Ernst Schering Research Foundation workshop最新文献

Cardiac magnetic resonance imaging (CMR) permits a detailed look at the myocardium in patients with recent onset heart failure. Late-enhancement CMR provides information that is similar to that obtained by the naked eye of a pathologist. Myocardial scarring is endocardial in myocardial infarction, but it is epicardial in myocarditis and intramyocardial in hypertrophic cardiomyopathy. Thus, the distinction between these entities is possible by depicting scar via late-enhancement CMR and observing myocardial function by cine magnetic resonance imaging. Moreover, non-invasive follow-up--and hence observation of the healing or remodelling process--can be achieved using CMR. New CMR pulse sequences also permit depiction of myocardial oedema, which may occur early in patients with myocarditis and may be the only sign of the disease in the absence of necrosis. It is anticipated that cardiac MRI will become a standard diagnostic technique in patients with new onset of heart failure, left-ventricular hypertrophy or clinical symptoms suggestive of myocarditis.

Targeting TNFalpha provided proof of concept for the role of pro-inflammatory cytokines in promoting cutaneous inflammation, particularly psoriasis. Recent studies have elucidated the presence of numerous cytokine and chemokine activities in psoriatic skin and synovium. There is considerable interest in the potential of such activities as novel therapeutic targets. IL-15 is an innate response cytokine that activates leukocyte subsets via binding to its unique IL-15Ralpha and shared beta and gamma chain receptors. IL-15 promotes T cell memory and sustains local T cell activation, in part via prevention of apoptosis and mediates activation of monocytes, neutrophils and NK cells. IL-15 is up-regulated in psoriatic skin and psoriatic arthritis synovium. IL-15 blockade in a murine model of psoriasis led to marked suppression of typical psoriatic skin features. Clinical intervention in other chronic inflammatory disease states is now ongoing with encouraging early efficacy, raising the possibility for the first time of targeting this novel inflammatory moiety in psoriasis.

The human parvovirus B19 (PVB19), an erythrovirus causing diverse clinical manifestations ranging from asymptomatic or mild to more severe outcomes such as hydrops fetalis, is the only currently known human pathogenic parvovirus. Recently, PVB19 has been identified as a causative agent of pediatric and adult inflammatory cardiac diseases. The first hints for a possible etiopathogenetic role of the PVB19 infection and the development of cardiac dysfunction were demonstrated by molecular biology methods such as in situ hybridization (ISH) and polymerase chain reaction (PCR). In this regard, PVB19-associated inflammatory cardiomyopathy is characterized by infection of endothelial cells of small intracardiac arterioles and venules, which may be associated with endothelial dysfunction, impairment of myocardial microcirculation, and penetration of inflammatory cells in the myocardium.

Embryonic stem cells (ESCs), derivatives of cells of early mammalian embryos, have proven to be one of the most powerful tools in developmental and stem cell biology. When injected into embryos, ESCs can contribute to tissues derived from all three germ layers and to the germline. Prior studies have successfully shown that ESCs can recapitulate features of embryonic development by spontaneously forming somatic lineages in culture. Amazingly, recently it has been shown that mouse ESCs can also give rise to primordial germ cells (PGCs) in culture that are capable of undergoing meiosis and forming both male and female gametes. While the full potential of these ES-derived germ cells and gametes remains to be demonstrated, these discoveries provide a new approach for studying reproductive biology and medicine.

This review addresses the issue of histone deacetylase (HDAC) inhibitors as developed for the treatment of cancer and for the investigation of the inhibition of inflammation. The review focuses on both in vitro and in vivo models of inflammation and autoimmunity. Of particular interest is the inhibition of pro-inflammatory cytokines. Although the reduction in cytokines appears paradoxical at first, upon examination, some genes that are anti-inflammatory are upregulated by inhibition of HDAC. Whether skin diseases will be affected by inhibitors of HDAC remains to be tested.

Chronic heart failure (CHF) represents a major public health burden in developed countries. The introduction of new treatments has helped to improve its prognosis in recent years. However, it is still not possible to directly target the immunological aspects of the disease. In fact, chronic immune activation with the up-regulation of pro-inflammatory substances in the plasma remains an important feature of the disease, independently of its aetiology. Autoimmune mechanisms play a significant role in a subgroup of patients with dilated cardiomyopathy. The interplay between the two systems has not been established so far. This review briefly summarizes immune and autoimmune mechanisms in CHF.

T cell homeostasis is required for normal immune responses and prevention of pathological responses. Transforming growth factor beta (TGFbeta) plays an essential role in that regulation. Owing to its broad expression and inhibitory effects on multiple immune cell types, TGFbeta regulation is complex. Through recent advances in cell-specific targeting of TGFbeta signaling in vivo, the role of TGFbeta in T cell regulation is emerging. We demonstrated here a critical role for TGFbeta in regulating effector vs regulatory T cell homeostasis.

One of the most dramatic chromatin remodelling events takes place during mammalian spermatogenesis involving massive incorporation of somatic and testis-specific histone variants, as well as generalized histone modifications before their replacement by new DNA packaging proteins. Our data suggest that the induced histone acetylation occurring after meiosis may direct the first steps of genome compaction. Indeed, a double bromodomain-containing protein expressed in postmeiotic cells, Brdt, shows the extraordinary capacity to specifically condense acetylated chromatin in vivo and in vitro. In elongating spermatids, Brdt widely co-localizes with acetylated histones before accumulating in condensed chromatin domains. These domains preferentially maintain their acetylation status until late spermatogenesis. Based on these data, we propose that Brdt mediates a general histone acetylation-induced chromatin compaction and also maintains differential acetylation of specific regions, and is therefore involved in organizing the spermatozoon's genome.

Inflammatory cardiomyopathy defined as myocarditis associated with cardiac dysfunction, represents a main cause of heart failure. Despite the improvement of diagnostic techniques, a specific standardized treatment of myocarditis is not yet available. The immunohistochemical detection of myocardial HLA up-regulation has been demonstrated useful in the identification of a sub-group of autoimmune inflammatory dilated cardiomyopathy (DCM) in part susceptible to immunosuppression. Recently, in a retrospective study, we defined the virologic and immunologic profile of responders and non-responders to immunosuppressive therapy of active lymphocytic myocarditis and chronic heart failure in patients who had failed to benefit from conventional supportive treatment. Non-responders were characterized by high prevalence (85%) of viral genomes in the myocardium and no detectable cardiac autoantibodies in the serum. Conversely, 90% of responders were positive for autoantibodies, while only 3 (15%) of them presented viral particles at PCR analysis on frozen endomyocardial tissue. With regard to the type of virus involved in non-responders, enterovirus, adenovirus, or their combination was associated with the worst clinical outcome. Hepatitis C virus (HCV) was the only viral agent of our series associated with detectable cardiac autoantibodies, suggesting a relevant immunomediated mechanism of damage by HCV and explaining the relief of myocardial inflammation after immunosuppressive treatment. The assessment of virologic and immunologic features of patients with biopsy-proven inflammatory cardiomyopathy may allow us to identify a specific treatment leading to recovery of cardiac function.

Lysosomal proteinases are involved in two critical stages of MHC class II-mediated antigen presentation, i.e., degradation of invariant chain, a chaperone molecule critical for MHC class II assembly and transport, and generation of class II-binding peptides in the endocytic compartment. We found that two lysosomal cysteine proteinases, cathepsins S and L, were found to be differentially expressed in different types of "professional" and "nonprofessional" antigen presenting cells, including B cells, macrophages, specialized thymic epithelium, intestinal epithelium, and dendritic cells. In this chapter, our recent studies on the role of cathepsin S and L in MHC class II-mediated antigen processing and presentation in these cells types are highlighted.