Apoptotic cell-based therapies against transplant rejection: role of recipient’s dendritic cells

One of the ultimate goals in transplantation is to develop novel therapeutic methods for induction of donor-specific tolerance to reduce the side effects caused by the generalized immunosuppression associated to the currently used pharmacologic regimens. Interaction or phagocytosis of cells in early apoptosis exerts potent anti-inflammatory and immunosuppressive effects on antigen (Ag)-presenting cells (APC) like dendritic cells (DC) and macrophages. This observation led to the idea that apoptotic cell-based therapies could be employed to deliver donor-Ag in combination with regulatory signals to recipient’s APC as therapeutic approach to restrain the anti-donor response. This review describes the multiple mechanisms by which apoptotic cells down-modulate the immuno-stimulatory and pro-inflammatory functions of DC and macrophages, and the role of the interaction between apoptotic cells and APC in self-tolerance and in apoptotic cell-based therapies to prevent/treat allograft rejection and graft-versus-host disease in murine experimental systems and in humans. It also explores the role that in vivo-generated apoptotic cells could have in the beneficial effects of extracorporeal photopheresis, donor-specific transfusion, and tolerogenic DC-based therapies in transplantation

Numerical investigation of confinement effects on a supercritical LOX-methane flame

In this contribution we numerically investigate the effects of lateral confinement on a turbulent, non-premixed, LOx-methane jet-flame at supercritical pressure. The simulations are carried out using a flamelet-based numerical framework capable of including both non-adiabatic and real-fluid effects. It is found that the confinement strongly influences the flame flow-field and as the confinement distance increases the average heat flux insisting on the injector face plate also increases in a more than linear fashion

Induction of regulatory T cells after prophylactic treatment with photopheresis in renal transplant recipients

Extracorporeal photopheresis (ECP), originally used to treat cutaneous T-cell lymphoma, also has been applied to the therapy of transplant rejection. Our aim was to investigate the biologic response in two children who underwent kidney transplantation with ECP as prophylactic treatment. They received conventional immunosuppressive therapy and ECP immediately after transplantation: six applications over the course of 3 weeks. During a 12-month follow-up, the clinical course was favorable in both patients; renal histology was normal 6 months after transplantation. When compared with four transplanted controls, the ECP-treated patients showed lower tumor necrosis factor-a serum levels in the short-term and a marked increase of Foxp3-positive T-regulatory cells. T-regulatory cells were still higher than in the controls I year after transplantation. These preliminary results suggest. that the addition of ECP to standard immunosuppressive therapy induces a tolerogenic shift in the immune system of kidney transplanted patients and may pave the way to preventing chronic rejection

Data-driven subfilter modelling of thermo-diffusively unstable hydrogen–air premixed flames

This article is dedicated to Moshe Matalon on the occasion of his 70th birthday, for his numerous contributions to the field of combustion and, in particular, to the rich and varied topic of premixed flame stability. Here, we follow in his footsteps and propose a subfilter modelling framework for thermo-diffusively unstable premixed flames, such as lean hydrogen–air flames. Performing an optimal estimator analysis for the unfiltered and filtered heat release rate of the lean premixed hydrogen–air flames, the latter is found to require at least two scalars for an appropriate representation while for large filter sizes, the heat release appears to require only one scalar for parametrisation. As a result, we develop a modelling strategy based on the construction of thermochemical tables for each unclosed term as a function of two variables as well as the filter size. The framework is based on the filtered tabulated chemistry approach, where, in lieu of a one-dimensional unstretched flame, we adopt a data-driven paradigm and filter fully resolved two-dimensional simulations of variable size. Models originating from small- and medium-sized simulations are tested a-priori on a large-size simulation, thus highlighting the role of the lateral domain in the dataset used for tabulation. The concept of a minimum domain size is thus discussed, leading to a dataset exhibiting the minimal properties for sufficiently accurate thermochemical tables. The strategy is shown to be more accurate than a classical one-dimensional filtered tabulated chemistry approach and shows promise in future LES modelling of laboratory and industrial scale hydrogen flames

Pressure-induced Hydrodynamic Instability in Premixed Methane-Air Slot Flames

The impact of pressure on the hydrodynamic instability mechanism is investigated in weakly turbulent, lean methane-air premixed slot flames by means of direct numerical simulations (DNS) employing multi-step chemistry and two different species diffusion models. A dedicated set of slot flames at four different pressures, featuring the same hydrodynamic lengthscale in units of flame thickness, is designed such that the Darrieus-Landau instability mechanism is either suppressed or present in the different flames. For the DNS design, a linear stability analysis is conducted to determine the flame stability characteristics and in particular the cutoff length scale of the Darrieus-Landau instability. As the pressure increases, the cutoff length scale decreases significantly in both dimensional and nondimensional units using the flame thickness as a reference. As a result, an increase in pressure promotes the onset and persistence of the Darrieus-Landau (or hydrodynamic) instability in the slot flame configuration considered. The impact of pressure is investigated in terms of flame morphology using well-established hydrodynamic instability markers. Then, the effect of pressure on the flame speed enhancement caused by the instability is assessed and quantified resorting to the global consumption speed concept. In particular, it is found that over the entire flame brush, the curvature skewness is more negative as pressure increases from 1 to 8 atm and the flame speed is increased by a factor that spans from (Formula presented.) to (Formula presented.) trough the flame brush

The effect of pressure on the hydrodynamic stability limit of premixed flames

The effect of pressure on the hydrodynamic stability limits of lean methane-air premixed flames is investigated with Direct Numerical Simulation based on multi-step chemistry and using a simplified one-step chemistry formulation. The dependency on pressure p of the cut-off length scale λc , that separates stable from unstable wavelengths of the initial perturbation, is computed for a number of different conditions. An increase of pressure causes a significant decrease of the cut-off length, as observed already in previous simulations and experiments. However, this decrease cannot be ascribed only to the decreased flame thickness due to elevated pressures, but the cut-off is reduced significantly even if normalized by either the thermal flame thickness lT or the diffusive flame thickness lD. For the conditions analyzed, the cut-off can be well approximated by the power-law λc ∝ p-0.8, while the thermal and diffusive flame thicknesses, in accordance with previous experiments, are proportional and scale as lT ∝ lD ∝ p-0.3. Therefore, the non-dimensional cut-off scales as λc/lT ∝ λc/lD ∝ p-0.5. This behavior is linked to the increase of the Zeldovich number with pressure, caused by higher inner layer temperatures at higher pressures, which is a result of increased importance of chain termination reactions. The same behavior is observed also in a one-step chemistry approach if the Zeldovich number, appearing explicitly in the one-step model equations, is varied with pressure according to the results from multi-step chemistry. The analysis is extended to the non-linear phase of the instability, when typical strong cusps are observed on the flame surface, simulating a two-dimensional slot burner for different pressures; it is confirmed that the same pressure effects are observed also in more complex settings and in the non-linear regime

The immunological effects of extracorporeal photopheresis unraveled: Induction of tolerogenic dendritic cells in vitro and regulatory T cells in vivo

Extracorporeal photopheresis (ECP) may represent an alternative to immunosuppression, as a means of reducing rejection after thoracic organ transplantation. The mechanism by which ECP exerts its protective effects has, until now, remained elusive. We analyzed peripheral blood mononuclear cells of four children with chronic heart and lung transplant rejection, who received ECP in addition to conventional immunosuppressive treatment. The effects of ECP were evaluated at each cycle, comparing blood samples from the same patient collected before and after treatment. In vitro, peripheral blood mononuclear cells treated with ECP undergo apoptosis and are phagocytosed by immature dendritic cells, which, in turn, acquire a tolerogenic phenotype. The frequency of T cells, with a regulatory phenotype and strong suppressive activity, was significantly increased in the blood of ECP-treated patients. The immunomodulatory effects of ECP may be explained by its ability to increase the frequency of regulatory T cells with inhibitory action on transplant immune rejection