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Biomedical subjects

K Asadullah

Publications and source records attributed to K Asadullah.

At least 19 recordsLinked to original sources
PubMed2002

SEGRAs: a novel class of anti-inflammatory compounds.

Dissociated GCs show a separation between anti-inflammatory effects and certain side effects. This renders them as attractive compounds with better effect/side-effect profile as promising drug candidates and tool compounds for analyzing the molecular mechanisms of single side effects. A number of the GC-mediated side effects (e.g., osteoporosis, skin atrophy) are regulated in a very complex manner and use more than one molecular mechanism of the GR. Thus, theoretical predictions about the behavior of selective GR agonists regarding these effects are very difficult to make. Investigations of SEGRA compounds in relevant animal models will be the only way to get this important information. By availability of these tool compounds we now are in the advantageous situation to test them in vivo and to learn more about the possibilities and even the limitations of the selective GR agonists. Considering that the compounds have a non-steroidal structure, i.e., totally unrelated to steroids or other hormones at all, displaying only partially the molecular effects of GCs and are dissociated in their clinical profile, they should not be considered as GCs. Therefore, we introduced the term selective glucocorticoid receptor agonists (SEGRAs). These SEGRAs seem to represent a useful novel therapeutic modality which may complement existing therapeutic principles for the topical and especially the systemic treatment of inflammatory diseases. In summary, we and others are convinced that dissociated GCs are therapeutic compounds that exert many of the anti-inflammatory and immunosuppressive effects of standard GCs, while their potential to induce side effects is reduced. Whereas the in vitro dissociated profile of other compound classes (Belvisi et al. 2001) was not translated into a separation between anti-inflammatory activity and the induction of side effects in in vivo models, we could demonstrate this for the SEGRA compounds. Regarding the diversity of molecular mechanisms involved in mediating the complex side effects of GCs, it might be that only some of these unwanted effects can be reduced. However, as GCs are one of the most important anti-inflammatory therapeutics in the treatment of severe and chronic inflammatory diseases, even a partial reduction of side effect induction would be a great advantage for many patients.

Administration, Topical↗
PubMed2002

Cytokine therapy in dermatology.

Cytokines have been in the focus of scientific interest for some years now. Analysing their expression permitted a better understanding of the pathogenesis of various diseases, including in dermatology. Moreover, they are now far beyond the stage when they were of interest only to the pathophysiological research sector: some cytokine therapies are already being employed as part of the clinical practice. In fact, several cytokines are used for the treatment of malignant, inflammatory and infectious skin diseases. Their stage of development ranges from advanced, already approved and well established therapies (e.g. IFN-alpha and IL-2 for melanoma) to early explorative trials (e.g. IL-4 and IL-10 for psoriasis). Some of the new approaches currently under investigation will actually lead to registration of new drugs for dermatological treatment and to supplement existing therapeutic options. Beside this, the results of clinical trials with cytokines are significantly contributing to our understanding of the pathophysiology of diseases. They will give a better insight into which mechanisms play a greater or lesser part in their development and may generate momentum for still better targeted pharmacological approaches. Here we would like to give an overview about the current stage of cytokine therapy and the prospects for dermatological indications. The terminology and immunobiology of cytokines are also briefly discussed, since for a sensible interpretation of the relevant findings a basic knowledge of these biologically highly active messenger substances is essential.

Chronic Disease↗
PubMed2002

Cytokines: interleukin and interferon therapy in dermatology.

Cytokines are highly potent biologically active proteins that play an essential role in intercellular communication. They are vital to the mediation and regulation of inflammatory and specific immune reactions as well as to nonimmunological processes. Several cytokines are already used for the treatment of malignant, inflammatory and infectious skin diseases. This in particular includes certain interleukins (ILs) and interferons (IFNs). Whereas some cytokine therapies are already approved and well established, such as IFN-alpha and IL-2 (approved in the USA) for melanoma, others are in the early stages of development and are used in explorative trials (e.g. IL-4 and IL-10 in the treatment of psoriasis). It is likely that some of the new approaches currently under investigation will actually lead to both the registration of new drugs for dermatological treatment, and to supplementation of existing therapeutic options. The aim of this review is to give an overview on the current state of cytokine therapy in dermatology.

Antineoplastic Agents↗
PubMed2001

A novel, soluble homologue of the human IL-10 receptor with preferential expression in placenta.

The cytokine receptor family type 2 (CRF2) comprises receptors for important immunomediators like interferons and interleukin-10 (IL-10). We identified a novel member of this family which represents the first exclusively soluble receptor in this group and was therefore designated as CRF2-soluble 1 (CRF2-s1). The CRF2-s1 gene covers about 28 kb and is located on chromosome 6 in close proximity to the CRF2 members interferon (IFN)-gamma receptor 1 and IL-20 receptor 1. It comprises seven exons and generates two different mRNA splice variants, CRF2-s1-long and CRF2-s1-short. CRF2-s1-long and CRF2-s1-short encode proteins of 263 and 231 amino acids, respectively. A comparison of predicted protein structures led to the postulation that each receptor variants binds a different ligand. Quantitative analysis of human mRNA expression revealed a very restricted pattern for both splice forms. CRF2-s1 turned out to be the first member of this receptor family which was expressed neither in resting nor in stimulated leucocyte populations. CRF2-s1-long was only expressed in placenta, whereas CRF2-s1-short was additionally expressed in human mammary gland and, at a lower level, in skin, spleen, thymus and stomach. The preferential expression of CRF2-s1 in placenta suggests a role for this receptor in establishing and maintaining successful pregnancy.

Amino Acid Sequence↗
PubMed2001

Effects of systemic interleukin-10 therapy on psoriatic skin lesions: histologic, immunohistologic, and molecular biology findings.

Interleukin-10 is an important anti-inflammatory and immunosuppressive cytokine with major impact on several immune reactions, including regulatory mechanisms in the skin. Recently, we performed a phase II trial in psoriatic patients receiving subcutaneously interleukin-10 over 7 wk. The clinical response suggested that interleukin-10 might represent a novel anti-psoriatic drug. In order to understand better the mode of action and to elucidate the effects of systemic interleukin-10 treatment on the skin immune system, skin punch biopsies from sites different from interleukin-10 injection were analyzed. Biopsies were obtained from the patients before, at the end, and 3 wk after interleukin-10 therapy. The results are reported here. Histologic examination showed a decrease of several parameters reflecting the psoriatic disease activity as acanthosis and extension of the horny layer. Immunohistologic examination demonstrated decreasing numbers of infiltrating T cells, dermal CD1a+ cells, and a diminished proliferation of epidermal cells. Using a novel, quantitative reverse transcriptase-polymerase chain reaction approach a significant shift within the cytokine pattern was found. Interleukin-10 therapy led to a decrease of cutaneous interleukin-8 and interleukin-10 mRNA expression. Whereas no significant changes of interleukin-6, tumor necrosis factor-alpha, and interferon-gamma expression were found, interleukin-4 was strongly upregulated suggesting a shift from a type 1 towards a type 2 cytokine pattern. The changes within the local cytokine pattern seem to be disease-related, as an inverse course was found in a single interleukin-10 nonresponding patient. Our findings demonstrate considerable effects of systemic interleukin-10 application on the skin immune systems, which might contribute to the anti-psoriatic activity of interleukin-10.

Adult↗
PubMed2001

Interleukin-10 promoter polymorphism in psoriasis.

Beneficial effects of interleukin-10 therapy and lower endogenous interleukin-10 formation compared with atopic dermatitis and cutaneous T cell lymphomas indicated that interleukin-10 is a key cytokine in psoriasis. The interleukin-10 promoter is highly polymorphic, with two informative microsatellites, interleukin-10.G and interleukin-10.R. In order to understand whether interleukin-10 itself is a predisposing gene for the psoriasis susceptibility we analyzed interleukin-10 promotor polymorphism in patients. The distribution of interleukin-10.G and interleukin10.R microsatellite alleles did not vary between patients (n = 78) and healthy controls (n = 80). In addition, when the psoriasis patients were stratified according to age of onset (younger than 40 y of age, or age 40 and older), no difference in allele distribution was observed; however, a clear differential distribution was revealed at the interleukin10.G locus when patients were stratified according to whether they had a positive family history of psoriasis (p = 0.04). This difference was due to an over-representation of the interleukin10.G13 allele in those patients with familial disease (40.4% vs 19.6%, Chi-square = 7.292, p = 0.007). The positive association of allele interleukin10.G13 with familial psoriasis was especially true when patients with an early onset (< 40 y of age) of the disease were compared with those patients with early onset against a nonfamilial background (39.6% vs 14.5%, Chi-square = 8.959, p = 0.003). Patients with age-of-onset of less than 40 were 4-fold [odds ratio = 3.85 (1.55--9.62)] more likely to have a psoriatic family background if they carried this interleukin10.G13 allele. These data suggest that the interleukin-10 locus contributes to the heritability of psoriasis susceptibility.

Alleles↗
PubMed2000

Inhibition of keratinocyte apoptosis by IL-15: a new parameter in the pathogenesis of psoriasis?

Keratinocytes (KC) are important source of and targets for several cytokines. Although KC express IL-15 mRNA, the functional effects of IL-15 on these epithelial cells remain to be dissected. Investigating primary human foreskin KC and HaCaT cells, we show here by semiquantitative RT-PCR and flow cytometric analysis that both translate IL-15 and IL-15R mRNA and express IL-15 and IL-15Ralpha protein on the cell surface, suggesting that human KC can employ IL-15 for juxtacrine signaling. While IL-15 exerted no significant effect on KC proliferation and IL-6 or IL-8 secretion, IL-15 inhibited both anti-Fas and methylcellulose-induced KC apoptosis in vitro. This is in line with the recognized potent anti-apoptotic effects of IL-15. IL-2, whose receptor shares two components with the IL-15R, failed to inhibit KC apoptosis. Together with the role of IL-15 in sustaining chronic immune reactions, this invited the question of whether a reduction of KC apoptosis by IL-15 may be involved in the pathogenesis of psoriasis, a chronic hyperproliferative inflammatory skin disease characterized by abnormally low KC apoptosis in the epidermis. Remarkably, compared with nonlesional psoriatic skin and skin of healthy volunteers, lesional psoriatic epidermis showed high IL-15 protein expression in the epidermis and enhanced binding activity for IL-15. Therefore, antagonizing the inhibitory effects of IL-15 on KC apoptosis deserves exploration as a novel therapeutic strategy in psoriasis management.

Apoptosis↗
PubMed2000

The antipsoriatic activity of IL-10 is rather caused by effects on peripheral blood cells than by a direct effect on human keratinocytes.

IL-10 is a promising candidate for the treatment of cutaneous disorders. Antipsoriatic efficacy of systemic IL-10 treatment has been already demonstrated. This includes histomorphological changes in the epidermis, suggesting effects on keratinocytes. However, less is known about direct effects of IL-10 on this cell population, although effects are likely since IL-10 receptor expression on keratinocytes has been demonstrated recently. Therefore we analysed the effects of IL-10 on keratinocytes in vitro, using concentrations of human recombinant IL-10 corresponding to those detectable in plasma during therapy. Proliferation, cytokine formation (IL-6, IL-8, IL-1ra), and expression of surface molecules (MHC class I and II, costimulatory molecules CD80 and CD86, CD29, CD54, CD95) were measured in stimulated and unstimulated cells. Although stimulation influenced the expression levels of certain surface markers, no or only slight effects of IL-10 were found. In contrast considerable inhibitory effects of IL-10 on surface molecule expression and cytokine secretion by peripheral blood human monocytes were observed. Our results suggest that the antipsoriatic activity of IL-10 is rather caused by modulatory effects on circulating immune cells, which subsequently might infiltrate the skin, than by direct effects on human keratinocytes. Considering the remarkable antipsoriatic activity of IL-10 and the observation that IL-10 seem to act on peripheral blood mononuclear cells but not on keratinocytes provide further evidence that circulating immune cells play a key role in the pathology of psoriasis. Finally, our results argue against the value of IL-10 therapy in dermatoses strictly limited to keratinocyte involvement.

Antigens, CD↗
PubMed2000

Cytokine expression in primary cutaneous germinal center cell lymphomas.

Physiologically, B-lymphocytes are not present in the skin. Even in pathological situations they rarely occur. In contrast, primary cutaneous B-cell lymphomas (CBCL) are characterized by proliferation of B lymphocytes within the skin. This suggests the existence of a certain microenvironment supporting homing and expansion of clonal B cells. Cytokines were demonstrated to be involved in the pathogenesis of cutaneous lymphomas of T-cell origin. Cytokine expression in cutaneous B-cell lymphoma lesions, however, has not been investigated so far. Therefore, the mRNA level of several cytokines was analyzed in biopsies from 7 patients with CBCL and compared to pleomorphic T-cell lymphoma (n = 6), psoriasis (n = 9), and healthy skin (n = 7), using a competitive RT-PCR approach. An overexpression of TNF-alpha, IL-10, and IL-6 was found. Enhanced IL-8 mRNA expression was detected in 2/7 cases. The overexpression of IL-6 and IL-10 in CBCL might be of particular importance, since these cytokines are considered to support B-cell growth. Additionally, the overexpression of IL-10 may contribute to tumor progression since this immunosuppressive cytokine might be involved in downregulation of immunological tumor surveillance, in part by inhibiting type 1 cytokine formation. In fact, we did not detect IFN-gamma and IL-2 expression. Taken together, we found a cytokine pattern in CBCL lesions which might contribute to tumor B-cell growth.

Adult↗
PubMed2000

IL-15 and IL-16 overexpression in cutaneous T-cell lymphomas: stage-dependent increase in mycosis fungoides progression.

Cytokines are of major importance for the pathogenesis of cutaneous T-cell lymphomas (CTCL). Recent data suggested that IL-15 and IL-16 are survival/growth factors for the malignant T cells in these entities. To investigate the expression of IL-15 and IL-16 in mycosis fungoides (MF) and CD30+ pleomorphic T-cell lymphoma in vivo, we established a competitive RT-PCR technique. Analyzing skin biopsies from CTCL patients at different stages in comparison to psoriatic and healthy skin, we found IL-15 and IL-16 mRNA overexpression in both CTCL entities. Remarkably, there was some evidence for a stage-dependent increase during MF progression. We found only slight overexpression in early stage MF, when only few tumor cells are detectable within the infiltrates, whereas marked overexpression was found in more advanced lesions, which are characterized by a higher density of malignant cells. These results suggested that CTCL cells themselves might produce the cytokines. To further elucidate this hypothesis, two CTCL cell lines were analyzed but gave conflicting results. Therefore, the cellular origin of the IL-15 and IL-16 overexpression in CTCL remains unclear. Considering the significant overexpression of IL-15 and IL-16 and their biological capacities it is likely that these cytokines contribute to the tumor development. So, they might be involved in growth and skin homing of CTCL cells.

Adult↗
PubMed2000

The treatment of psoriasis with IL-10: rationale and review of the first clinical trials.

By virtue of its anti-inflammatory and immunosuppressive properties, IL-10 plays a crucial role in several immune reactions, including regulatory mechanisms in the skin. In psoriasis, a common cutaneous immune disease, a relative deficiency in cutaneous IL-10 expression is observed. Several lines of evidence suggest that IL-10 could have antipsoriatic abilities. One pilot and two Phase II trials with sc. IL-10 administration over 3 - 7 weeks in patients with moderate to severe psoriasis have supported this hypothesis. The therapy was well-tolerated and clinical efficiency was found in the majority of patients. Immunosuppressive effects (depressed monocytic HLA-DR expression, TNF-alpha and IL-12 secretion capacity, IL-12 plasma levels and responsiveness to recall antigens) as well as a shift towards a Type 2 cytokine pattern (increasing proportion of IL-4, IL-5, and IL-10 producing T-cells, selective increase in IgE serum levels) were observed. These investigations suggest that IL-10 is of major importance in psoriasis and show that IL-10 administration represents a new therapeutic approach. However, long-term administration of large recombinant protein limits the value of this novel therapeutic approach. As such, neither oral nor topical applications are possible; there is a risk of the development of neutralising antibodies.

Clinical Trials as Topic↗
PubMed1999

Crosstalk between keratinocytes and T lymphocytes via Fas/Fas ligand interaction: modulation by cytokines.

Apoptosis mediated by Fas/FasL interaction plays an important role during many inflammatory skin disorders. To estimate whether the expression of FasL, the ligand for Fas, might be regulated by cytokines we stimulated primary human keratinocytes with several pro- and anti-inflammatory cytokines. Keratinocytes cultured to subconfluence expressed FasL constitutively. Cells stimulated with the proinflammatory cytokines IL-1beta, TNF-alpha, IFN-gamma, and IL-15, respectively, increased significantly their intracellular as well as cell surface-bound FasL expression in a time- and dose-dependent manner. This cytokine-induced FasL expression was dependent on new protein synthesis. Despite enhanced expression of cell surface-bound FasL, no release of soluble FasL was measured in the cell supernatants determined by ELISA. Stimulation of the cells with IL-6, IL-10, IL-12, TGF-beta1, and GM-CSF did not modulate the constitutive FasL expression, but IFN-gamma-mediated FasL up-regulation was significantly diminished by IL-10 and TGF-beta1, respectively. Up-regulation of FasL on IFN-gamma-stimulated keratinocytes led to increased apoptosis within monolayers cultured for 48 h. Moreover, coculture experiments performed with Fas+ Jurkat T cells revealed that enhanced FasL expression on IFN-gamma-stimulated keratinocytes induced apoptosis in cocultured T cells, demonstrating that up-regulated FasL was functionally active. In summary, our data suggest the important regulatory role of cytokine-controlled Fas/FasL interaction in the cross-talk between keratinocytes and skin-infiltrating T cells for maintenance of homeostasis in inflammatory skin processes.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Interleukin 10 treatment of psoriasis: clinical results of a phase 2 trial.

OBJECTIVE: To determine the safety and clinical effects of interleukin 10 (IL-10) treatment of psoriasis. DESIGN AND METHODS: In an open-label phase 2 trial, 10 patients with psoriasis subcutaneously received recombinant human IL-10 over a 7-week period in a dosage of 8 microg/kg daily (n=5) or 20 microg/kg 3 times per week (n=5). Patients were followed up for an additional 5 weeks. RESULTS: The treatment was well tolerated. Antipsoriatic effects were found in all but 1 patient. A significant decrease of the psoriasis area and severity index by 55.3% +/- 11.5% (mean +/- SEM) was observed (P<.02). The antipsoriatic efficiency was confirmed by histological examination. Heterogeneity in the effectiveness was found among the patients, but seems to be independent of the dosage regimen. However, a tendency to a better response was found in the patients who received 20-microg/kg IL-10 3 times per week. Decreasing response in the delayed-type hypersensitivity reaction against recall antigens indicated immunosuppressive effects. Moderate effects on hematopoietic cells were observed. CONCLUSIONS: Our data suggest that IL-10 therapy for psoriasis is safe and possibly clinically effective. Consequently, its value in psoriasis and similar immune diseases should be further determined. Dose-finding, placebo-controlled, double-blind trials are necessary now.

Adult↗
PubMed1999

[Interleukin-10 in dermatology].

In recent years the investigation of cytokines has been a focus of scientific interest in order to understand the pathogenesis of a variety of diseases. In additions cytokines are increasingly being used for therapeutic purposes, including dermatologic disorders. IL-10 is a recently described cytokine with anti-inflammatory and immunosuppressive qualities which plays an important role in immunoregulation. The overexpression of this mediator has been proven in some inflammatory dermatoses as well as in various skin tumors. These observations help to understand down regulatory events in hyper-inflammatory conditions such as allergic or toxic dermatitis on the one hand and the suppression of an adequate anti-tumor response and thereby the progression of malignant tumors on the other hand. Recent investigations indicate a relative IL-10 deficiency in psoriasis. Initial therapeutic applications of IL-10 in psoriasis underline the pathophysiological importance of this cytokine.

Humans↗