Recombinant human PDCD5 (rhPDCD5) protein is protective in a mouse model of multiple sclerosis.

BackgroundIn multiple sclerosis (MS) and its widely used animal model, experimental autoimmune encephalomyelitis (EAE), autoreactive T cells contribute importantly to central nervous system (CNS) tissue damage and disease progression. Promoting apoptosis of autoreactive T cells may help eliminate cells responsible for inflammation and may delay disease progression and decrease the frequency and severity of relapse. Programmed cell death 5 (PDCD5) is a protein known to accelerate apoptosis in response to various stimuli. However, the effects of recombinant human PDCD5 (rhPDCD5) on encephalitogenic T cell-mediated inflammation remain unknown.MethodsWe examined the effects of intraperitoneal injection of rhPDCD5 (10 mg/kg) on EAE both prophylactically (started on day 0 post-EAE induction) and therapeutically (started on the onset of EAE disease at day 8), with both of the treatment paradigms being given every other day until day 25. Repeated measures two-way analysis of variance was used for statistical analysis.ResultsWe showed that the anti-inflammatory effects of rhPDCD5 were due to a decrease in Th1/Th17 cell frequency, accompanied by a reduction of proinflammatory cytokines, including IFN-γ and IL-17A, and were observed in both prophylactic and therapeutic regimens of rhPDCD5 treatment in EAE mice. Moreover, rhPDCD5-induced apoptosis of myelin-reactive CD4+ T cells, along with the upregulation of Bax and downregulation of Bcl-2, and with activated caspase 3.ConclusionsOur data demonstrate that rhPDCD5 ameliorates the autoimmune CNS disease by inhibiting Th1/Th17 differentiation and inducing apoptosis of predominantly pathogenic T cells. This study provides a novel mechanism to explain the effects of rhPDCD5 on neural inflammation. The work represents a translational demonstration that rhPDCD5 has prophylactic and therapeutic properties in a model of multiple sclerosis

Analysis of Inertial Migration of Neutrally Buoyant Particle Suspensions in a Planar Poiseuille Flow with a Coupled Lattice Boltzmann Method-Discrete Element Method

In this study a hybrid numerical framework for modelling solid-liquid multiphase flow is established with a single-relaxation-time lattice Boltzmann method and the discrete element method implemented with the Hertz contact theory. The numerical framework is then employed to systematically explore the effect of particle concentration on the inertial migration of neutrally buoyant particle suspensions in planar Poiseuille flow. The results show that the influence of particle concentration on the migration is primarily determined by the characteristic channel Reynolds number Re0. For relatively low Re0 (Re0˂20), the migration behaviour can only be observed at a very low particle concentration (≤5%). However, when Re0˃20 the migration behaviour can be observed at a high concentration (≥20%). Furthermore, a focusing number Fc is proposed to characterise the degree of inertial migration. It was found that the inertial migration can be classified into three regimes depending on two critical values of the focusing number, Fc+ and Fc-: i) when Fc˃Fc+, a full inertial migration occurs; ii) when Fc˂Fc-, particles are laterally unfocused; iii) when Fc-˂Fc˂Fc+, a partially inertial migration takes place

Kirenol attenuates experimental autoimmune encephalomyelitis by inhibiting differentiation of Th1 and th17 cells and inducing apoptosis of effector T cells.

Experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), is characterized by CNS demyelination mediated by autoreactive T cells. Kirenol, a biologically active substance isolated from Herba Siegesbeckiae, has potent anti-inflammatory activities. Here we investigated effects of kirenol on EAE. Kirenol treatment markedly delayed onset of disease and reduced clinical scores in EAE mice. Kirenol treatment reduced expression of IFN-γ and IL-17A in the serum and proportion of Th1 and Th17 cells in draining lymph nodes. Priming of lymphocytes was reduced and apoptosis of MOG-activated CD4+ T cells was increased in kirenol treated EAE mice. Kirenol treatment of healthy animals did not affect the lymphocytes in these non-immunized mice. Further in vitro studies showed that kirenol inhibited viability of MOG-specific lymphocytes and induced apoptosis of MOG-specific CD4+ T cells in a dose- and time-dependent manner. Kirenol treatment upregulated Bax,downregulated Bcl-2,and increased activation of caspase-3 and release of cytochrome c, indicating that a mitochondrial pathway was involved in kirenol induced apoptosis. Moreover, pretreatment with either a pan-caspase inhibitor z-VAD-fmk or a more specific caspase 3 inhibitor Ac-DEVD-CHO in lymphocytes reduced kirenol induced apoptosis. Our findings implicate kirenol as a useful agent for the treatment of MS