Abstract-Increased arterial stiffness, as estimated from aortic pulse wave velocity (Ao-PWV), and albuminuria are independent predictors for cardiovascular disease in type 2 diabetes mellitus (T2DM). Whether angiotensin receptor blockers (ARBs), drugs with cardio-renal protective effects, improve Ao-PWV to a greater extent than other equipotent antihypertensive medications remains unclear. After a 4-week washout phase, we compared the effects of valsartan (nϭ66), an ARB, with that of amlodipine (nϭ65), a calcium channel blocker on Ao-PWV in 131 T2DM patients with pulse pressure (PP) Ն60 mm Hg and raised albumin excretion rate (AER) in a 24-week randomized, double-blind, parallel group study. Hydrochlorothiazide (HCTZ) 25 mg/d was added to valsartan 160 mg and amlodipine 5 mg/od uptitrated to 10 mg/od after 4 weeks to ensure equivalent BP control. After 24 weeks brachial and central aortic PP had fallen to a similar extent with attained mean (SD) brachial and central PP of 61.6 (13.6) and 47.3 (14.1) mm Hg in the valsartan/HCTZ group and 61.5 (12.2) and 47.3 (9.9) mm Hg in the amlodipine group, respectively. Ao-PWV showed a significantly greater reduction, mean (95% CI), Ϫ0.9 m/s (Ϫ1.4 to Ϫ0.3) for valsartan/HCTZ compared to amlodipine (Pϭ0.002). AER fell significantly only with Val/HCTZ from 30.8(20.4, 46.5) to 18.2(12.5, 26.3) mcg/min, (Pϭ0.01) with between treatment difference in favor of Val/HCTZ of Ϫ15.3mcg/min (PϽ0.001). Changes in AER and Ao-PWV were not correlated. Valsartan/HCTZ improves arterial stiffness and AER to a significantly greater extent than amlodipine despite similar central and brachial BP control. These 2 effects, which appear independent of each other, may explain the specific cardio-renal protective properties of ARBs. Key Words: type 2 diabetes Ⅲ hypertension Ⅲ arterial stiffness Ⅲ albuminuria Ⅲ angiotensin receptor blockers C ardiovascular disease (CVD) is the main cause of death in patients with type 2 diabetes mellitus (T2DM). 1 In T2DM angiotensin type 1 (AT 1 ) receptor blockers (ARB) reduce albumin excretion and prevent the progression of diabetic renal disease, 2,3 and inhibition of the renin angiotensin system (RAS) may also provide cardio-protective benefits. 4,5 These effects would appear independent of the brachial blood pressure lowering action of these drugs. [2][3][4][5] However, some authors have questioned whether antihypertensive drugs offer cardio-renal protection beyond blood pressure lowering. 6,7 In T2DM systolic hypertension is often associated with albuminuria, and both are strong predictors of CVD mortality and morbidity and progressive renal failure. 8 Recent evidence indicates that increased arterial stiffness, involving accelerated vascular aging of the aorta, is a powerful and independent risk factor for early mortality and provides prognostic information above and beyond traditional CVD risk factors such as blood pressure itself, age, gender, diabetes, smoking, and cholesterol. 9,10 As arterial stiffness is the principal determinant of pulse pressure (PP), a...
Abstract. A feature of the tolerance that has been described in experimental models is that it can be transferred by CD4ϩ T cells to a naive recipient. Described is a novel approach to induce indirect pathway regulatory T cells in a rat model that exploits the natural processing and presentation of major histocompatability complex (MHC) molecules as peptide by the MHC class II molecules of the same cell. Dendritic cells (DC) coexpressing donor (AUG) and recipient (LEW) MHC molecules were rendered tolerogenic by treatment with dexamethasone. After injection into LEW animals followed by a single low dose of CTLA4-Ig, T cells were rendered unresponsive to indirectly presented AUG alloantigens, but retained direct pathway responsiveness to fully allogeneic AUG cells. The T cells from the DC-injected rats were unresponsive to (LEW ϫ AUG)F1 stimulator cells, suggesting the presence of indirect pathway regulatory cells whose activity depended on the presence of LEW MHC molecules. Depletion of CD25
Coordinated migratory events are required for the development of effective and regulated immunity. Naïve T lymphocytes are programmed to recirculate predominantly in secondary lymphoid tissue by non-specific stimuli. In contrast, primed T cells must identify specific sites of antigen location in non-lymphoid tissue to exert targeted effector responses. Following priming, T cells acquire the ability to establish molecular interactions mediated by tissueselective integrins and chemokine receptors (homing receptors) that allow their access to specific organs, such as the skin and the gut. Recent studies have shown that an additional level of specificity is provided by the induction of specific T cell migration into the tissue following recognition of antigen displayed by the endothelium. In addition, co-stimulatory signals (such as those induced by CD28 and CTLA-4 molecules) have been shown not only to regulate T cell activation and differentiation, but also to orchestrate the anatomy of the ensuing T cell response.
Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by immune-mediated destruction of insulin-secreting β cells of the pancreas. Near complete dependence on exogenous insulin makes T1DM very difficult to control, with the result that patients are exposed to high blood glucose and risk of diabetic complications and/or intermittent low blood glucose that can cause unconsciousness, fits and even death. Allograft transplantation of pancreatic islets restores normoglycemia with a low risk of surgical complications. However, although successful immediately after transplantation, islets are progressively lost, with most of the patients requiring exogenous insulin within 2 years post-transplant. Therefore, there is an urgent requirement for the development of new strategies to prevent islet rejection. In this study, we explored the importance of human regulatory T cells in the control of islets allograft rejection. We developed a pre-clinical model of human islet transplantation by reconstituting NOD-scid IL2rγnull mice with cord blood-derived human CD34+ stem cells and demonstrated that although the engrafted human immune system mediated the rejection of human islets, their survival was significantly prolonged following adoptive transfer of ex vivo expanded human Tregs. Mechanistically, Tregs inhibited the infiltration of innate immune cells and CD4+ T cells into the graft by down-regulating the islet graft-derived monocyte chemoattractant protein-1. Our findings might contribute to the development of clinical strategies for Treg therapy to control human islet rejection. We also show for the first time that CD34+ cells-reconstituted NOD-scid IL2rγnull mouse model could be beneficial for investigating human innate immunity in vivo.
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