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Michael P Schön

Publications and source records attributed to Michael P Schön.

At least 19 recordsLinked to original sources
PubMed2007

Targeting leukocyte trafficking to inflamed skin: still an attractive therapeutic approach?

Research into leukocyte trafficking and its therapeutic exploitation appears to be a multistep process, just like the trafficking cascade itself. The initial euphoria evoked by an early understanding of the trafficking steps was followed by considerable disappointment following the clinical failure of the first selectin antagonist Cylexin (CY-1503), a sialyl Lewis(X) mimetic. The research area recovered and identified additional attractive pharmacological targets such as chemokine receptors and integrins. However, after lack of efficacy in anti-chemokine trials and the fatalities associated with anti VLA-4 therapy (Tysabri), the question arose again whether targeting leukocyte trafficking is really promising or whether such a complex, multistep process with many redundant and/or functionally overlapping molecules is simply too challenging to deal with. In this article, we delineate some pros and cons of this approach followed by a brief update on where we stand in the field and where we might move in the future.

Animals↗
PubMed2006

Diminished lymphocyte adhesion and alleviation of allergic responses by small-molecule- or antibody-mediated inhibition of L-selectin functions.

Selectins are attractive targets for specific anti-inflammatory therapies. Using human lymphocytes as well as an L-selectin-transfected pre-B-cell line in dynamic flow chamber experiments, we could demonstrate that the small-molecule compound efomycine M blocks L-selectin-mediated lymphocyte rolling on sialylated Lewis(X), an action that was confirmed by plasmon resonance spectroscopy. Recruitment of naive lymphocytes to peripheral lymph nodes depends on L-selectin-mediated adhesion to high endothelial venules. We performed intravital microscopy studying lymphocyte rolling in peripheral lymph nodes and showed a 53% reduction (P=0.0006) of lymphocyte rolling in mice treated with efomycine M or a function-blocking antibody against L-selectin. In addition, the number of lymph node-homing T cells was reduced by >60% using either efomycine M or L-selectin-blocking antibodies. As recruitment of naive lymphocytes is a prerequisite for sensitization in T-cell-mediated immune reactions and allergic responses, mice were treated with efomycine M or an L-selectin-specific antibody during contact sensitization with DNFB. After adoptive transfer of corresponding T cells into non-sensitized recipient mice, the capacity of these cells to induce contact hypersensitivity was significantly reduced (P=0.0002 and P=0.0001, respectively). Our data demonstrate that it is possible, in principle, to diminish T-cell-mediated allergic reactions through interference with L-selectin functions during the early sensitization phase.

Adoptive Transfer↗
PubMed2006

Structure-function relation of efomycines, a family of small-molecule inhibitors of selectin functions.

Selectin-mediated leukocyte adhesion to endothelia, the crucial first step initiating the pathogenic cascade of inflammation, is an attractive target for specific therapies. The small-molecule macrolide, efomycine M, inhibits selectin-mediated leukocyte adhesion in vitro and in vivo, and effectively alleviates inflammatory disorders in vivo. To define the molecular basis of the therapeutically relevant antiadhesive properties of efomycines, several new species of this family were purified and/or synthesized. Efomycines E and G were isolated from Steptomyces BS1261. Efomycine O was synthesized by Lewis acid-catalyzed acetalization and efomycine M was generated by base-catalyzed deglycosylation. Efomycine S resulted from ester cleavage of the macrolide ring system, and efomycine T represents the peracetylated form of efomycine M. When the functional activity of efomycines on adhesion of leukocytes to vascular endothelium was studied, some remarkable differences between the compounds became apparent, inasmuch as efomycines E, G, M, and O significantly inhibited adhesion of both human and porcine leukocytes to the vascular endothelium, whereas efomycines S and T did not show any biological activity. A novel docking engine (ProPose), generating an improved, fully configurable protein-ligand interaction model, demonstrated that biological activities of efomycines can be predicted in silico, thus highlighting the utility of such combinatorial approaches.

Animals↗
PubMed2006

The small antitumoral immune response modifier imiquimod interacts with adenosine receptor signaling in a TLR7- and TLR8-independent fashion.

Imiquimod, a small-molecule immune response modifier of the imidazoquinoline family, has shown profound antitumoral and antiviral efficacy both in vitro and in clinical applications in vivo. It has been demonstrated that this activity is mediated through the Toll-like receptor (TLR)7- and TLR8-signaling cascade resulting in the secretion of proinflammatory cytokines and, consecutively, induction of a tumor-directed cellular immune response. In addition, imiquimod exerts a direct proapoptotic activity in tumor cells. We demonstrate here that imiquimod induces activation of the transcription factor NF-kappaB and the downstream production of proinflammatory cytokines in the absence of TLR7 and TLR8. In Chinese hamster ovary cells stably transfected with the human adenosine receptor subtypes, we then show in radioligand-binding competition experiments that imiquimod binds to adenosine receptors at concentrations relevant in clinical settings, with highest affinities to the A(1) and A(2A) subtypes. The effect on the receptor-mediated activation of adenylyl cyclase was also studied, and these experiments revealed that imiquimod acts as an adenosine receptor antagonist. In addition, imiquimod had an inhibitory effect on adenylyl cyclase activity downstream from the receptor. Finally, using transformed human keratinocytes, we provide experimental evidence that imiquimod and A(2A) adenosine receptor-specific compounds similarly induce proinflammatory cytokines in the absence of immune cells. Thus, imiquimod appears to suppress an important feedback mechanism of inflammation by antagonism of adenosine receptor-dependent increase of cAMP and a concomitant receptor-independent inhibition of cAMP production. These novel mechanisms presumably act synergistic with the positive induction of proinflammatory cytokines and can, at least in part, explain the profound inflammation observed in some patients in vivo.

Adjuvants, Immunologic↗
PubMed2006

The small-molecule immune response modifier imiquimod--its mode of action and clinical use in the treatment of skin cancer.

Due to its good clinical efficacy against malignant skin tumours, the topical immune response modifier, imiquimod, has attracted much interest among researchers and clinicians alike. Imiquimod exerts its antitumoural effect, at least in part, through agonistic stimulation of TLR-7 and TLR-8 on dendritic cells, followed by NF-kappaB-dependent secretion of a multitude of pro-inflammatory cytokines. The net result of this pro-inflammatory activity is a profound tumour-directed cellular immune response. Recent research has revealed an additional mode of action inasmuch as imiquimod interferes with adenosine receptor signalling, even in TLR-7- and TLR-8-negative cells, thereby presumably augmenting inflammatory signalling cascades. Moreover, at higher concentrations imiquimod also exerts direct proapoptotic activity against tumour cells. This mode of action appears to be independent of membrane-bound death receptors but is mediated, at least in part, through Bcl-2-dependent release of mitochondrial cytochrome c and subsequent caspase activation. Overall, a combination of several complementary antitumoural modes of action appears to underlie the great utility of imiquimod for treating cutaneous tumours.

Aminoquinolines↗
PubMed2006

Cell adhesion molecules as therapeutic targets: interview with Professor Michael P Schön. Interviewed by Emma Quigley.

Professor Michael P Schön (University of Würzburg) was interviewed by Emma Quigley (Commissioning Editor, Expert Opinion) on 17th October 2006. Professor Michael P Schön currently holds the position of Professor of Dermatology and Experimental Biomedicine at the University of Würzburg. He received his MD degree in 1992 from the University of Ulm in Germany. His internationally successful scientific career has led him to study dermatology and immunology at the University of Berlin, Harvard Medical School, the University of Düsseldorf and the University of Magdeburg. With various research awards and certificates in dermatology, immunology and dermatopathology, Professor Schön has published > 100 papers. He has also been a guest editor and on the Editorial Board of various publications.

Anti-Inflammatory Agents↗
PubMed2005

Migration matters: regulatory T-cell compartmentalization determines suppressive activity in vivo.

Regulatory T cells (Tregs) play a fundamental role in the suppression of different immune responses; however, compartments at which they exert suppressive functions in vivo are unknown. Although many groups have described the presence of Tregs within inflammatory sites, it has not been shown that inflamed tissues are, indeed, the sites of active suppression of ongoing immune reactions. Here, by using alpha(E)+ effector/memory-like Tregs from fucosyltransferase VII-deficient animals, which lack E/P-selectin ligands and fail to migrate into inflamed sites, we analyzed the functional importance of appropriate Treg localization for in vivo suppressive capacity in an inflammation model. Lack of suppression by Tregs deficient in E/P-selectin ligands demonstrates that immigration into inflamed sites is a prerequisite for the resolution of inflammatory reactions in vivo because these selectin ligands merely regulate entry into inflamed tissues. In contrast, control of proliferation of naive CD4+ T cells during the induction phase of the immune response is more efficiently exerted by the naive-like alpha(E)-CD25+ Treg subset preferentially recirculating through lymph nodes when compared with its inflammation-seeking counterpart. Together, these findings provide the first conclusive evidence that appropriate localization is crucial for in vivo activity of Tregs and might have significant implications for anti-inflammatory therapies targeting recruitment mechanisms.

Animals↗
PubMed2005

Psoriasis.

Explore the source record for details and available documents.

Administration, Topical↗
PubMed2005

Expression of gp130 in tumors and inflammatory disorders of the skin: formal proof of its identity as CD146 (MUC18, Mel-CAM).

Two antibodies, BT14 and L101, detect a tumor-associated cell surface glycoprotein (gp130) whose properties in normal and diseased skin were assessed, and whose molecular identity was determined in this study. In normal skin, gp130 was constitutively expressed on dermal blood vessels and epidermal appendages, but not in interfollicular epidermis. Marked induction was detected within benign and malignant tumors of various origins including viral warts, basal cell carcinomas, squamous cell carcinomas, metastatic melanomas, and cutaneous T cell lymphomas. In vitro studies confirmed the general upregulation of gp130 expression in malignantly transformed cells. Surprisingly, gp130 was also induced in inflammatory skin diseases including psoriasis and allergic contact dermatitis. Halting proliferation of transformed keratinocytes through cytostatic drugs or increasing the Ca2+ concentration in the medium resulted in increased gp130 expression. In addition, overexpression of Bcl-2 led to upregulation of gp130. When the protein was purified and analyzed by peptide mass fingerprinting, we could demonstrate that it is MUC18 (Mel-CAM, CD146). Sequential immunoprecipitations and western blot analyses confirmed the identity of the antigen. Thus, both expression pattern and regulation characteristics of the now-known glycoprotein gp130 extended beyond previously published data regarding MUC18, thus shedding some new light on a supposedly well-known antigen.

Antigens, CD↗
PubMed2005

Junctional adhesion molecules (JAM)-B and -C contribute to leukocyte extravasation to the skin and mediate cutaneous inflammation.

Leukocyte extravasation is a finely tuned process, in which transmigration is the final step. Transmigration depends on molecules located at borders of endothelial cells; e.g., junctional adhesion molecules (JAM-A, -B and -C). In vivo blockade of JAM-A lead to decreased migration of monocytes into the skin. In contrast, the role of JAM-B and -C in development of cutaneous inflammation is unknown. We therefore elicited an allergic contact dermatitis in mice using 2,4-dinitro-1-fluorobenzene. RT-PCR and immunofluorescent staining of healthy skin revealed a constitutive JAM-B (66.4%+/-6.7% of all vessels) and -C expression (88.6+/-13.2%), which remained constant after induction of contact dermatitis. Functional studies, in which either JAM-B or -C neutralizing antibodies were injected into sensitized mice prior to allergen challenge showed a concentration-dependent reduction of the contact dermatitis. Decreased ear swelling was accompanied by reduction of leukocyte infiltration as analyzed by hematoxylin and eosin (H&E) histology and enzyme activity. Combined antibody treatment at doses of 1.25 mg per kg bodyweight lead to additive inhibition of allergic contact dermatitis, indicating that JAM-B and -C may have distinct functions. In conclusion, interactions with JAM-B and -C are essential for development of cutaneous inflammation.

Animals↗
PubMed2005

Lymphocyte trafficking to inflamed skin--molecular mechanisms and implications for therapeutic target molecules.

Tissue-selective recruitment of lymphocytes to peripheral organs, such as the skin, is crucial for spatial compartmentalisation within the immune system as well as immune surveillance under normal conditions. In addition, this process plays a key role for the pathogenesis of various diseases including common inflammatory disorders such as atopic dermatitis or psoriasis, but also malignancies such as cutaneous T cell lymphomas. Recruitment of lymphocytes to the skin is a highly complex process that involves adhesion to the endothelial lining, extravasation, migration through the connective tissue, and, finally, localisation of a subpopulation of lymphocytes to the epithelial compartment, the epidermis. An intertwined network of constitutively expressed and inducible cytokines, chemokines and other mediators provides guidance for lymphocyte migration, and a large number of adhesion receptors mediate sequential steps of cell-cell- and cell-substrate-interactions resulting in tissue-specific localisation of immune cells. Selectively targeting the functions of one or several key molecules involved in this complex cascade promises exciting new therapeutic options for treating inflammatory disorders, but at the same time, bears considerable imponderables which will be discussed in this article.

Animals↗
PubMed2004

Molecular interactions of B-CAM (basal-cell adhesion molecule) and laminin in epithelial skin cancer.

Molecular events underlying the progression of malignant tumors through the surrounding tissue are largely mediated by membrane-bound adhesion molecules. Basal-cell adhesion molecule (B-CAM), a 90-kDa laminin receptor of the immunoglobulin superfamily, is induced in some epithelial malignancies. Its function in these tumors, however, still remains obscure. We demonstrated that expression of B-CAM is very weak, if detectable at all, in normal epidermis but is strongly induced in both basal cell carcinomas and squamous cell carcinomas of the skin, and most pronounced at the basal surface of the tumor nests. Interestingly, the only known B-CAM ligand, laminin, was markedly upregulated within corresponding microanatomical sites surrounding the tumor nests, suggesting that both molecules may interact there. Consistent with this hypothesis, we were able to directly demonstrate binding of a B-CAM/Fc chimeric molecule to the peritumoral stroma in situ. Finally, in proof-of-principle experiments, human B-CAM was overexpressed both in murine and in human fibroblasts. The haptotactic migration of these novel B-CAM+ cell populations on a laminin matrix was significantly increased (P = 0.02) as compared to mock-transfected cells when integrin-mediated adhesion was blocked by chelation of divalent cations. Thus, our findings provide the first direct experimental evidence that interactions of B-CAM and laminin may be involved in progression of epithelial skin tumors.

Animals↗
PubMed2004

Imiquimod, a Toll-like receptor-7 agonist, induces perforin in cytotoxic T lymphocytes in vitro.

Imiquimod (IMQ), an activator of Toll-like receptor-7 (TLR-7), induces by several routes a profound anti-viral and anti-tumor effect in vivo. Physiologically, the immune system is using perforin-containing granules of cytotoxic T lymphocytes (CTL) towards the same biological purpose. This functional synergism prompted our current experiments addressing the question whether IMQ may influence perforin-release and/or induce perforin in CTLs in vitro. In peripheral lymphocytes of healthy and diseased subjects, IMQ induced a significant increase of perforin(+) CTLs within 12h in all experiments performed. This effect was most pronounced in CTLs of patients suffering from atopic dermatitis, a model disorder for subnormal perforin expression: as compared to perforin(+) CTLs detected at time point zero (100%), up to 270% of perforin(+) CTLs were induced by 2.5 microg/ml [corrected] IMQ. Perforin release from peripheral blood CTLs after PMA/ionomycin-stimulation was not influenced significantly by IMQ. Thus, the biological activity of IMQ appears to exceed its previously known functions, inasmuch as it boosts up significantly the perforin-granule system.

Adjuvants, Immunologic↗
PubMed2004

Death receptor-independent apoptosis in malignant melanoma induced by the small-molecule immune response modifier imiquimod.

Bypassing molecular mechanisms of apoptosis deficiency may be of great utility for the successful treatment of malignant tumors. We have discovered that imiquimod, a small-molecule immunomodulator, exerts rather tumor-selective direct pro-apoptotic activity in vivo and in vitro towards cutaneous metastases of malignant melanoma, an aggressive skin tumor. This pro-apoptotic activity was not detectable with resiquimod, a closely related structural analogue whose pro-inflammatory activity is even greater than that of imiquimod. Unresponsiveness of some melanoma metastases to imiquimod in vivo corresponded to resistance towards imiquimod-induced apoptosis in vivo and in vitro. At the molecular level, the pro-apoptotic activity of imiquimod was independent of membrane-bound death receptors, but depended on Bcl-2 expression as demonstrated by overexpression of Bcl-2 in melanoma cells. Imiquimod is the first topical compound with the potential to bypass molecular mechanisms of apoptosis deficiency, a concept that may be relevant for other tumors as well.

Administration, Topical↗
PubMed2004

Targeting selectin functions in the therapy of psoriasis.

As leukocytes play a primary role in the immunopathogenesis of psoriasis, it is a reasonable assumption that preventing those cells from localizing to the sites of cutaneous inflammation can stop the disease process. Selectins, a family of three single-chain transmembrane adhesion molecules, which bind to carbohydrate moieties displayed on other cells, are pivotally involved in the initial steps of leukocyte recruitment, i.e. tethering and rolling along the endothelial lining of blood vessels. Thus, compounds impairing selectin functions have been developed to treat inflammatory disorders, such as psoriasis. Potential strategies to interfere with selectin functions include direct inhibition through monoclonal antibodies or small-molecule compounds, transcriptional regulation of selectin expression, and modulation of the post-transcriptional glycosylation of selectin ligands. More than a dozen different compounds targeting selectin functions are currently under development, several of which have shown promising effects on leukocyte recruitment and the therapy of inflammatory conditions under experimental conditions. However, based on preclinical and early clinical investigations, it appears that in some cases specifically targeting the function of single selectins may not be sufficient to effectively interrupt the inflammatory cascade. This is, at least in part, due to considerable redundancies and overlaps in the functions of the selectins, a notion that is corroborated by the apparently more pronounced therapeutic efficacy of some compounds with broader activity against several selectins. Overall, while targeting selectin functions promises rather selective and pathogenesis-based therapeutic approaches against psoriasis, the clinical value of such strategies, alone or in combination with other therapies, remains to be seen.

Drug Delivery Systems↗
PubMed2003

Tumor-selective induction of apoptosis and the small-molecule immune response modifier imiquimod.

BACKGROUND: The incidence of nonmelanoma skin cancer, basal cell carcinomas (BCCs), and squamous cell carcinomas (SCCs) is increasing, representing a major medical and economic problem. Imiquimod, a topical small-molecule immune response modifier, has shown efficacy toward BCC and actinic keratoses in clinical trials. Imiquimod acts both indirectly, via cytokine-mediated stimulation of cellular immune responses, and directly, through unknown mechanisms against tumor cells. We examined the mechanism by which imiquimod induces apoptosis in cancer cells. METHODS: Apoptosis was assessed by enzyme-linked immunosorbent assay, western blot analysis, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays in five SCC cell lines, HaCaT cells (a spontaneously immortalized human keratinocyte cell line), and normal keratinocytes treated with imiquimod, with its analog resiquimod, or with neither. Expression of death receptors, caspases, and cytochrome c in the apoptotic signaling cascade was analyzed using western blot and flow cytometric analyses. The functional relevance of imiquimod-induced cytochrome c release was assessed by transfection of HaCaT cells with Bcl-2. Apoptosis in BCCs in vivo was assessed by TUNEL assays of imiquimod-treated and untreated tumors from three patients. Differences between treated and untreated cells and tumors were determined using a two-tailed Student's t test. RESULTS: Imiquimod, but not resiquimod, induced apoptosis in all SCC cell lines and HaCaT cells. This induction involved activation of several caspases and Bcl-2-dependent cytosolic translocation of cytochrome c but was independent of the membrane-bound death receptors Fas, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-R1-R4 receptors, and tumor necrosis factor-R1 and -R2 receptors. Topical application of imiquimod to BCC tumors in vivo induced apoptosis. CONCLUSION: Imiquimod has the potential to induce apoptosis in skin cancer cells, possibly by circumventing mechanisms developed by malignant tumors to resist apoptotic signals.

Aminoquinolines↗
PubMed2003

Interfering with leukocyte rolling--a promising therapeutic approach in inflammatory skin disorders?

Many novel anti-inflammatory compounds have been derived from research tools designed to better understand the complex process of leukocyte extravasation at sites of inflammation. Given that selectin-mediated rolling is the crucial initial step of leukocyte localization to the skin, specific interference with this mechanism is a particularly attractive target to treat cutaneous inflammation. Recently, several exciting advances have been reported aimed at selective interference with specific target molecules crucially involved in leukocyte rolling.

Animals↗