Search Results - (Author, Cooperation:K. Asadullah)

2012-10-13

Nature Publishing Group (NPG)

0028-0836

1476-4687

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

Animals ; Publishing/*standards/trends ; Random Allocation ; Research Design/*standards ; Sample Size ; Statistics as Topic

1365-2230

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Summary 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-α 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.

Electronic Resource

1600-0625

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Abstract: 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.

Electronic Resource

1600-0625

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Abstract: 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-α, 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-γ and IL-2 expression. Taken together, we found a cytokine pattern in CBCL lesions which might contribute to tumor B-cell growth.

Electronic Resource

1600-0625

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Abstract: Cytokines are considered to be of major importance for the pathogenesis of cutaneous T-cell lymphomas (CTCL). Their impact may result from autocrine, paracrine or endocrine effects. Several investigations demonstrated the overexpression of different cytokines in different CTCL entities. Interestingly, stage-dependent shifts in the cytokine pattern have been observed in mycosis fungoides (MF). There is evidence that the abnormal cytokine expression in CTCL might be responsible for tumor progression, resulting from an enhanced proliferation of the malignant cells and/or the depression of the anti-tumor immune response. Moreover, cytokine loops might explain phenomena like the epidermotropism of malignant cells or eosinophilia and increased plasma levels of IgE, which are present in advanced stages of CTCL. Analysis of the cytokine pattern in CTCL might give the basis for direct therapeutic intervention into the cytokine network as a new therapeutic approach. In this review, the current knowledge regarding cytokines in CTCL is summarized.

Electronic Resource

1600-0625

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Abstract: 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-α 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.

Electronic Resource

1365-2133

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Summary Background Microbiological infections are considered to be of pathophysiological importance in atopic dermatitis (AD). As yet, no information is available regarding cytomegalovirus (CMV) infection in this disease. This, however, is of interest because of the high prevalence of latent infections in the general population, the frequent reactivation in inflammatory diseases, and the immunomodulating capacity of CMV. Objectives To investigate the prevalence of latent CMV infection, the frequency of active CMV infection, and the immune response to CMV in patients with moderate to severe AD. Methods To detect active infection we analysed CMV antigen expression by peripheral blood mononuclear cells (PBMC) from 27 patients with moderate to severe AD in comparison with 53 healthy volunteers. We used three monoclonal antibodies recognizing different CMV-encoded antigens and immunocytological staining (alkaline phosphatase–antialkaline phosphatase technique). Results Patients with AD had a higher mean frequency of CMV-positive PBMC: 2·25 per 10 000 vs. 0·74 per 10 000 in controls (P = 0·001) as well as a higher incidence of CMV antigenaemia: 29·6% vs. 7·5% (P 〈 0·01). Seropositivity for anti-CMV IgG antibodies indicated subclinical activation of latent infection. Remarkably, a clearance of CMV antigenaemia was observed during anti-eczematous treatment. Significantly higher plasma levels of tumour necrosis factor-α, which is involved in CMV reactivation, and interleukin-12, which is crucial for an antiviral cellular immune response, were observed in AD patients in comparison with healthy volunteers. Furthermore, a significantly enhanced frequency of circulating activated HLA-DR+ T cells especially in CMV-seropositive AD patients (19·3% vs. 13·5% in seronegative AD patients vs. 10·2% in controls) suggested that the active CMV infection triggers a cellular immune response. This was also supported by a high frequency of CMV-specific interferon-γ-producing T cells in CMV-seropositive patients with AD. Conclusions Our data suggest that active, subclinical CMV infection is more frequent in patients with moderate to severe AD and may have immunopathophysiological relevance.

Electronic Resource

1365-2133

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Summary  Background The anti-inflammatory cytokine interleukin (IL)-10 is considered to play a major role in the pathophysiology of psoriasis, which is characterized by an IL-10 deficiency. Systemic administration of IL-10 has been shown to be an effective therapy for psoriasis. The IL-10 promoter region contains a highly polymorphic microsatellite (IL10.G) and in a recent case–control study the IL10.G13 (144 bp) allele was found to be associated with familial early onset psoriasis (type 1 psoriasis) having a susceptible effect. Objectives As it is essential in multifactorial diseases to replicate findings before definite conclusions can be drawn, we decided to perform a follow-up study and to follow a genetic approach analysing allele transmission in families with a positive family history of psoriasis. Methods We studied 137 nuclear families (trio-design) comprising 456 individuals and genotyped the IL10.G marker. For comparison we also genotyped the microsatellite tn62 as a reference marker of the major psoriasis susceptibility locus on chromosome 6p21 (PSORS1). In the present study allele transmission was evaluated using the family-based association test (FBAT) and GENEHUNTER 2.0 based on the transmission/disequilibrium test. Results The G13 allele (144 bp) had a frequency of 24%, was present in 88 families and clearly showed an even transmission (FBAT, P = 0·753). In contrast, allele 3 (IL10.G9) (136 bp) had a frequency of 39%, was present in 110 families and was transmitted in 43 trios and remained untransmitted in 67 trios (FBAT, P = 0·026), thus showing preferential nontransmission. For the HLA-linked tn62-marker we obtained a P-value of 0·000 27 for allele 4 in the same study group. Conclusions In conclusion, we failed to confirm the susceptible effect of the G13 allele, but provide the first data for a protective effect of allele 3 (IL10.G9) for familial psoriasis. Our results suggest that the IL10.G polymorphism is not a major locus, but acts as a minor locus.

Electronic Resource

1432-069X

Key words IL-7 ; CTCL ; Cytokines ; Mycosis ; fungoides ; Semiquantitative RT-PCR

Springer Online Journal Archives 1860-2000

Medicine

Abstract Interleukin-7 (IL-7) is thought to be a growth factor for cutaneous T-cell lymphoma (CTCL) since it has been shown that IL-7 transgenic mice develop a cutaneous disorder characterized by enhanced T-cell proliferation with progression to malignancy and that in vitro growth of Sézary cell lines is IL-7 dependent. However, no direct in vivo evidence exists for the involvement of IL-7 in the pathogenesis of CTCL. Therefore, we examined IL-7 mRNA expression in skin biopsies from patients with mycosis fungoides (MF) ( n = 20) and pleomorphic T-cell lymphoma ( n = 5). By semiquantitative RT-PCR, IL-7 mRNA was not detectable in any of the CTCL samples, or in normal human skin ( n = 8) or in skin from patients with psoriasis ( n = 7) or atopic dermatitis ( n = 5). In contrast, IL-7 mRNA was detected in a biopsy from a kidney allograft transplant, in normal keratinocytes under various culture conditions and in several cell lines. Interestingly, using a highly sensitive nested PCR, IL-7 mRNA was detectable in all specimens tested, but there was no indication of IL-7 overexpression in MF when analysing lesions of patch, plaque or tumour stages. In contrast, increasing CD3 expression was found, which was most likely a consequence of the enhanced density of malignant T cells in advanced tumour stages. In summary, by the use of semiquantitative RT-PCR we were not able to detect IL-7 overexpression in MF or pleomorphic T-cell lymphoma. This indicates that IL-7 is probably not an autocrine growth factor in these CTCLs.

Electronic Resource

1432-069X

Key words IL-10 ; Keratinocytes ; Monocytes ; Psoriasis

Springer Online Journal Archives 1860-2000

Medicine

Abstract 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.

Electronic Resource

1432-069X

Key words Dermatology IL-10 ; Cytokines ; Inflammation ; Psoriasis

Springer Online Journal Archives 1860-2000

Medicine

Abstract With its antiinflammatory and immunosuppressive properties interleukin-10 (IL-10) plays a dominant role in several immune reactions including regulatory mechanisms in the skin. The overexpression of this mediator has been reported in some inflammatory dermatoses as well as in various skin tumors. These observations are of importance since they may explain the limitation of hyperinflammatory conditions as in eczemas and erythemas on the one hand and the suppression of an adequate antitumor response and thereby the progression of malignant tumors on the other hand. Moreover, elevated IL-10 expression might contribute to an enhanced risk of development of microbacterial superinfections, a frequent finding in several dermatoses, and might also be involved in the pathogenesis of connective tissue diseases. In contrast, recent studies indicate a relative IL-10 deficiency in psoriasis. Early clinical data from psoriatic patients treated with recombinant human IL-10 suggest the therapeutic potential of this cytokine and underline its impact on the regulation of the skin immune system.

Electronic Resource

1432-069X

Key words Monomethylfumarate ; Psoriasis ; Monocytes ; Cytokine formation ; IL-10 ; TNF-alpha

Springer Online Journal Archives 1860-2000

Medicine

Abstract Although the effectiveness of systemic antipsoriatic treatment with fumaric acid esters has been proven, their mode of action is still not understood. Recent results indicate their potency in inducing cytokine production in stimulated T cells. Since monocytes and their cytokines are also considered to be of pathogenic importance in psoriasis, we investigated the effect of monomethylfumarate (MMF) on proinflammatory (TNF-α, IL-12) and antiinflammatory (IL-10, IL-1RA) cytokine production by peripheral blood mononuclear cells (PBMC) and separated monocytes. In 24-h PBMC cultures from both psoriatic patients ( n = 6–13) and healthy volunteers ( n = 7–9), MMF at 100 μ M induced secretion of TNF-α, IL-10, and IL-1RA. Kinetics of IL-10 protein and mRNA expression indicated de novo production. Moreover, MMF significantly augmented endotoxin-induced synthesis of TNF-α, IL-10 and IL-1RA. In contrast, no influence on IL-12 secretion was found. Similar effects of MMF in purified monocytes indicated these cells to be responsible for aberrant cytokine formation. Furthermore, enhanced expression of costimulatory molecules after MMF stimulation confirmed monocyte activation. Multiple restimulation with fumaric acid esters in vitro, however, and immunomonitoring in a patient during Fumaderm initial therapy suggested that initial monocyte activation is followed by subsequent deactivation associated with an antiinflammatory response. Our results may explain the well-known effects of therapy with fumaric acid esters. Thus, initial treatment is often accompanied by adverse effects which may be caused by MMF-induced TNF-α formation. The change in the IL-10/IL-12 balance as a result of elective induction of IL-10, however, may have antipsoriatic activity by diminishing type-1/proinflammatory cytokine overexpression and the antigen-presenting capacity of monocytes/macrophages, and by upregulation of IL-1RA.

Electronic Resource

1432-069X

Key words Psoriasis ; T cells ; Immunophenotypic characterization ; CXCR3 ; Cytokines

Springer Online Journal Archives 1860-2000

Medicine

Electronic Resource

0942-0940

Cytokines ; brain tumours ; neurosurgery ; cerebrospinal fluid ; brain injury

Springer Online Journal Archives 1860-2000

Medicine

Summary To elucidate the role of cytokines in brain repair processes and in local inflammation after neurosurgical procedures, cerebrospinal fluid (CSF) samples from 8 patients with intra-axial tumours and 8 patients with extra-axial tumours were analysed for interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1ra), IL-6, IL-8, IL-10, and tumour necrosis factor (TNF)-alpha at the beginning and after surgery. Levels of IL-6 and IL-8 increased dramatically in all patients just hours after surgery and fell during subsequent days. IL-1beta was found only in low amounts in the CSF of both patient groups. Other cytokines demonstrated different courses. In patients with intra-axial tumours IL-1ra peaked two to four hours after surgery with a subsequent decrease. In patients with extra-axial tumours there was a continuous low-level IL-1ra release into the CSF without a peak. TNF-alpha was not present in detectable levels in the CSF after surgery for extra-axial tumours but was found to peak two to four hours after surgery for intra-axial tumours. IL-10 was detected in the CSF of both patient groups, but a higher peak was seen after surgery for extra-axial tumours. These results suggest different requirements for the cytokine response and an involvement of different cell types in cytokine release. However, the analysis of the CSF from both patient groups showed no differences in cell counts and populations, with a mild pleocytosis being present in both patient groups after surgery. Therefore, we conclude that after surgery for extra-axial tumours cytokines were predominately produced by non-immune cells stimulated through hypoxia or mechanical irritation. After surgery for intra-axial tumours with a significant brain injury immune cells — activated by necrotic material —seem to be involved in the process of cytokine synthesis. In these cases an additional IL-1ra and TNF-alpha peak was found and these cytokines may be markers for cerebral injury.

Electronic Resource

1432-1238

Sepsis ; Peritonitis ; Monocyte deactivation ; IL-10 ; TNF-alpha ; IFN-gamma ; GM-CSF ; Plasmapheresis

Springer Online Journal Archives 1860-2000

Medicine

Abstract Inflammatory cells, in particular monocytes/macrophages, release pro-inflammatory mediators in response to several infectious and non-infectious stimuli. The excessive release of these mediators, resulting in the development of whole body inflammation, may play an important role in the pathogenesis of sepsis and septic shock. TNF-alpha, acting synergistically with cytokines such as IL-1, GM-CSF and IFN-gamma, is the key mediator in the induction process of septic shock, as shown in several experimental models. Based on this concept and on the encouraging results obtained in several experimental models, a number of clinical sepsis trials targeting the production or action of TNF-alpha or IL-1 have been performed in recent years. Unfortunately, these trials have failed to demonstrate a therapeutic benefit. One reason for this may be the lack of exact immunologic analyses during the course of septic disease. Recently, we demonstrated that there is a biphasic immunologic response in sepsis: an initial hyperinflammatory phase is followed by a hypo-inflammmatory one. The latter is associated with immunodeficiency which is characterized by monocytic deactivation, which we have called “immunoparalysis”. While anti-inflammatory therapy (e.g. anti-TNF antibodies, IL-1 receptor antagonist, IL-10) makes sense during the initial hyperinflammatory phase, immune stimulation by removing inhibitory factors (plasmapheresis) or the administration of monocyte activating cytokines (IFN-gamma, GM-CSF) may be more useful during “immunoparalysis”.

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