Mobilization of early hematopoietic progenitor cells with BB-10010: a genetically engineered variant of human macrophage inflammatory protein- 1 alpha

BB-10010 is a genetically engineered variant of human macrophage inflammatory protein-1 alpha with improved solution properties. We show here that it mobilizes stem cells into the peripheral blood. We investigated the mobilizing effects of BB-10010 on the numbers of circulating 8-day spleen colony-forming units (CFU-S8), CFU-S12, and progenitors with marrow repopulating ability (MRA). A single subcutaneous dose of BB-10010 caused a twofold increase in circulating numbers of CFU-S8, CFU-S12, and MRA 30 minutes after dosing. We also investigated the effects of granulocyte colony-stimulating factor (G- CSF) and the combination of G-CSF with BB-10010 on progenitor mobilization. Two days of G-CSF treatment increased circulating CFU-S8, CFU-S12, and MRA progenitors by 25.7-, 19.8-, and 27.7-fold. A single administration of BB-10010 after 2 days of G-CSF treatment increased circulating CFU-S8, CFU-S12, and MRA even further to 38-, 33-, and 100- fold. Splenectomy resulted in increased circulating progenitor numbers but did not change the pattern of mobilization. Two days of treatment with G-CSF then increased circulating CFU-S8, CFU-S12, and MRA by 64-, 69-, and 32-fold. A single BB-10010 administration after G-CSF treatment further increased them to 85-, 117-, and 140-fold, respectively, compared with control. We conclude that BB-10010 causes a rapid increase in the number of circulating hematopoietic progenitors and further enhances the numbers induced by pretreatment with G-CSF. BB- 10010 preferentially mobilized the more primitive progenitors with marrow repopulating activity, releasing four times the number achieved with G-CSF alone. Translated into a clinical setting, this improvement in progenitor cell mobilization may enhance the efficiency of harvest and the quality of grafts for peripheral blood stem cell transplantation.     

Adenosine affects expression of membrane molecules,cytokine and chemokine release,and the T-cell stimulatory capacity of human dendritic cells

Dendritic cells (DCs) express functional purinergic type 1 receptors, but the effects of adenosine in these antigen-presenting cells have been only marginally investigated. Here, we further characterized the biologic activity of adenosine in immature DCs (iDCs) and lipopolysaccharide (LPS)-matured DCs (mDCs). Chronic stimulation with adenosine enhanced the macropinocytotic activity and the membrane expression of CD80, CD86, major histocompatibility complex (MHC) class I, and HLA-DR molecules on iDCs. Adenosine also increased LPS-induced CD54, CD80, MHC class I, and HLA-DR molecule expression in mDCs. In addition, adenosine dose-dependently inhibited tumor necrosis factor alpha and interleukin-12 (IL-12) release, whereas it enhanced the secretion of IL-10 from mDCs. The use of selective receptor agonists revealed that the modulation of the cytokine and cell-surface marker profile was due to activation of A(2) adenosine receptor. Functionally, adenosine reduced the allostimulatory capacity of iDCs, but not of mDCs. More important, DCs matured in the presence of adenosine had a reduced capacity to induce T helper 1 (Th1) polarization of naive CD4(+) T lymphocytes. Finally, adenosine augmented the release of the chemokine CCL17 and inhibited CXCL10 production by mDCs. In aggregate, the results provide initial evidence that adenosine diminishes the capacity of DCs to initiate and amplify Th1 immune responses.     

Atrial natriuretic factor and arterial baroreceptor reflexes in unanesthetized rats

The modulation exerted by atrial natriuretic factor (ANF) on the cardiac and vascular influences of arterial baroreceptors was investigated in two groups of unanesthetized, chronically instrumented normotensive rats. In group 1, the reflex control of heart rate was assessed by graded baroreceptor stimulations and deactivations obtained by intravenous boluses of phenylephrine and nitroprusside. Under either circumstance, baroreceptor reflex sensitivity was expressed as the linear regression slope relating the chronotropic responses to the drug-induced mean arterial pressure changes. In group 2, right common carotid occlusion was performed in rats with their aortic and left carotid sinus baroreceptors denervated to assess the baroreceptor control of blood pressure; the reflex response was quantitated as the peak blood pressure rise observed during the maneuver. The reflex studies were performed before and during atriopeptin III infusion (0.15-0.20 micrograms/kg/min for 60 minutes). ANF augmented the bradycardic response to phenylephrine by 102.5 +/- 29% (p less than 0.01), reduced the tachycardic response to nitroprusside by 67.7 +/- 6.4% (p less than 0.01), and failed to modify the pressor response to carotid occlusion (-6.8 +/- 2.1%, p = NS). In a separate group of rats infused with low dose nitroprusside, no change in the baroreceptor-heart rate reflex was observed. ANF infusion (0.20 micrograms/kg/min) performed in further separate groups of conscious rats raised plasma ANF to 480 +/- 58 fmol/ml. Values in control vehicle-infused rats were 50 +/- 8 fmol/ml. Vascular reactivity (pressor response to intravenous phenylephrine boluses in anesthetized, sinoaortic-denervated rats) was only minimally reduced by ANF.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of TAVR in patients with heart failure: do we have the responses to all questions?

Heart Failure Reviews - Severe aortic stenosis (AS) is the most prevalent valvular heart disease in developed countries. Heart failure (HF) is a frequent comorbidity of this condition and...     

Treatment of asthma with antileukotrienes and Churg-Strauss syndrome

Since antileukotriene treatment for asthma was introduced, there has been debate about whether such therapy can lead to Churg-Strauss Syndrome (CSS) or whether CSS is simply inhibited by the use of steroids, as various authors have suggested. We report a case in which we suspected CSS in a patient with bronchopulmonary, cutaneous and analytical signs and whom we treated with oral steroids. After clinical improvement, one year later, steroids were replaced by antileukotrienes, after which the same clinical picture developed. The vasculitis characteristic of CSS was confirmed pathologically.     

Systemic inflammation after inspiratory loading in chronic obstructive pulmonary disease

Objective

Patients with chronic obstructive pulmonary disease (COPD) present systemic inflammation. Strenuous resistive breathing induces systemic inflammation in healthy subjects. We hypothesized that the increased respiratory load that characterizes COPD can contribute to systemic inflammation in these patients.

Patients and methods

To test this hypothesis, we compared leukocyte numbers and levels of circulating cytokines (tumor necrosis factor alpha [TNFα], interleukin-1β [IL-1β], IL-6, IL-8, and IL-10), before and 1 hour after maximal incremental inspiratory loading in 13 patients with stable COPD (forced expiratory volume in one second [FEV₁] 29 ± 2.5% ref) and in 8 healthy sedentary subjects (FEV₁ 98 ± 5% ref).

Results

We found that: (1) at baseline, patients with COPD showed higher leukocyte counts and IL-8 levels than controls (p < 0.01); and, (2) one hour after maximal inspiratory loading these values were unchanged, except for IL-10, which increased in controls (p < 0.05) but not in patients with COPD.

Conclusions

This study confirms the presence of systemic inflammation in COPD, shows that maximal inspiratory loading does not increase the levels of pro-inflammatory cytokines (IL-1β, IL-8) in COPD patients or controls, but suggests that the former may be unable to mount an appropriate systemic anti-inflammatory response to exercise.     

Prevalence and correlates of multiple organ damage in referred treated hypertensives: data from the ETODH study

This study, carried out in a large cohort of treated essential hypertensives attending an out-patient hospital hypertension clinic, extends previous observations by showing that a clustering of two or three markers of organ damage (OD) has a higher prevalence than a single organ involvement. These findings call for a systematic evaluation of cardiac and extracardiac OD in treated hypertensive patients referred to a specialist setting.