Deconvoluting hepatic processing of carbon nanotubes

Single-wall carbon nanotubes present unique opportunities for drug delivery, but have not advanced into the clinic. Differential nanotube accretion and clearance from critical organs have been observed, but the mechanism not fully elucidated. The liver has a complex cellular composition that regulates a range of metabolic functions and coincidently accumulates most particulate drugs. Here we provide the unexpected details of hepatic processing of covalently functionalized nanotubes including receptor-mediated endocytosis, cellular trafficking and biliary elimination. Ammonium-functionalized fibrillar nanocarbon is found to preferentially localize in the fenestrated sinusoidal endothelium of the liver but not resident macrophages. Stabilin receptors mediate the endocytic clearance of nanotubes. Biocompatibility is evidenced by the absence of cell death and no immune cell infiltration. Towards clinical application of this platform, nanotubes were evaluated for the first time in non-human primates. The pharmacologic profile in cynomolgus monkeys is equivalent to what was reported in mice and suggests that nanotubes should behave similarly in humans

A Systems Model for Immune Cell Interactions Unravels the Mechanism of Inflammation in Human Skin

Inflammation is characterized by altered cytokine levels produced by cell populations in a highly interdependent manner. To elucidate the mechanism of an inflammatory reaction, we have developed a mathematical model for immune cell interactions via the specific, dose-dependent cytokine production rates of cell populations. The model describes the criteria required for normal and pathological immune system responses and suggests that alterations in the cytokine production rates can lead to various stable levels which manifest themselves in different disease phenotypes. The model predicts that pairs of interacting immune cell populations can maintain homeostatic and elevated extracellular cytokine concentration levels, enabling them to operate as an immune system switch. The concept described here is developed in the context of psoriasis, an immune-mediated disease, but it can also offer mechanistic insights into other inflammatory pathologies as it explains how interactions between immune cell populations can lead to disease phenotypes

Radioresistant T lymphocytes in mice: distribution in organs, Thy-1 antigen content and helper activity.

Radioresistant T lymphocytes (RRTL) were derived from spleens of CBA mice after gamma-irradiation (2000 rad). RRTL comprise 2.2-3.5% of the total T-cell population. Adult thymectomy and treatment with ATS or cortisol do not affect the yield of RRTL. The Thy-1 antigen content on RRTL surfaces exceeds that on thymocytes and splenic T lymphocytes. 51Cr-labelled RRTL fail to home into lymph nodes: a considerable number of labelled RRTL persist in the blood. In an adoptive transfer system RRTL display poor helper activity. The adoptive response of normal B cells plus RRTL was reduced when RRTL donors were preimmunized with the same antigen. It is not clear if the unusual properties of RRTL were induced by irradiation or if they pre-existed

REGULATORY T CELLS IN CHILDREN WITH ALLERGY

Abstract. Percentage of CD4+CD25hi is increased in children with allergy, and it is independent on their nosology, severity, sensitization and IgE level in blood. FOXP3 expression virtually was not altered. Inhalation of corticosteroids in asthma causes increase of FOXP3 expression that may represent some mechanisms of their therapeutic effects. The amount of Treg’s gradually decrease with age in non-atopic children; they also decrease in atopic ones until 6 years, followed by their subsequent stabilization. Thus, a hypothesis is proposed, that the initial changes of Treg’s in case of allergy comprise a reduction in their functions, and, upon complete or partial compensation of this defect by increasing of cell amounts, a remission is initiated. However, in absence of compensation, acute attacks of allergic disorders are developed. (Med. Immunol., 2008, vol. 10, N 2-3, pp 159-166)

Multiple sclerosis: elevated expression of matrix metalloproteinases in blood monocytes

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) characterized by blood-brain barrier (BBB) breakdown. Disruptions of BBB continuity result in an influx of activated T cells and monocytes, and could contribute to lesion formation in the CNS. Matrix metalloproteinases (MMP) are enzymes implicated in BBB disruption, and in degradation of extracellular matrix proteins and myelin components. An imbalance in levels of MMP and tissue inhibitors of MMP (TIMP) has been implicated in the pathogenesis of MS. Since monocytes form a major cell population in acute MS lesions and may facilitate their entrance into the CNS by secretion of MMP, knowledge on MMP expression by blood monocytes could be useful to improve our understanding of the pathogenesis of MS. In the present study, we examined the expression of MMP-1, -3, -7, -9, -14 and TIMP-1 mRNA by blood monocytes in patients with MS using in situ hybridization. Levels of MMP-1, -3, -7, -9 and of TIMP-1 mRNA expressing monocytes were elevated in MS compared to controls, while those of MMP-14 did not differ. We therefore conclude that MS is associated with elevated levels of MMP and TIMP expressing blood monocytes that may contribute to MS pathogenesis