tests (LFTs). We find that the phosphomonoester (PME) to ATP, and the PME to Pi ratios are the best indication of liver involvement as in all the patients with liver involvement apparent on CT or US, these ratios were elevated (greater than 2 s.d. above the control mean). Of the patients with deranged LFTs but normal CT or US, five out of nine showed increased PME/ATP and PME/Pi ratios, and in the patients with normal LFTs and normal CT or US, three out of eight patients had raised PME ratios. Extracts of lymphomatous lymph nodes contain high concentrations of phosphoethanolamine which suggests that this compound is responsible for the increase in the PME peak. Eleven patients were studied again after chemotherapy, and those with initially raised PME/ATP and PME/Pi ratios all showed a decrease in these ratios towards normal. The patients with initially normal ratios showed no changes.