Lymphocyte recruitment and homing to the liver in primary biliary cirrhosis and primary sclerosing cholangitis

The mechanisms operating in lymphocyte recruitment and homing to liver are reviewed. A literature review was performed on primary biliary cirrhosis (PBC), progressive sclerosing cholangitis (PSC), and homing mechanisms; a total of 130 papers were selected for discussion. Available data suggest that in addition to a specific role for CCL25 in PSC, the CC chemokines CCL21 and CCL28 and the CXC chemokines CXCL9 and CXCL10 are involved in the recruitment of T lymphocytes into the portal tract in PBC and PSC. Once entering the liver, lymphocytes localize to bile duct and retain by the combinatorial or sequential action of CXCL12, CXCL16, CX3CL1, and CCL28 and possibly CXCL9 and CXCL10. The relative importance of these chemokines in the recruitment or the retention of lymphocytes around the bile ducts remains unclear. The available data remain limited but underscore the importance of recruitment and homing

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Synergistic Innate and Adaptive Immune Response to Combination Immunotherapy with Anti-Tumor Antigen Antibodies and Extended Serum Half-Life IL-2

Cancer immunotherapies under development have generally focused on either stimulating T cell immunity or driving antibody-directed effector functions of the innate immune system such as antibody-dependent cell-mediated cytotoxicity (ADCC). We find that a combination of an anti-tumor antigen antibody and an untargeted IL-2 fusion protein with delayed systemic clearance induces significant tumor control in aggressive isogenic tumor models via a concerted innate and adaptive response involving neutrophils, NK cells, macrophages, and CD8(+) T cells. This combination therapy induces an intratumoral "cytokine storm'' and extensive lymphocyte infiltration. Adoptive transfer of anti-tumor T cells together with this combination therapy leads to robust cures of established tumors and development of immunological memory

Accuracy of a novel approach to measuring arterial thermodilution cardiac output during intra-aortic counterpulsation

Objective: To assess the agreement between a novel approach of arterial and the pulmonary artery bolus thermodilution for measuring cardiac output in critically ill patients during aortic counterpulsation. Methods: Eighteen male patients aged 37-80years, undergoing preoperative insertion of an intra-aortic balloon pump (IABP) and elective coronary artery bypass grafting. A thin 1.3FG thermistor was introduced through the pressure lumen to the tip of an 8FG IABP catheter, and the pump rate was set at 1:1. After arrival in the intensive care unit cardiac output (CO) was measured under haemodynamic steady-state conditions hourly for 8-11h, and arterial bolus thermodilution (BCOiabp) and pulmonary artery bolus thermodilution (BCOpulm) were determined after the patients' admission to the intensive care unit. Results: A total of 198 data pairs were obtained: 177 with aortic counterpulsation and 21 without. During aortic counterpulsation, median CO was 6.8l/min for BCOiabp and 6.1l/min for BCOpulm, without aortic counterpulsation; corresponding values were 7.1l/min for BCOiabp and 6.5l/min for BCOpulm with aortic counterpulsation. Mean bias was +0.77l/min, limits of agreement ( ± 2SD) were -1.27/+2.81l/min, and mean error (2SD/[(BCOiabp+BCOpulm)/2] was 31.4%. Without aortic counterpulsation, corresponding values were +0.43l/min, -1.03/+1.87l/min, and 22.4%. Conclusions: Agreement between BCOiabp and BCOpulm was satisfactory for CO values between 2.0 and 10l/min only without aortic counterpulsation. BCOiabp CO measurements during aortic counterpulsation after coronary artery bypass grafting cannot be recommended at the present tim