Biomedical subjects

Elmar Jaeckel

Publications and source records attributed to Elmar Jaeckel.

10 recordsLinked to original sources

PubMed2006

Instruction of Treg commitment in peripheral T cells is suited to reverse autoimmunity.

In order to exploit regulatory T cells in a clinical setting it is desirable to be able to generate such cells by a variety of antigens that elicit unwanted immune responses. This goal has been achieved by targeting antigen to dendritic cells under subimmunogenic conditions which results in the conversion of naïve Foxp3 negative T cells into Foxp3-expressing regulatory T cells that are indistinguishable from what has been referred to as natural Treg. Such cells have the ability to interfere with immunity at early as well as late stages of the immune response during which effector cells have already been formed. This suggests that Treg cannot only be exploited to prevent immune responses but also to interfere with already established immunity.

Animals↗

PubMed2006

Early monotherapy with pegylated interferon alpha-2b for acute hepatitis C infection: the HEP-NET acute-HCV-II study.

Early treatment of acute hepatitis C with interferon alpha-2b for 24 weeks prevents chronic infection in almost all patients. Because pegylated interferons have replaced conventional interferon in the therapy of chronic hepatitis C, the aim of this study was to analyze the efficacy of an early treatment of acute hepatitis C with peginterferon alpha-2b. Between February 2001 and February 2004, 89 individuals with acute HCV infection were recruited at 53 different centers in Germany. Patients received 1.5 microg/kg peginterferon alpha-2b for 24 weeks; treatment was initiated after a median of 76 days after infection (range 14-150). End-of-treatment response and sustained virological response were defined as undetectable HCV RNA at the end of therapy and after 24 weeks of follow-up, respectively. In the total study population, virological response was 82% at the end of treatment and 71% at the end of follow-up. Of 89 individuals, 65 (73%) were adherent to therapy, receiving 80% of the interferon dosage within 80% of the scheduled treatment duration. End-of-treatment and sustained virological response rates in this subpopulation were 94% and 89%, respectively. A maximum alanine aminotransferase level of more than 500 U/L prior to therapy was the only factor associated with successful treatment. In conclusion, in acute HCV infection, early treatment with peginterferon alpha-2b leads to high virological response rates in individuals who are adherent to treatment. The high number of dropouts underlines the importance of thorough patient selection and close monitoring during therapy. Thus, future studies should identify factors predicting spontaneous viral clearance to avoid unnecessary therapy.

Acute Disease↗

PubMed2006

Making regulatory T cells with defined antigen specificity: role in autoimmunity and cancer.

There is increasing evidence that agonist ligand presentation either intrathymically or extrathymically plays a crucial if not essential role in the generation of regulatory T cells (Tregs). Thus, it is possible to induce Tregs of any desired specificity in vivo. The same goal can be achieved in vitro by expanding antigen-specific CD4+ T cells and retrovirally transducing them. In contrast, in vitro expansion of Tregs is limited to antigens that have resulted in Treg generation in vivo. Antigen-specific Tregs can be used in cellular therapy with the goal to prevent autoimmune disease or even to interfere with established autoimmunity. The latter requires that the Tregs can suppress effector cells that have already caused harm, which is possible because of the antigen-dependent homing properties of Tregs, i.e. these cells can accumulate in antigen-draining lymph nodes and exit into inflamed tissue. Generally, the in vivo interference is dependent on cytokines such as transforming growth factor-beta and interleukin-10 that were dispensable in in vivo analysis of immunosuppression. The precise mechanisms of suppression remain enigmatic, however, but may be further elucidated by the molecular analysis of suppressed versus non-suppressed T cells.

Animals↗

PubMed2004

Antigen-specific FoxP3-transduced T-cells can control established type 1 diabetes.

CD4(+)CD25(+) T-cells can be used to interfere with spontaneous autoimmune diseases such as type 1 diabetes. However, their low frequency and often unknown specificity represent major obstacles to their therapeutic use. Here we have explored the fact that ectopic expression of the transcription factor Foxp3 can confer a suppressor phenotype to naive CD4(+) T-cells. We found that retroviral transduction of polyclonal CD4 T-cells with FoxP3 was not effective in interfering with established type 1 diabetes. Thus, more subtle and more organ-specific regulation might be required to prevent type 1 diabetes, as well as to avoid systemic immunosuppression. However, a single injection of 10(5) FoxP3-transduced T-cells with specificity for islet antigen stabilized and reversed disease in mice with recent-onset diabetes. By comparing FoxP3-transduced T-cells with various antigen specificities, it became clear that the in vivo effect correlated with specific homing to and activation in pancreatic lymph nodes and not with in vitro suppressor activity or cytokine production. Our results complement recent results on in vitro-amplified antigen-specific T-cells in ameliorating type 1 diabetes and suggest that FoxP3 transduction of expanded T-cells might achieve the same goal.

Animals↗

PubMed2004

Recessive tolerance to preproinsulin 2 reduces but does not abolish type 1 diabetes.

Although autoimmune diseases can be initiated by immunization with a single antigen, it is not clear whether a single self antigen is essential for the initiation and, perhaps, the perpetuation of spontaneous autoimmunity. Some studies have suggested that insulin may represent an essential autoantigen in type 1 diabetes. Here we show that unlike tolerance to glutamic acid decarboxylase, tolerance to transgenically overexpressed preproinsulin 2 substantially reduced the onset and severity of type 1 diabetes in nonobese diabetic mice. However, some mice still developed type 1 diabetes, suggesting that insulin is a key, but not absolutely essential, autoantigen. The results are consistent with the idea that the human IDDM2 locus controls susceptibility to type 1 diabetes by regulating intrathymic preproinsulin expression.

Amino Acid Sequence↗

PubMed2004

Ouabain treatment is associated with upregulation of phosphatase inhibitor-1 and Na+/Ca(2+)-exchanger and beta-adrenergic sensitization in rat hearts.

Cardiac glycosides are widely used in the treatment of congestive heart failure. While the mechanism of the positive inotropic effect after acute application of cardiac glycosides is explained by blockade of the Na+/K+-pump, little is known about consequences of a prolonged therapy. Here male Wistar rats were treated for 4 days with continuous infusions of ouabain (6.5 mg/kg/day) or 0.9% NaCl (control) via osmotic minipumps. Electrically driven (1 Hz, 35 degrees C) papillary muscles from ouabain-treated rats exhibited shorter relaxation time (-15%) and a twofold increase in the sensitivity for the positive inotropic effect of isoprenaline. The density and affinity of beta1- and beta2-adrenoceptors as well as mRNA and protein levels of stimulatory (G(s)alpha) and inhibitory (G(i)alpha-2, G(i)alpha-3) G-proteins were unaffected by ouabain. Similarly, SR-Ca2+-ATPase 2A, phospholamban, ryanodine-receptor expression as well as the oxalate-stimulated 45Ca-uptake of membrane vesicles remained unchanged. However, mRNA abundance of the protein phosphatase inhibitor-1 (I-1) and the Na+/Ca2+-exchanger (NCX) were increased by 52% and 26%, respectively. I-1 plays an amplifier role in cardiac signaling. Downregulation of I-1 in human heart failure is associated with desensitization of the beta-adrenergic signaling pathway. The present data suggest that the ouabain-induced increase in I-1 expression might be at least partly responsible for the increased isoprenaline sensitivity and increased expression of NCX for the accelerated relaxation after chronic ouabain in this model.

Adrenergic beta-Agonists↗

PubMed2003

Normal incidence of diabetes in NOD mice tolerant to glutamic acid decarboxylase.

Experiments in nonobese diabetic (NOD) mice that lacked expression of glutamic acid decarboxylase (GAD) in beta cells have suggested that GAD represents an autoantigen essential for initiating and maintaining the diabetogenic immune response. Several attempts of inducing GAD-specific recessive tolerance to support this hypothesis have failed. Here we report on successful tolerance induction by expressing a modified form of GAD under control of the invariant chain promoter resulting in efficient epitope display. In spite of specific tolerance insulitis and diabetes occurred with normal kinetics indicating that GAD is not an essential autoantigen in the pathogenesis of diabetes.

Amino Acid Sequence↗

PubMed2003

Thymic selection revisited: how essential is it?

Intrathymic T cell development represents one of the best studied paradigms of mammalian development. Lymphoid committed precursors enter the thymus and the Notch1 receptor plays an essential role in committing them to the T cell lineages. The pre-T cell receptor (TCR), as an autonomous cell signaling receptor, commits cells to the alphabeta lineage while its rival, the gammadeltaTCR, is involved in generating the gammadelta lineage of T cells. Positive and negative selection of immature alphabetaTCR-expressing cells are essential mechanisms for generating mature T cells, committing them to the CD4 and CD8 lineages and avoiding autoimmunity. Additional lineages of alphabetaT cells, such as the natural killer T cell lineage and the CD25+ regulatory T cell lineage, are formed when the alphabetaTCR encounters specific ligands in suitable microenvironments. Thus, positive selection and receptor-instructed lineage commitment represent a hallmark of the thymus. Ectopically expressed organ-specific antigens contribute to thymic self-nonself discrimination, which represents an essential feature for the evolutionary fitness of mammalian species.

Animals↗

PubMed2002

Animal models of autoimmune hepatitis.

Autoimmune hepatitis (AIH) is difficult to study in humans because of the late diagnosis, the heterogenic genetic background and the lack of tissue specimens. Therefore, animal models have been used for more than 90 years to study liver-specific immune regulation. This article summarizes how early studies of experimental AIH established the importance of T cells for causing the liver injury and how regulatory pathways were detected. Studies in transgenic models demonstrated that T cells can be tolerant to liver antigens by ignorance, deletion, anergy, and receptor downregulation. They furthermore defined functions in antigen presentation for hepatocytes and sinusoidal endothelial cells. Studies in cytokine-induced models show common effector cascades resulting from T-cell activation and the interaction of innate and adaptive immune response. The use of animal models of AIH will improve our understanding of the pathophysiology of the disease and might help to explore new possibilities for therapy and prevention.

Animals↗

PubMed2002

Viruses and diabetes.

Insulin-dependent diabetes mellitus (IDDM) is a multifactorial disease. Besides a genetic predisposition environmental factors have been implicated in the pathogenesis of beta cell destruction. Among these environmental factors viruses have been the focus of many studies. Some viruses are diabetogenic in animals, and others have been implicated as triggers in human IDDM by temporal and geographical association between IDDM and viral infections, serological evidence of infection in recently diagnosed diabetic patients, and the isolation of viruses from the pancreas of affected individuals. We discuss possible pathomechanisms of viral infections in beta cell destruction and review the studies on involvement of enteroviruses, retroviruses, rubella viruses, cytomegaloviruses, and Epstein-Barr viruses in human IDDM. We also report on studies of diabetogenic viruses in animal models as well as on viral infections protecting from IDDM. Some of the difficulties in linking viral infections to IDDM will be illustrated with data from a transgenic mouse model in which IDDM can be precipitated by infections with certain strains of lymphocytic choriomeningitis virus (LCMV). Emerging treatment concepts that do not rely on defining the initiating autoantigens but involve self-reactive regulatory lymphocytes such as oral antigen administration, as well as DNA vaccines, will be discussed briefly.

Animals↗