Effects of combined administration of FK 506 and the purine biosynthesis inhibitors mizoribine or mycophenolic acid on lymphocyte DNA synthesis and T cell activation molecule expression in human mixed lymphocyte cultures

Our objective was to obtain new information on the in vitro antilymphocytic action of the cytokine synthesis inhibitor FK 506 and the purine biosynthesis inhibitors mycophenolic acid (MPA; the active moiety of RS61443) and mizoribine (MZB) when used alone or in combination. When added at the initiation of six-day human mixed lymphocyte cultures (MLC), FK 506, MPA or MZB exhibited dose-dependent inhibition of T-lymphocyte DNA synthesis. FK 506, however, was 100-fold more potent than MPA, and 10000-fold more potent than MZB. Combination of FK 506 with either MPA or MZB, each at suboptional concentrations, produced no more than additive inhibitory effects on 3H thymidine incorporation. Two-colour flow cytometric analysis of lymphocytes revealed that none of the drugs affected cell surface activation molecule expression (CD25 = IL-2R 55 kD α-chain, HLA-DR or CD71 = transferrin receptor [TR]) on allostimulated CD4+ or CD8+ cells harvested at three days of culture. By day six, however, all three agents, at levels which markedly inhibited proliferation, suppressed the expression of activation markers on both CD4+ and CD8+ cells. Also at day six, inhibition of activation molecule expression on CD4+ cells was achieved with the combination of FK 506 and either MPA or MZB at concentrations which, on their own, were ineffective. These data provide new, additional information on the in vitro antilymphocytic action of FK 506, MPA and MZB when used alone and in combination. © 1993

Dendritic cells as sensors, mediators, and regulators of ischemic injury

Dendritic cells (DCs) are highly specialized, bone marrow (BM)-derived antigen-processing and -presenting cells crucial to the induction, integration and regulation of innate, and adaptive immunity. They are stimulated by damage-associated molecular patterns (DAMPS) via pattern recognition receptors to promote inflammation and initiate immune responses. In addition to residing within the parenchyma of all organs as part of the heterogeneous mononuclear phagocyte system, DCs are an abundant component of the inflammatory cell infiltrate that appears in response to ischemia reperfusion injury (IRI). They can play disparate roles in the pathogenesis of IRI since their selective depletion has been found to be protective, deleterious, or of no benefit in mouse models of IRI. In addition, administration of DC generated and manipulated ex vivo can protect organs from IRI by suppressing inflammatory cytokine production, limiting the capacity of DCs to activate NKT cells, or enhancing regulatory T cell function. Few studies however have investigated specific signal transduction mechanisms underlying DC function and how these affect IRI. Here, we address current knowledge of the role of DCs in regulation of IRI, current gaps in understanding and prospects for innovative therapeutic intervention at the biological and pharmacological levels.Helong Dai, Angus W. Thomson and Natasha M. Roger

A neuroendocrine role for chemerin in hypothalamic remodelling and photoperiodic control of energy balance

YesLong-term and reversible changes in body weight are typical of seasonal animals. Thyroid hormone (TH) and retinoic acid (RA) within the tanycytes and ependymal cells of the hypothalamus have been implicated in the photoperiodic response. We investigated signalling downstream of RA and how this links to the control of body weight and food intake in photoperiodic F344 rats. Chemerin, an inflammatory chemokine, with a known role in energy metabolism, was identified as a target of RA. Gene expression of chemerin (Rarres2) and its receptors were localised within the tanycytes and ependymal cells, with higher expression under long (LD) versus short (SD) photoperiod, pointing to a physiological role. The SD to LD transition (increased food intake) was mimicked by 2 weeks of ICV infusion of chemerin into rats. Chemerin also increased expression of the cytoskeletal protein vimentin, implicating hypothalamic remodelling in this response. By contrast, acute ICV bolus injection of chemerin on a 12h:12h photoperiod inhibited food intake and decreased body weight with associated changes in hypothalamic neuropeptides involved in growth and feeding after 24hr. We describe the hypothalamic ventricular zone as a key site of neuroendocrine regulation, where the inflammatory signal, chemerin, links TH and RA signaling to hypothalamic remodeling.BBSRC (grant number BB/K001043/1) and the Scottish Government

Transplant tolerance induction: insights from the liver

A comparison of pre-clinical transplant models and of solid organs transplanted in routine clinical practice demonstrates that the liver is most amenable to the development of immunological tolerance. This phenomenon arises in the absence of stringent conditioning regimens that accompany published tolerizing protocols for other organs, particularly the kidney. The unique immunologic properties of the liver have assisted our understanding of the alloimmune response and how it can be manipulated to improve graft function and survival. This review will address important findings following liver transplantation in both animals and humans, and how these have driven the understanding and development of therapeutic immunosuppressive options. We will discuss the liver's unique system of immune and non-immune cells that regulate immunity, yet maintain effective responses to pathogens, as well as mechanisms of liver transplant tolerance in pre-clinical models and humans, including current immunosuppressive drug withdrawal trials and biomarkers of tolerance. In addition, we will address innovative therapeutic strategies, including mesenchymal stem cell, regulatory T cell, and regulatory dendritic cell therapy to promote liver allograft tolerance or minimization of immunosuppression in the clinic.Helong Dai, Yawen Zheng, Angus W. Thomson and Natasha M. Roger

Magnetic Fields in the Milky Way

This chapter presents a review of observational studies to determine the magnetic field in the Milky Way, both in the disk and in the halo, focused on recent developments and on magnetic fields in the diffuse interstellar medium. I discuss some terminology which is confusingly or inconsistently used and try to summarize current status of our knowledge on magnetic field configurations and strengths in the Milky Way. Although many open questions still exist, more and more conclusions can be drawn on the large-scale and small-scale components of the Galactic magnetic field. The chapter is concluded with a brief outlook to observational projects in the near future.Comment: 22 pages, 5 figures, to appear in "Magnetic Fields in Diffuse Media", eds. E.M. de Gouveia Dal Pino and A. Lazaria

An ALMA survey of CO in submillimetre galaxies: companions, triggering, and the environment in blended sources

We present ALMA observations of the mid-J 12CO emission from six single-dish selected 870-μm sources in the Extended Chandra Deep Field-South and UKIDSS Ultra-Deep Survey fields. These six single-dish submillimetre sources were selected based on previous ALMA continuum observations, which showed that each comprised a blend of emission from two or more individual submillimetre galaxies (SMGs), separated on 5–10 arcsec scales. The six single-dish submillimetre sources targeted correspond to a total of 14 individual SMGs, of which seven have previously measured robust optical/near-infrared spectroscopic redshifts, which were used to tune our ALMA observations. We detect CO(3–2) or CO(4–3) at z = 2.3–3.7 in 7 of the 14 SMGs, and in addition serendipitously detect line emission from three gas-rich companion galaxies, as well as identify four new 3.3 mm selected continuum sources in the six fields. Joint analysis of our CO spectroscopy and existing data suggests that 64(±18)percent of the SMGs in blended submillimetre sources are unlikely to be physically associated. However, three of the SMG fields (50 per cent) contain new, serendipitously detected CO-emitting (but submillimetre-faint) sources at similar redshifts to the 870 μm selected SMGs we targeted. These data suggest that the SMGs inhabit overdense regions, but that these are not sufficiently overdense on ∼100 kpc scales to influence the source blending given the short lifetimes of SMGs. We find that 21±12percent of SMGs have spatially distinct and kinematically close companion galaxies (∼8–150 kpc and ≲ 300 km s−1), which may have enhanced their star formation via gravitational interactions

An ALMA Survey of the SCUBA-2 Cosmology Legacy Survey UKIDSS/UDS Field: The Far-infrared/Radio Correlation for High-redshift Dusty Star-forming Galaxies

We study the radio properties of 706 submillimeter galaxies (SMGs) selected at 870 μm with the Atacama Large Millimeter Array from the SCUBA-2 Cosmology Legacy Survey map of the Ultra Deep Survey field. We detect 273 SMGs at >4σ in deep Karl G. Jansky Very Large Array 1.4 GHz observations, of which a subset of 45 SMGs are additionally detected in 610 MHz Giant Metre-Wave Radio Telescope imaging. We quantify the far-infrared/radio correlation (FIRRC) through parameter q IR, defined as the logarithmic ratio of the far-infrared and radio luminosity, and include the radio-undetected SMGs through a stacking analysis. We determine a median q IR = 2.20 ± 0.03 for the full sample, independent of redshift, which places these z ~ 2.5 dusty star-forming galaxies 0.44 ± 0.04 dex below the local correlation for both normal star-forming galaxies and local ultra-luminous infrared galaxies (ULIRGs). Both the lack of redshift evolution and the offset from the local correlation are likely the result of the different physical conditions in high-redshift starburst galaxies, compared to local star-forming sources. We explain the offset through a combination of strong magnetic fields (B gsim 0.2 mG), high interstellar medium (ISM) densities and additional radio emission generated by secondary cosmic rays. While local ULIRGs are likely to have similar magnetic field strengths, we find that their compactness, in combination with a higher ISM density compared to SMGs, naturally explains why local and high-redshift dusty star-forming galaxies follow a different FIRRC. Overall, our findings paint SMGs as a homogeneous population of galaxies, as illustrated by their tight and nonevolving far-infrared/radio correlation