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Double-knockout Mice (double-knockout + mouse)

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Medical Sciences	100%

Selected Abstracts

IL-18, but not IL-12, is required for optimal cytokine production by influenza virus-specific CD8+ T cells

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2007
Alice
Abstract The potent innate cytokines IL-12 and IL-18 are considered to be important antigen-independent mediators of IFN-, production by NK cells and T,lymphocytes. The present analysis addresses the physiological role of IL-12 and IL-18 in the generation of virus-specific CD8+ T cells. Both wt C57BL/6J (B6) mice and mice with disrupted IL-12p40 (IL-12p40,/,) or IL-18 (IL-18,/,) genes were infected with an influenza,A virus and the characteristics of the resultant epitope-specific CD8+ T cell responses were compared. While IL-12 appeared to have no notable effect on either virus growth or on CD8+ T cell response profiles, the absence of IL-18 was associated with delayed virus clearance from the lung and, despite normal numbers, a significantly reduced production of IFN-,, TNF-,, and IL-2 by epitope-specific CD8+ T cells. While this cytokine phenotype was broadly maintained in IL-12p40/IL-18 double-knockout mice, no evidence was seen for any additive effect. Together, our results suggest that IL-18, but not IL-12, induces optimal, antigen-specific production of key cytokines by CD8+ T cells for the efficient clearance of influenza virus from the lungs of infected mice. [source]

Balancing role of nitric oxide in complement-mediated activation of platelets from mCd59a and mCd59b double-knockout mice,

AMERICAN JOURNAL OF HEMATOLOGY, Issue 4 2009
Xuebin Qin
CD59 is a membrane protein inhibitor of the membrane attack complex (MAC) of complement. mCd59 knockout mice reportedly exhibit hemolytic anemia and platelet activation. This phenotype is comparable to the human hemolytic anemia known as paroxysmal nocturnal hemoglobinuria (PNH), in which platelet activation and thrombosis play a critical pathogenic role. It has long been suspected but not formally demonstrated that both complement and nitric oxide (NO) contribute to PNH thrombosis. Using mCd59a and mCd59b double knockout mice (mCd59ab,/, mice) in complement sufficient (C3+/+) and deficient (C3,/,) backgrounds, we document that mCd59ab,/, platelets are sensitive to complement-mediated activation and provide evidence for possible in vivo platelet activation in mCd59ab,/, mice. Using a combination of L-NAME (a NO-synthase inhibitor) and NOC-18 or SNAP (NO-donors), we further demonstrate that NO regulates complement-mediated activation of platelets. These results indicate that the thrombotic diathesis of PNH patients could be due to a combination of increased complement-mediated platelet activation and reduced NO-bioavailability as a consequence of hemolysis. Am. J. Hematol. 2009. © 2009 Wiley-Liss, Inc. [source]

Clearance of coagulation factor VIII in very low-density lipoprotein receptor knockout mice

BRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2004
Niels Bovenschen
Summary Low-density lipoprotein receptor-related protein (LRP) contributes to factor VIII (FVIII) catabolism in vivo. Besides LRP, FVIII also interacts with very low-density lipoprotein receptor (VLDLR) in vitro. We investigated the physiological role of VLDLR in FVIII catabolism, using knockout mouse models for VLDLR and LRP, alone and in combination. VLDLR,/, mice displayed normal plasma FVIII, whereas VLDLR,/, LRP, double-knockout mice had slightly increased FVIII compared with LRP-deficient mice. Remarkably, VLDLR deficiency slightly accelerated FVIII clearance. Adenovirus-mediated overexpression of VLDLR did not lower plasma FVIII in LRP-deficient mice. We conclude that VLDLR does not act in concert with LRP in FVIII clearance in vivo. [source]

HUMAN HEART ,-ADRENOCEPTORS: ,1 -ADRENOCEPTOR DIVERSIFICATION THROUGH ,AFFINITY STATES' AND POLYMORPHISM

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 10 2007
P Molenaar
SUMMARY 1In atrium and ventricle from failing and non-failing human hearts, activation of ,1 - or ,2 -adrenoceptors causes increases in contractile force, hastening of relaxation, protein kinase A-catalysed phosphorylation of proteins implicated in the hastening of relaxation, phospholamban, troponin I and C-protein, consistent with coupling of both ,1 - and ,2 -adrenoceptors to stimulatory Gsa -protein but not inhibitory Gia -protein. 2Two ,affinity states', namely ,1H and ,1L, of the ,1 -adrenoceptor exist. In human heart, noradrenaline elicits powerful increases in contractile force and hastening of relaxation. These effects are blocked with high affinity by ,-adenoceptor antagonists, including propranolol, (,)-pindolol, (,)-CGP 12177 and carvedilol. Some beta-blockers, typified by (,)-pindolol and (,)-CGP 12177, not only block the receptor, but also activate it, albeit at much higher concentrations (approximately 2 log units) than those required to antagonize the effects of catecholamines. In human heart, both (,)-CGP 12177 and (,)-pindolol increase contractile force and hasten relaxation. However, the involvement of the ,1 -adrenoceptor was not immediately obvious because (,)-pindolol- and (,)-CGP 12177-evoked responses were relatively resistant to blockade by (,)-propranolol. Abrogation of cardiostimulant effects of (,)-CGP 12177 in ,1 -/,2 -adrenoceptor double-knockout mice, but not ,2 -adrenoceptor-knockout mice, revealed an obligatory role of the ,1 -adrenoceptor. On the basis of these results, two ,affinity states' have been designated, the ,1H - and ,1L -adrenoceptor, where the ,1H -adrenoceptor is activated by noradrenaline and blocked with high affinity by beta-blockers and the ,1L -adrenoceptor is activated by drugs such as (,)-CGP 12177 and (,)-pindolol and blocked with low affinity by beta-blockers such as (,)-propranolol. The ,1H - and ,1L -adrenoceptor states are consistent with high- and low-affinity binding sites for (,)-[3H]-CGP 12177 radioligand binding found in cardiac muscle and recombinant ,1 -adrenoceptors. 3There are two common polymorphic locations of the ,1 -adrenoceptor, at amino acids 49 (Ser/Gly) and 389 (Arg/Gly). Their existence has raised several questions, including their role in determining the effectiveness of heart failure treatment with beta-blockers. We have investigated the effect of long-term maximally tolerated carvedilol administration (> 1 year) on left ventricular ejection fraction (LVEF) in patients with non-ischaemic cardiomyopathy (mean left ventricular ejection fraction 23 ± 7%; n = 135 patients). The administration of carvedilol improved LVEF to 37 ± 13% (P < 0.005); however, the improvement was variable, with 32% of patients showing £ 5% improvement. Upon segregation of patients into Arg389Gly-,1 -adrenoceptors, it was found that carvedilol caused a greater increase in left ventricular ejection faction in patients carrying the Arg389 allele with Arg389Arg > Arg389Gly > Gly389Gly. [source]