Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study)

Purpose The CIGMA study investigated a novel human polyclonal antibody preparation (trimodulin) containing ~ 23% immunoglobulin (Ig) M, ~ 21% IgA, and ~ 56% IgG as add-on therapy for patients with severe community-acquired pneumonia (sCAP). Methods In this double-blind, phase II study (NCT01420744), 160 patients with sCAP requiring invasive mechanical ventilation were randomized (1:1) to trimodulin (42 mg IgM/kg/day) or placebo for five consecutive days. Primary endpoint was ventilator-free days (VFDs). Secondary endpoints included 28-day all-cause and pneumonia-related mortality. Safety and tolerability were monitored. Exploratory post hoc analyses were performed in subsets stratified by baseline C-reactive protein (CRP; ≥ 70 mg/L) and/or IgM (≤ 0.8 g/L). Results Overall, there was no statistically significant difference in VFDs between trimodulin (mean 11.0, median 11 [n = 81]) and placebo (mean 9.6; median 8 [n = 79]; p = 0.173). Twenty-eight-day all-cause mortality was 22.2% vs. 27.8%, respectively (p = 0.465). Time to discharge from intensive care unit and mean duration of hospitalization were comparable between groups. Adverse-event incidences were comparable. Post hoc subset analyses, which included the majority of patients (58–78%), showed significant reductions in all-cause mortality (trimodulin vs. placebo) in patients with high CRP, low IgM, and high CRP/low IgM at baseline. Conclusions No significant differences were found in VFDs and mortality between trimodulin and placebo groups. Post hoc analyses supported improved outcome regarding mortality with trimodulin in subsets of patients with elevated CRP, reduced IgM, or both. These findings warrant further investigation

Clinical application of stem cell therapy in Parkinson's disease

Cell replacement therapies in Parkinson's disease (PD) aim to provide long-lasting relief of patients' symptoms. Previous clinical trials using transplantation of human fetal ventral mesencephalic (hfVM) tissue in the striata of PD patients have provided proof-of-principle that such grafts can restore striatal dopaminergic (DA-ergic) function. The transplants survive, reinnervate the striatum, and generate adequate symptomatic relief in some patients for more than a decade following operation. However, the initial clinical trials lacked homogeneity of outcomes and were hindered by the development of troublesome graft-induced dyskinesias in a subgroup of patients. Although recent knowledge has provided insights for overcoming these obstacles, it is unlikely that transplantation of hfVM tissue will become routine treatment for PD owing to problems with tissue availability and standardization of the grafts. The main focus now is on producing DA-ergic neuroblasts for transplantation from stem cells (SCs). There is a range of emerging sources of SCs for generating a DA-ergic fate in vitro. However, the translation of these efforts in vivo currently lacks efficacy and sustainability. A successful, clinically competitive SC therapy in PD needs to produce long-lasting symptomatic relief without side effects while counteracting PD progression

The Tumorigenicity of Mouse Embryonic Stem Cells and In Vitro Differentiated Neuronal Cells Is Controlled by the Recipients' Immune Response

Embryonic stem (ES) cells have the potential to differentiate into all cell types and are considered as a valuable source of cells for transplantation therapies. A critical issue, however, is the risk of teratoma formation after transplantation. The effect of the immune response on the tumorigenicity of transplanted cells is poorly understood. We have systematically compared the tumorigenicity of mouse ES cells and in vitro differentiated neuronal cells in various recipients. Subcutaneous injection of 1×106 ES or differentiated cells into syngeneic or allogeneic immunodeficient mice resulted in teratomas in about 95% of the recipients. Both cell types did not give rise to tumors in immunocompetent allogeneic mice or xenogeneic rats. However, in 61% of cyclosporine A-treated rats teratomas developed after injection of differentiated cells. Undifferentiated ES cells did not give rise to tumors in these rats. ES cells turned out to be highly susceptible to killing by rat natural killer (NK) cells due to the expression of ligands of the activating NK receptor NKG2D on ES cells. These ligands were down-regulated on differentiated cells. The activity of NK cells which is not suppressed by cyclosporine A might contribute to the prevention of teratomas after injection of ES cells but not after inoculation of differentiated cells. These findings clearly point to the importance of the immune response in this process. Interestingly, the differentiated cells must contain a tumorigenic cell population that is not present among ES cells and which might be resistant to NK cell-mediated killing

MEF2C Enhances Dopaminergic Neuron Differentiation of Human Embryonic Stem Cells in a Parkinsonian Rat Model

Human embryonic stem cells (hESCs) can potentially differentiate into any cell type, including dopaminergic neurons to treat Parkinson's disease (PD), but hyperproliferation and tumor formation must be avoided. Accordingly, we use myocyte enhancer factor 2C (MEF2C) as a neurogenic and anti-apoptotic transcription factor to generate neurons from hESC-derived neural stem/progenitor cells (NPCs), thus avoiding hyperproliferation. Here, we report that forced expression of constitutively active MEF2C (MEF2CA) generates significantly greater numbers of neurons with dopaminergic properties in vitro. Conversely, RNAi knockdown of MEF2C in NPCs decreases neuronal differentiation and dendritic length. When we inject MEF2CA-programmed NPCs into 6-hydroxydopamine—lesioned Parkinsonian rats in vivo, the transplanted cells survive well, differentiate into tyrosine hydroxylase-positive neurons, and improve behavioral deficits to a significantly greater degree than non-programmed cells. The enriched generation of dopaminergic neuronal lineages from hESCs by forced expression of MEF2CA in the proper context may prove valuable in cell-based therapy for CNS disorders such as PD

Effects of histocompatibility and host immune responses on the tumorigenicity of pluripotent stem cells

Pluripotent stem cells hold great promises for regenerative medicine. They might become useful as a universal source for a battery of new cell replacement therapies. Among the major concerns for the clinical application of stem cell-derived grafts are the risks of immune rejection and tumor formation. Pluripotency and tumorigenicity are closely linked features of pluripotent stem cells. However, the capacity to form teratomas or other tumors is not sufficiently described by inherited features of a stem cell line or a stem cell-derived graft. The tumorigenicity always depends on the inability of the recipient to reject the tumorigenic cells. This review summarizes recent data on the tumorigenicity of pluripotent stem cells in immunodeficient, syngeneic, allogeneic, and xenogeneic hosts. The effects of immunosuppressive treatment and cell differentiation are discussed. Different immune effector mechanisms appear to be involved in the rejection of undifferentiated and differentiated cell populations. Elements of the innate immune system, such as natural killer cells and the complement system, which are active also in syngeneic recipients, appear to preferentially reject undifferentiated cells. This effect could reduce the risk of tumor formation in immunocompetent recipients. Cell differentiation apparently increases susceptibility to rejection by the adaptive immune system in allogeneic hosts. The current data suggest that the immune system of the recipient has a major impact on the outcome of pluripotent stem cell transplantation, whether it is rejection, engraftment, or tumor development. This has to be considered when the results of experimental transplantation models are interpreted and even more when translation into clinics is planned

Transplantation of human embryonic stem cell-derived cells to a rat model of Parkinson’s disease: effect of in vitro differentiation on graft survival and teratoma formation

Human embryonic stem cells (hESCs) have been proposed as a source of dopamine (DA) neurons for transplantation in Parkinson's disease (PD). We have investigated the effect of in vitro predifferentiation on in vivo survival and differentiation of hESCs implanted into the 6-OHDA (6-hydroxydopamine)-lesion rat model of PD. The hESCs were cocultured with PA6 cells for 16, 20, or 23 days, leading to the in vitro differentiation into DA neurons. Grafted hESC-derived cells survived well and expressed neuronal markers. However, very few exhibited a DA neuron phenotype. Reversal of lesion-induced motor deficits was not observed. Rats grafted with hESCs predifferentiated in vitro for 16 days developed severe teratomas, whereas most rats grafted with hESCs predifferentiated for 20 and 23 days remained healthy until the end of the experiment. This indicates that prolonged in vitro differentiation of hESCs is essential for preventing formation of teratomas