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21.
Crosslinking the CD27 antigen on T cells provides a costimulatory signal that, in concert with T-cell receptor crosslinking, can induce T- cell proliferation and cellular immune activation. We find that chronic lymphocytic leukemia (CLL) B cells from most patients coexpress both membrane-bound and soluble CD27, along with its newly identified ligand, CD70. The expression of soluble CD27 may preclude leukemic B cells from stimulating T cells via CD70, thereby potentially impairing their ability to function as effective antigen-presenting cells. We find that leukemic B-cell expression of soluble and membrane-bound CD27 can be downmodulated through a CD40-dependent signal. This signal also induces enhanced expression of CD70 on both normal and leukemic B cells. We find that tumor necrosis factor (TNF)-alpha, or the Th1 cytokine interferon (IFN)-gamma, also can induce downmodulation of CD27, whereas Th2-associated cytokines interleukin-4 (IL-4) or IL-10 can enhance leukemic B-cell expression of this accessory molecule. The modulation of CD27 induced by these conditions is accompanied by reciprocal changes in the expression levels of CD70, suggesting that these accessory molecules may be engaged in reciprocal receptor-ligand downmodulation. Consistent with this, we observe that co-culture of CLL B cells with transfected murine plasmacytoma cells that express human CD70 affects downmodulation of CD27 and enhanced expression of CD70 on leukemic B cells, but does not affect expression of CD27 mRNA. However, we find that CD40-crosslinking, in addition to reducing the level of CD27 protein, also reduces leukemic B-cell expression of CD27 mRNA. This argues that the changes in the expression levels of CD27 following CD40-signaling are not simply due to induced increases in the expression levels of CD70. Finally, we demonstrate that reciprocal changes in expression of CD27 and CD70 may contribute to the enhanced antigen-presenting capacity of CLL B cells after CD40-dependent leukemic B-cell activation. These findings expand the understanding of the regulation of costimulatory molecules important in antigen presentation and also have implications for the immunobiology of and therapy for CLL. 相似文献
22.
High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy 总被引:2,自引:1,他引:2
Brown RA; Herzig RH; Wolff SN; Frei-Lahr D; Pineiro L; Bolwell BJ; Lowder JN; Harden EA; Hande KR; Herzig GP 《Blood》1990,76(3):473-479
Seventy-five patients with resistant acute leukemia or lymphoma received high-dose cyclophosphamide and etoposide to explore the activity of this combination in resistant hematologic malignancies, and to determine the maximum doses of these drugs that can be combined without bone marrow transplantation. Etoposide was administered over 29 to 69 hours by continuous infusion corresponding to total doses of 1.8 g/m2 to 4.8 g/m2. Cyclophosphamide, 50 mg/kg/d, was administered on 3 or 4 consecutive days total 150 to 200 mg/kg ideal body weight). At all dose levels myelosuppression was severe but reversible. Mucosal toxicity was dose-limiting with the maximum tolerated dose level combining etoposide 4.2 g/m2 with cyclophosphamide 200 mg/kg. Continuous etoposide infusion produced stable plasma levels that were lower than would be achieved after administration by short intravenous infusion, and this could explain our ability to escalate etoposide above the previously reported maximum tolerated dose. There were 28 complete (35%) and 12 partial (16%) responses. Median duration of complete response (CR) was 3.5 months (range 1.1 to 20+). Seventeen of 40 patients (42%) with acute myelogenous leukemia (AML) achieved CR, including 6 of 20 (30%) with high-dose cytosine arabinoside resistance. We conclude that bone marrow transplantation is not required after maximum tolerated doses of etoposide and cyclophosphamide. This regimen is active in resistant hematologic neoplasms, and the occurrence of CR in patients with high-dose cytosine arabinoside-resistant AML indicates a lack of complete cross-resistance between these regimens. 相似文献
23.
24.
Jane Topolovec-Vranic Marlene Santos Andrew J Baker Orla M Smith Karen EA Burns 《Canadian respiratory journal》2014,21(5):293-296
INTRODUCTION:
Alterations from first-party and surrogate decision-maker consent can enhance the feasibility of research involving critically ill patients.OBJECTIVE:
To describe the use of a deferred-consent model to enable participation of critically ill patients in a minimal-risk biomarker study.METHODS:
A prospective observational study was conducted in which serum biomarker samples were collected three times daily over the first 14 days following aneurysmal subarachnoid hemorrhage. Sample collection was initiated on intensive care unit admission and consent was obtained when research personnel could approach the patient or the patient’s surrogate decision maker.RESULTS:
Twenty-seven patients were eligible for the study, of whom only five were capable of providing informed consent. Full consent was obtained for 21 (78%) patients through self- (n=4) and surrogate (n=17) consent. Partial consent or refusal (only permitting the collection of blood samples as a part of routine care or use of data) occurred in three patients. Among the 22 consents sought from surrogates, three (11%) refused participation. The refusals included the sickest patients in the cohort. Once consent was provided, no patient or surrogate withdrew consent before study completion.DISCUSSION:
Use of a deferred consent model enabled participation of critically ill patients in a minimal-risk biomarker study with no withdrawals.CONCLUSIONS:
Further research and enhanced awareness of the potential utility of hybrid models, including deferred consent in addition to patient or surrogate consent, in the conduct of low-risk and minimally interventional time-sensitive studies of critically ill patients are required. 相似文献25.
26.
Hematologic and immunomodulatory effects of an interleukin-1 receptor antagonist coinfusion during low-dose endotoxemia in healthy humans 总被引:3,自引:0,他引:3
Granowitz EV; Porat R; Mier JW; Orencole SF; Callahan MV; Cannon JG; Lynch EA; Ye K; Poutsiaka DD; Vannier E 《Blood》1993,82(10):2985-2990
Endotoxin is a component of gram-negative bacteria that causes hematologic and immunologic changes through its induction of cytokines. Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of IL-1 that competes with IL-1 for occupancy of cell-surface receptors but possesses no agonist activity. We investigated the ability of human recombinant IL-1Ra to block the effects of low-dose endotoxin. Fourteen healthy male volunteers between 18 and 30 years old were injected intravenously with 3 ng/kg Escherichia coli endotoxin. Concurrent with the injections, nine volunteers received a 3-hour continuous intravenous infusion of IL-1Ra. The other five subjects were given a 3-hour infusion of saline. Volunteers injected with endotoxin experienced a threefold increase in circulating neutrophils over baseline. This neutrophilia was significantly reduced by 48% in subjects administered endotoxin plus IL-1Ra (P = .0253). Ex vivo mitogen-induced peripheral blood mononuclear cell proliferation decreased by greater than 60% at 3 and 6 hours after endotoxin injection (P = .0053). This endotoxin-induced reduction in mitogen response was reversed in subjects coinjected with IL-1Ra (P = .0253). Endotoxin-induced symptoms, fever, and tachycardia were unaffected by IL-1Ra. IL-1 appears to be an important mediator in endotoxemia because some of its hematologic and immunomodulatory effects can be blocked by IL-1Ra. 相似文献
27.
The balance of tissue-type plasminogen activator (t-PA) production and degradation determines its concentration in blood and tissues. Disturbance of this balance may result in either increased or decreased proteolysis. In the present study, we identified the receptor systems involved in the degradation of t-PA by human monocytes/macrophages in culture. Monocytes were cultured and became macrophages within 2 days. At 4 degrees C, 125I-t-PA bound to macrophages with high (apparent dissociation constant [kd], 1 to 5 nmol/L) and low affinity (kd > 350 nmol/L). At 37 degrees C, the cells internalized and degraded t-PA via the high affinity binding sites, which were partially inhibited by mannan. The low affinity binding sites were 6-aminohexanoic acid- inhibitable and not involved in t-PA degradation. Degradation of t-PA was upregulated during differentiation of monocytes to macrophages. Dexamethasone further upregulated the mannan-inhibitable t-PA degradation. Lipopolysaccharide downregulated both mannan-inhibitable and non-mannan-inhibitable t-PA degradation. Non-mannan-inhibitable degradation was completely blocked by recombinant 39-kD receptor- associated protein (RAP, inhibitor of lipoprotein receptor-related protein [LRP]), whereas mannan-inhibitable degradation was blocked by the addition of a monoclonal antibody against the mannose receptor. No differences between the degradation of t-PA and functionally inactivated t-PA were observed. We conclude that human monocyte-derived macrophages are able to bind, internalize, and degrade t-PA. Degradation of t-PA does not require complex formation with plasminogen activator inhibitors. The macrophages use two independently regulated receptors, namely, the mannose receptor and LRP, for the uptake and degradation of t-PA. 相似文献
28.
Systemic non‐biologic agents have long been in clinical use in medicine – often with considerable efficacy, albeit with some adverse effects – as with all medications. With the advent of biologic agents, all of which currently are restricted to systemic use, there is a growing need to ensure which agents have the better therapeutic ratio. The non‐biologic agents (NBAs) include a range of agents, most especially the corticosteroids (corticosteroids). This study reviews the corticosteroids in systemic use in management of orofacial mucocutaneous diseases; subsequent studies discuss corticosteroid‐sparing agents used in the management of orofacial diseases, such as calcineurin inhibitors used to produce immunosuppression; purine synthetase inhibitors; and cytotoxic and other immunomodulatory agents. 相似文献
29.
30.
Human and mouse cortical astrocytes differ in aquaporin‐4 polarization toward microvessels 下载免费PDF全文
Vigdis Andersen Eidsvaag Rune Enger Hans‐Arne Hansson Per Kristian Eide Erlend A. Nagelhus 《Glia》2017,65(6):964-973
Aquaporin‐4 (AQP4), the predominant water channel in the brain, is expressed in astrocytes and ependymal cells. In rodents AQP4 is highly polarized to perivascular astrocytic endfeet and loss of AQP4 polarization is associated with disease. The present study was undertaken to compare the expression pattern of AQP4 in human and mouse cortical astrocytes. Cortical tissue specimens were sampled from 11 individuals undergoing neurosurgery wherein brain tissue was removed as part of the procedure, and compared with cortical tissue from 5 adult wild‐type mice processed similarly. The tissue samples were immersion‐fixed and prepared for AQP4 immunogold electron microscopy, allowing quantitative assessment of AQP4's subcellular distribution. In mouse we found that AQP4 water channels were prominently clustered around vessels, being 5 to 10‐fold more abundant in astrocytic endfoot membranes facing the capillary endothelium than in parenchymal astrocytic membranes. In contrast, AQP4 was markedly less polarized in human astrocytes, being only two to three‐fold enriched in astrocytic endfoot membranes adjacent to capillaries. The lower degree of AQP4 polarization in human subjects (1/3 of that in mice) was mainly due to higher AQP4 expression in parenchymal astrocytic membranes. We conclude that there are hitherto unrecognized species differences in AQP4 polarization toward microvessels in the cerebral cortex. 相似文献