Browsing by Author "Wolf, Peter"

To elucidate the molecular action of 8-methoxypsoralen plus UVA (PUVA), a standard dermatological therapy, we used K5. hTGF-beta 1 transgenic mice exhibiting a skin phenotype and cytokine abnormalities with strong similarities to human psoriasis. We observed that impaired function of CD4(+)CD25(+) regulatory T cells (Tregs) and increased cytokine levels of the IL-23/Th17 pathway were responsible for the psoriatic phenotype in this mouse model. Treatment of K5.hTGF-beta 1 transgenic mice with PUVA suppressed the IL-23/Th17 pathway, Th1 milieu, as well as transcription factors STAT3 and orphan nuclear receptor ROR gamma t. PUVA induced the Th2 pathway and IL-10-producing CD4(+)CD25(+)Foxp3(+)Tregs with disease-suppressive activity that was abolished by anti-CTLA4 mAb treatment. These findings were paralleled by macroscopic and microscopic clearance of the diseased murine skin. Anti-IL-17 mAb treatment also diminished the psoriatic phenotype of the mice. This indicated that both induced Tregs involving CTLA4 signaling and inhibition of the IL-23/Th17 axis are central for the therapeutic action of PUVA. The Journal of Immunology, 2010, 184: 7257-7267.

8-Methoxypsoralen plus UVA (PUVA) photochemotherapy is an effective treatment for many skin diseases including psoriasis. However, its exact mechanism of therapeutic action is incompletely understood. Previously, in K5.hTGF beta 1 transgenic psoriatic mice, we found that PUVA induces Foxp3+ CD25+ CD4+ regulatory T cells in both lymph node and spleen. Now, in the same model, we investigated whether cutaneous lymphocyte-associated antigen (CLA) mediates PUVAs effect on homing of CD25+ CD4+ T cells to the lymph nodes of K5.hTGF beta 1 transgenic mice. We found that a low dose of topical PUVA maximally increased the proportion of CLA + CD25+ CD4 + T cells in the lymph nodes by up to 8-fold. We also observed an increased number of Foxp3+ CD25+ T cells in the skin of the mice after PUVA treatment. Together, these findings suggest that PUVA affects the homing of regulatory T cells.

The purpose of our study was to elucidate the dynamics of muscle activation during generalised tonic-clonic seizures (GTCS). We recorded surface electromyography (EMG) from the deltoid muscle during 26 GTCS from 13 patients and compared it with GTCS-like events acted by 10 control subjects. GTCS consisted of a sequence of phases best described quantitatively by dynamics of the low frequency (LF) wavelet component (2-8 Hz). Contrary to the traditional view, the tonic phase started with a gradual increase in muscle activity. A longer clonic phase was associated with a shorter onset of the tonic phase and a higher seizure occurrence. Increase in LF occurred during the onset phase and during the transition from the tonic to the clonic phase, corresponding to the vibratory movements. The clonic phase consisted of EMG discharges of remarkably constant duration (0.2 s) separated by silent periods (SP) of exponentially increasing duration - features that could not be reproduced voluntarily. The last SP was longer in seizures with higher EMG peak frequency whereas the energy of the last clonus was higher in seizures with a short clonic phase. We found specific features of muscle activation dynamics during GTCS. Our findings suggest that the same inhibitory mechanisms that contribute to GTCS termination counteract seizure initiation, accounting for the gradual onset. Both active inhibition and mechanisms related to metabolic depletion act synergistically to stop the seizure. Analysis of the ictal EMG dynamics is a valuable toot for monitoring the balance between pro-convulsive and anti-convulsive factors. (c) 2012 Elsevier B.V. All rights reserved.

It is thought that a Th1/Th17-weighted immune response plays a predominant role in the pathogenesis of psoriasis. Our findings now indicate a link between IL-9, a Th2 and Th9 cytokine, and Th17 pathway in psoriasis. In K5.hTGF-beta 1 transgenic mice, exhibiting a psoriasis-like phenotype, we found increased IL-9R and IL-9 expression in the skin and intradermal IL-9 injection induced Th17-related inflammation. IL-9 also promoted angiogenesis and VEGF and CD31 overexpression in mice in vivo and increased tube formation of human endothelial cells in vitro. Injecting anti-IL-9 antibody into K5.hTGF-beta 1 transgenic mice not only diminished inflammation (including skin infiltration by T cells, monocytes/macrophages, and mast cells) and angiogenesis but also delayed the psoriasis-like skin phenotype. Notably, injection of anti-psoriatic acting anti-IL17 antibody reduced skin IL-9 mRNA and serum IL-9 protein levels in K5.hTGF-beta 1 transgenic mice and prevented IL-9-induced epidermal hyperplasia and inflammation of the skin of wild type mice. In addition, we observed that IL-9R expression in lesional skin from psoriasis patients was markedly higher than in healthy skin from control subjects. Moreover, IL-9 significantly enhanced IL-17A production by cultured human peripheral blood mononuclear cells or CD4+ T cells, especially in psoriasis patients. Thus, IL-9 may play a role in the development of psoriatic lesions through Th17-associated inflammation and angiogenesis.

Platelet-activating factor (PAF), a potent biolipid mediator, is involved in a variety of cellular transduction pathways and plays a prominent role in inducing inflammation in different organs. We used K5.hTGF-beta 1 transgenic mice, which exhibit an inflammatory skin disorder and molecular and cytokine normalities with strong similarities to human psoriasis, to study the pathogenic role of PAF. We found that injecting PAF into the skin of transgenic mice led to inflammation and accelerated manifestation of the psoriatic phenotype by a local effect. In contrast, injecting mice with PAF receptor antagonist PCA-4248 lowered the PAF level (most likely by depressing an autocrine loop) and neutrophil, CD68(+) cell (monocyte/macrophage), and CD3(+) T-cell accumulation in the skin and blocked progression of the psoriasis-like phenotype. This effect of PAF blockade was specific and similar to that of psoralen-UV-A and was paralleled by a decrease in abnormally elevated mRNA and/or protein levels of T-helper type 17 cell-related cytokines IL-17A, IL-17F, IL-23, IL-12A, and IL-6 and its transcription factor signal transducer and activator of transcription 3. In contrast, PCA-4248 treatment up-regulated mRNA levels of cyclooxygenase-2 and IL-10 in dorsal skin and release of IL-10 in serum and skin. Interfering with PAF may offer the opportunity to develop novel therapeutic strategies for inflammatory psoriasis and associated comorbidities, including metabolic syndrome and atherosclerosis, in which the IL-17 axis may be involved. (Am J Pathol 2011, 178:699-708; DOI: 10.1016/j.ajpath.2010.10.008)