Cure of chronic viral infection and virus-induced type 1 diabetes by neutralizing antibodies

The use of neutralizing antibodies is one of the most successful methods to interfere with receptor–ligand interactions in vivo. In particular blockade of soluble inflammatory mediators or their corresponding cellular receptors was proven an effective way to regulate inflammation and/or prevent its negative consequences. However, one problem that comes along with an effective neutralization of inflammatory mediators is the general systemic immunomodulatory effect. It is, therefore, important to design a treatment regimen in a way to strike at the right place and at the right time in order to achieve maximal effects with minimal duration of immunosuppression or hyperactivation. In this review, we reflect on two examples of how short time administration of such neutralizing antibodies can block two distinct inflammatory consequences of viral infection. First, we review recent findings that blockade of IL-10/IL-10R interaction can resolve chronic viral infection and second, we reflect on how neutralization of the chemokine CXCL10 can abrogate virus-induced type 1 diabetes

Regulatory T cells in rheumatoid arthritis : contributions from different functional subsets

Rheumatoid arthritis (RA) is a complex and multifactorial disease characterized by chronic joint inflammation and tissue destruction, which can affect all ethnic groups with a prevalence of 0.5-1%. FOXP3+ regulatory T cells (Treg cells) are crucial for the maintenance of self-tolerance and loss of function or reduced frequencies have been implicated in chronic inflammatory and autoimmune diseases. In patients with inflammatory arthritis including RA, Treg cells are significantly enriched at the site of inflammation compared with levels in the circulation, and are further functional in suppressing autologous effector T cells from both peripheral blood and joint origin. Given the accumulation of functional Treg cells in the rheumatic joint, an unresolved question is why local inflammation processes persist in a chronic way. In this thesis, we investigated the presence, frequency and functionality of different Treg-cell subsets in patients with inflammatory arthritis, and further studied the impact of commonly used treatment regimes on the suppressive capacity of Treg cells. We could show that synovial FOXP3+ Treg cells were increased in frequency compared with peripheral blood, displayed a high degree of FOXP3 demethylation and a low capacity of secreting pro-inflammatory cytokines upon stimulation. Moreover, the activation status of effector T cells and locally produced pro-inflammatory cytokines reduced regulatory Treg cell function in vitro and presumably in the rheumatic joint. Furthermore, expression of CD39, an ecto-nucleotidase, which together with CD73 generates anti-inflammatory adenosine, was significantly increased on synovial FOXP3+ Treg cells. Such FOXP3+CD39+ Treg cells did not produce pro-inflammatory cytokines and were good suppressors of several effector T-cell functions including secretion of IFN-γ and TNF, but did not limit IL-17A, a cytokine implicated in RA pathogenesis. Additional investigations of FOXP3+ Treg cells in the context of Helios, a suggested marker of thymus-derived Treg cells, revealed that synovial Helios+FOXP3+ T cells were abundant in the joint, displayed a more classical Treg-cell phenotype with regard to expression of surface markers and cytokine secretion capacity compared with Helios-FOXP3+ T cells. Finally, biologicals commonly used for the treatment of RA were shown to have profound effects on Treg-cell function, however by different mechanisms. Blocking of IL-6 and TNF by tocilizumab or adalimumab increased suppressive capacity of synovial Treg cells. Abatacept, in contrast, had no beneficial effect on Treg-cell function, but due to its mutual effect on effector and regulatory T cells, the inflammatory pressure in the joint could still be alleviated. In summary, our data suggest that joint-derived Treg cells in general are not impaired in their function and rather the inflammatory pressure needs to be reduced to allow for optimal Treg-cell functionality. Further, this work emphasizes the importance of dissecting synovial Treg-cell subsets to gain a better understanding on how Treg cells could be targeted for the treatment of chronic arthritis. ::doi::10.1002/eji.201041004. ::pmid::21607944 ::isi::00029326430001

Sexualitätsbezogene Qualifizierung für pädagogische und beraterische Handlungsfelder - Konzeption und Erprobung eines Nachdiplomstudienganges

Erstmalig in der Geschichte sexualitätsbezogener Aus- und Fortbildung professioneller MultiplikatorInnen werden - neben dem Studienangebot an der FH Merseburg - im Nachdiplomstudium "Sexualität in Pädagogik und Beratung" an der Hochschule für Soziale Arbeit Luzern die Handlungsfelder Erziehung und Beratung in einem Qualifizierungsgang konzeptionell systematisch zusammengeführt. Die Arbeit beschreibt Voraussetzungen, Konzeption und Veranstaltung des Studiengangs, dokumentiert die evaluative Zwischenbilanz des Projektverlaufs und entwickelt - im Lichte der sich verändernden Lernprozesse und Bildungsplanungen in der reflexiven Moderne - Lehren für zukünftige sexualitätsbezogene Hochschulqualifizierung

Lost in translation: barriers to implementing clinical immunotherapeutics for autoimmunity

Induction of selective, autoantigen-specific tolerance is the “holy grail” for the treatment and prevention of autoimmune diseases. Despite successes in many differential murine models, rational and efficient translation to the clinic has been difficult. During the 5th Annual Federation of Clinical Immunological Societies (FOCIS) Meeting, May 12–16, 2005, in Boston, MA, a Kirin-sponsored “Ideashop” was convened to discuss this theme amongst scientists, clinicians, industry partners, and funding agencies

Can We Learn From Viruses How to Prevent Type 1 Diabetes?: The Role of Viral Infections in the Pathogenesis of Type 1 Diabetes and the Development of Novel Combination Therapies

We will take a journey from basic pathogenetic mechanisms elicited by viral infections that play a role in the development of type 1 diabetes to clinical interventions, where we will discuss novel combination therapies. The role of viral infections in the development of type 1 diabetes is a rather interesting topic because in experimental models viruses appear capable of both accelerating as well as decelerating the immunological processes leading to type 1 diabetes. Consequently, I will discuss some of the underlying mechanisms for each situation and consider methods to investigate the proposed dichotomy for the involvement of viruses in human type 1 diabetes. Prevention of type 1 diabetes by infection supports the so-called “hygiene hypothesis.” Interestingly, viruses invoke mechanisms that need to be exploited by novel combinatorial immune-based interventions, the first one being the elimination of autoaggressive T-cells attacking the β-cells, ultimately leading to their immediate but temporally limited amelioration. The other is the invigoration of regulatory T-cells (Tregs), which can mediate long-term tolerance to β-cell proteins in the pancreatic islets and draining lymph nodes. In combination, these two immune elements have the potential to permanently stop type 1 diabetes. It is my belief that only combination therapies will enable the permanent prevention and curing of type 1 diabetes

Blockade but not overexpression of the junctional adhesion molecule C influences virus-induced type 1 diabetes in mice

Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing beta-cells in the pancreas. Recruitment of inflammatory cells is prerequisite to beta-cell-injury. The junctional adhesion molecule (JAM) family proteins JAM-B and JAM–C are involved in polarized leukocyte transendothelial migration and are expressed by vascular endothelial cells of peripheral tissue and high endothelial venules in lympoid organs. Blocking of JAM-C efficiently attenuated cerulean-induced pancreatitis, rheumatoid arthritis or inflammation induced by ischemia and reperfusion in mice. In order to investigate the influence of JAM-C on trafficking and transmigration of antigen-specific, autoaggressive T-cells, we used transgenic mice that express a protein of the lymphocytic choriomeningitis virus (LCMV) as a target autoantigen in the β-cells of the islets of Langerhans under the rat insulin promoter (RIP). Such RIP-LCMV mice turn diabetic after infection with LCMV. We found that upon LCMV-infection JAM-C protein was upregulated around the islets in RIP-LCMV mice. JAM-C expression correlated with islet infiltration and functional beta-cell impairment. Blockade with a neutralizing anti-JAM-C antibody reduced the T1D incidence. However, JAM-C overexpression on endothelial cells did not accelerate diabetes in the RIP-LCMV model. In summary, our data suggest that JAM-C might be involved in the final steps of trafficking and transmigration of antigen-specific autoaggressive T-cells to the islets of Langerhans

Sensitization to self (virus) antigen by in situ expression of murine interferon-gamma.

Autoimmune disease results from inflammatory destruction of tissues by aberrant self-reactive lymphocytes. We studied the autoimmune potential of T lymphocytes immunologically ignorant of viral antigens acting as self antigens and whether the host defense molecule IFN-gamma could stimulate these cells to cytotoxic competency. For this purpose, we produced double transgenic mice expressing pancreatic IFN-gamma as well as lymphocytic choriomeningitis virus (LCMV) nucleoprotein (NP) or glycoprotein (GP) antigen. 100% of the NP+/IFN-gamma+ mice became diabetic before 2 mo of age, while none of the NP single transgenic littermates and only 10% of IFN-gamma single transgenic littermates did. Strikingly, NP+/IFN-gamma+ mice spontaneously developed cytotoxic T lymphocyte activity on LCMV-infected targets and vaccinia virus-NP-infected ones without prior LCMV infection but NP+/IFN-gamma- mice did not, which indicates specific sensitization to the viral antigen by IFN-gamma. These results suggest that lymphocytes ignorant of self antigens can be activated by IFN-gamma released after immunologic stimulation such as viral infection. This mechanism may account for the loss of apparent tolerance to self antigens in autoimmune diseases such as insulin-dependent diabetes mellitus

A Novel Technique for the In Vivo Imaging of Autoimmune Diabetes Development in the Pancreas by Two-Photon Microscopy

Type 1 diabetes (T1D) is characterized by the immune-mediated destruction of beta cells in the pancreas. Little is known about the in vivo dynamic interactions between T cells and beta cells or the kinetic behavior of other immune cell subsets in the pancreatic islets. Utilizing multiphoton microscopy we have designed a technique that allows for the real-time visualization of diabetogenic T cells and dendritic cells in pancreatic islets in a live animal, including their interplay with beta cells and the vasculature. Using a custom designed stage, the pancreas was surgically exposed under live conditions so that imaging of islets under intact blood pressure and oxygen supply became possible. We demonstrate here that this approach allows for the tracking of diabetogenic leukocytes as well as vascularization phenotype of islets and accumulation of dendritic cells in islets during diabetes pathogenesis. This technique should be useful in mapping crucial kinetic events in T1D pathogenesis and in testing the impact of immune based interventions on T cell migration, extravasation and islet destruction