Modulation of IL-33/ST2-TIR and TLR signalling pathway by fingolimod and analogues in immune cells.

For the immune modulatory drug fingolimod (FTY720), lymphocyte sequestration has been extensively studied and accepted as mode of action. Further, direct effects on immune cell signalling are incompletely understood. Herein, we used the parent drug and newly synthesized analogues to investigate their effects on dendritic cell (DC) calcium signalling and on Th1, Th2 and Th17 responses. DC calcium signalling was determined with a single cell-based confocal assay and IL-33/ST2-TIR Th2-like response with ST2-transduced EL4-6.1 thymoma cells. The Th1/Th17 responses were examined with a LPS/TLR-enhanced antigen presentation assay with OVA-TCRtg CD4 and CD8 spleen cells. Our results revealed a comparable influence of fingolimod and S1P on intracellular calcium level in DC, while an oxy-derivative of fingolimod exhibited an EC50 of 3.3 nm, being 14 times more potent than FTY720-P. The IL-33/ST2-TIR Th2-like response in ST2-EL4 cells was inhibited by fingolimod and analogues at varying degrees. Using the OVA-TCRtg LPS/TLR-enhanced spleen cell assay, we found that fingolimod inhibited both IL-17 and IFN-γ production. In contrast, fingolimod phosphate failed to decrease Th1 cytokines. Interestingly, the effects of the parent compound fingolimod were modulated by the PP2A inhibitor okadaic acid, thus suggesting PP2A as relevant intracellular target. These studies describe detailed immune-modulating properties of fingolimod, including interference with a prototypical Th2 response via IL-33/ST2-TIR. Moreover, differential effects of fingolimod versus its phosphorylated derivative on TLR-activated and antigen-dependent Th1 activation suggest PP2A as an additional target of fingolimod immune therapy. Together with the analogues tested, these data may guide the development of more specific fingolimod derivatives.

[Diagnosis and therapy of malignant lymphedema]. / Diagnostik und Therapie maligner Lymphödeme.

In addition to the typical clinical symptoms, the diagnosis "malignant lymphedema" also requires the confirmation of a tumor or a metastasis obstructing lymph flow. With the standard physical treatment of edema described by Asdonk successful clinical management of malignant lymphedema is also possible. The sole contraindication of manual lymph drainage is, we believe, locoregional tumor recurrence, which can be completely eliminated by the immediate initiation of radical tumor treatment. The tumor recurrence is the result not of falsely indicated manual lymph drainage, but of inadequate primary treatment that leaves behind residual tumor tissue, the early detection of which still remains an unresolved problem. Manual lymph drainage is indispensable for improving the quality of life of tumor patients with lymphedema.

[Anasarca caused by rheumatic carditis]. / Anasarka durch rheumatische Karditis.

Report of a 55-year-old-male patient with most serious anasarca caused by insufficiency right heart. The reason of the heart failure was probably rheumatic carditis caused by streptococcal infections which followed recurrent erysipelas both legs with phleblymphedema. The necessity of consistent antibiotic treatment of the erysipelas, that's the only possibility to avoid more difficult secondary complications like this case of rheumatic carditis showed. The treatment of insufficiency heart was followed by physical decongestive therapy of the phleblymphedema of the legs. After a treatment period of 12 weeks a water loss of 112 kg and reduction of abdominal circumference from 250 cm to 150 cm could be achieved.

[Gigantic arm lymphedema]. / Gigantisches Armylmphödem.

It is told the course of a disease of a 44-year old woman who got a gigantic lymphedema of the arm within 5 years after a treatment caused by breast cancer 10 years ago. There are described the psychical and social consequences and there are also analyzed reasons how such an extreme lymphedema of the arm could be possible. An incessant success of the treatment could only be achieved by a combination of plastic operation to reduce the tissue and consistent use of physical therapy of edema according to Asdonk, a combination of manual lymph-drainage therapy according to Vodder-Asdonk and compression treatment.

[Lymphedema of the head in clinical practice]. / Das Kopflymphödem in der klinischen Praxis.

In the Feldberg clinic Dr. Asdonk in St. Blasien we treat primary and secondary lymphedemas of the head with the "Manual lymphdrainage according to Vodder-Asdonk." Secondary lymphedemas are a result of cancer therapy or are caused of tumors or their metastases respectively. A successful therapy is possible at primary lymphedemas of head or lymphedemas following an inflammation or an injury. If the cancer increases unstoppable the so-called "malignant lymphedema" not always decreases. Nevertheless we should treat with manual lymphdrainage therapy because if we do it not the lymphedema increases also unstoppable and it means a disaster for the patient. The manual lymphdrainage therapy is the only treatment we can do. Diuretics are only an indication in the final phase of the malignant lymphedema of the head because they do not take away the protein out of the interstitial tissue and so the edema becomes all the more.

[Differential diagnosis of liver and biliary tract diseases in a regional hospital]. / Die Differentialdiagnostik der Leber- und Gallenwegserkrankungen an einem Kreiskrankenhaus.

Between 1 Jan 1977 and 31 Dec 1979 459 patients were admitted as cases of hepatitis and with suspicion of hepatitis. Opposite to this number stood 613 patients with diseases of the biliary ducts. Only by the large-scale use of invasive-diagnostic methods we could perform and adequate diagnostics, the results of which are demonstrated in this paper. Clinic and results of serological examinations, the value of which is without doubt, are at the present date not yet suited to substitute the liver blind puncture and the laparoscopy in the same value. Recently decisive progress was achieved in the field of diagnosis by the introduction of sensitive radiotests and enzyme immune tests for the proof of virus hepatitides. By means of these new investigation methods prerequisites have been created to reduce the still high dark number in cases of anicteric hepatitis and subclinical cases of hepatitis.

[Rare liver damage caused by an antihypertensive and anti-arrhythmic agents]. / Seltene Leberschäden durch Antihypertensiva und Antiarrhythmika.

It is reported on lesions of the liver parenchyma after the application of dihydralazin and detajmium bitartrate with description of the clinical and morphological findings. By means of the morphological findings got in liver biopsy a clinically supposed acute virus hepatitis could be excluded. After the application of dihydralazin group cell necroses and an inflammation of the periportal fields, after detajmium bitartrate a typical intrahepatic cholestasis was in the front. The knowledge of medicamentous side-effects may avoid diagnostic and therapeutic errors in the individual case.