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ABSTRACT: Der diabetische Fuß entsteht durch das Zusammenwirken mehrerer pathogenetischer Faktoren: Periphere Neuropathie, Vaskulopathie
und erhöhte Infektanfälligkeit. Ein entscheidender Faktor des erhöhten Infektrisikos beim zuckerkranken Patienten stellt ein
Funktionsdefekt der neutrophilen Granulozyten dar. Dabei ist die neutrophile Chemotaxis sowie die oxidative Reaktion mit Bildung
von bakteriziden und fungiziden Super- und Peroxiden vermindert. Der rekombinante humane Granulozyten-Kolonien stimulierende
Faktor (G-CSF) fördert die Neubildung funktionsfähiger neutrophiler Granulozyten und deren Ausschüttung aus dem Knochenmark.
Wir berichten über einen 78jährigen Patienten mit nicht-insulin-pflichtigem Diabetes mellitus Typ II und eitrig infizierten
Ulzerationen im Bereiche der Großzehen. Der Patient zeigte sowohl eine generalisierte Arteriosklerose als auch eine Polyneuropathie
mit trockenem Fuß, sensiblen Ausfällen sowie als Ausdruck der motorischen Nervenschädigung die typische Fußfehlstellung mit
Krallenzehenbildung. Im Bereiche des Metatarsaleköpfchen plantar rechts fand sich ein Malum perforans. Trotz intensiv lokaltherapeutischen
Maßnahmen zeichnete sich nach 35 Behandlungstagen keine Besserung der Hautläsionen ab. Unter Anwendung von insgesamt 165 Mio
E G-CSF (Neupogen®) subkutan über 11 Behandlungstage (15–30 Mio E/d, je nach Leukozytenzahl im peripheren Blut) appliziert in Kombination mit
Ciprofloxacin (Ciproxin®) 500 mg 2/d, peroral verabreicht, konnte in der Folge eine praktisch vollständige Abheilung der Läsionen erzielt werden.
Wir berichten erstmalig im deutschen Schrifttum über eine erfolgreiche Abheilung diabetischer Fußulzerationen unter Anwendung
von G-CSF und stellen eine Kostenanalyse im Vergleich zu einer konservativen Therapie auf. G-CSF kann die Behandlungszeit
des infizierten diabetischen Fußes signifikant verkürzen und somit die Behandlungskosten senken. Es könnte somit in der Behandlung
diabetischer Fußulzerationen eine Kosten-effektive Ergänzung zur antimikrobiellen Therapie darstellen.
Several pathogenetic factors such as peripheral neuropathy, vasculopathy and infection are responsible for the development
of diabetic foot ulcerations. An important factor contributing to the high infection risk in diabetic patients is a defect
in neutrophil granulocytes. Deficencies in neutrophil chemotaxis, phagocytosis and respiratory burst activity with the decrease
of the super- and peroxids are known to be associated with diabetes. Granulocyte-colony stimulating factor (G-CSF) increases
the release of neutrophils from the bone marrow and improves neutrophil function. A 78-year old patient with non-insulin-dependent
diabetes presented with ulcerations of both big toes and a malum perforans on the right sole. He also had generalized arteriosclerosis
as well as a polyneuropathy with a dry foot and typical foot deformation as well as decreased in sensitivity. Intensive local
care for 35 days led to no improvement of the ulcerations. Then G-CSF (Neupogen®) was adminstered in a total dose of 165 million IU over 11 days; the daily dose varied between 15–30 million IU depending
on the absolute leucocyte count. In addition 500 mg of oral ciprofloxacin (Ciproxin®) was given b.i.d. This treatment led to a significant improvement of the lesions. Within 11 days cost analysis suggests G-CSF
may be a cost-effective addition to antimicrobial therapy in diabetic foot infection.
Der Hautarzt 04/2012; 52(4):327-330. · 0.58 Impact Factor
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ABSTRACT: Type I interferons (IFNs) play an important role in the pathogenesis of many autoimmune disorders including psoriasis. In the presence of IFN-alpha and granulocyte/macrophage colony-stimulating factor (GM-CSF), monocytes differentiate into dendritic cells (DCs) referred to as IFN-DCs. IFN-DCs potentially mimic DC populations involved in psoriasis and express a wide range of Toll-like receptor (TLR) subtypes.
Recently, it was shown that single-stranded RNA (ssRNA) triggers TLR7 and TLR8; therefore we studied ssRNA, as a surrogate for ssRNA viruses and their impact on IFN-DCs.
We established culture conditions for IFN-DCs, generated from plastic adherent monocytes using GM-CSF plus IFN-alpha. For DC stimulation ssRNA40, a 20-mer ssRNA oligonucleotide was used. The phenotypic analysis of DC preparations was performed using flow cytometry. The production of various cytokines was analysed by enzyme-linked immunosorbent assay, and real-time quantitative polymerase chain reaction was used to quantify TLR and cytokine gene expression. The ability of IFN-DCs to stimulate allogeneic T-cell proliferation was evaluated in a mixed leucocyte reaction.
We found that IFN-DCs express mRNA for TLR7 and TLR8 and that ssRNA stimulation significantly improves their costimulatory molecule expression, stabilizes their phenotype and enhances their capacity to stimulate naive T-cell proliferation. Unstimulated IFN-DCs did not produce bioactive interleukin (IL)-12 and produced low levels of other proinflammatory cytokines. In contrast, ssRNA stimulation led to a significant production of IL-12p70, IL-1beta, IL-6 and tumour necrosis factor alpha. IFN-DCs contained mRNA for IL-12p35, IL-12p40, IL-23p19, IL-27p28 and IL-27EBI, which was further increased by incubation with ssRNA.
Our study sheds light on a potential role for IFN-alpha and viral infections in triggering DC populations in psoriasis. These results provide additional data for the better understanding of human autoimmune and antiviral responses and may also have implications for strategies developing cancer immunotherapy.
British Journal of Dermatology 06/2008; 158(5):921-9. · 3.67 Impact Factor
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D Schadendorf,
S Ugurel,
B Schuler-Thurner, F O Nestle,
A Enk,
E-B Bröcker,
S Grabbe,
W Rittgen,
L Edler,
A Sucker,
C Zimpfer-Rechner,
T Berger,
J Kamarashev,
G Burg,
H Jonuleit,
A Tüttenberg,
J C Becker,
P Keikavoussi,
E Kämpgen,
G Schuler
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ABSTRACT: This randomized phase III trial was designed to demonstrate the superiority of autologous peptide-loaded dendritic cell (DC) vaccination over standard dacarbazine (DTIC) chemotherapy in stage IV melanoma patients.
DTIC 850 mg/m2 intravenously was applied in 4-week intervals. DC vaccines loaded with MHC class I and II-restricted peptides were applied subcutaneously at 2-week intervals for the first five vaccinations and every 4 weeks thereafter. The primary study end point was objective response (OR); secondary end points were toxicity, overall (OS) and progression-free survival (PFS).
At the time of the first interim analysis 55 patients had been enrolled into the DTIC and 53 into the DC-arm (ITT). OR was low (DTIC: 5.5%, DC: 3.8%), but not significantly different in the two arms. The Data Safety & Monitoring Board recommended closure of the study. Unscheduled subset analyses revealed that patients with normal serum LDH and/or stage M1a/b survived longer in both arms than those with elevated serum LDH and/or stage M1c. Only in the DC-arm did those patients with (i) an initial unimpaired general health status (Karnofsky = 100) or (ii) an HLA-A2+/HLA-B44- haplotype survive significantly longer than patients with a Karnofsky index <100 (P = 0.007 versus P = 0.057 in the DTIC-arm) or other HLA haplotypes (P = 0.04 versus P = 0.57 in DTIC-treated patients).
DC vaccination could not be demonstrated to be more effective than DTIC chemotherapy in stage IV melanoma patients. The observed association of overall performance status and HLA haplotype with overall survival for patients treated by DC vaccination should be tested in future trials employing DC vaccines.
Annals of Oncology 05/2006; 17(4):563-70. · 6.43 Impact Factor
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ABSTRACT: Recent progress in the approach towards immunotherapy of cancer consists in molecular definition of tumor antigens, new tools for phenotypical and functional characterization of tumor-specific effector cells and clinical use of novel adjuvants for optimal stimulation of a cancer-specific immune response such as dendritic cells. In spite of these advances and immunological as well as clinical responses in selected patients, mechanisms involved in dendritic-cell-based cancer immunotherapy are still poorly understood. Therefore, a standardized study design and small pilot trials are needed to explore open scientific questions in future clinical trials. This review focuses on the different parameters of dendritic cell biology relevant to cancer immunotherapy and on innovative approaches to hopefully enhance the efficacy of dendritic cell vaccination.
Skin pharmacology and physiology 02/2006; 19(3):124-31. · 2.92 Impact Factor
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ABSTRACT: Psoriasis is a common and chronic relapsing inflammatory skin disorder. Although a role for T cells in mediating the induction and maintenance of psoriatic lesions is well established, mechanisms responsible for activation of T cells by antigen-presenting cells (APCs) during disease relapse are poorly understood.
(i) To determine whether expression of the common heat shock protein (HSP) receptor CD91 correlated with development of psoriasis in a mouse model of psoriasis, (ii) to characterize the lesional cells on which CD91 was expressed, and (iii) to investigate whether CD91+ cells in psoriasis showed signs of activation.
Two systems were used in order to study the above-mentioned objectives: (i) skin biopsies taken directly from patients with psoriasis (either psoriatic plaques or symptomless prepsoriatic skin) or from healthy donors, respectively, or (ii) (human) skin biopsies collected during development of psoriasis using a novel xenograft mouse model of psoriasis. The skin samples were then either processed for analysis by light microscopy, or labelled with fluorochrome-conjugated antibodies and analysed by confocal laser scanning microscopy.
We observed a markedly increased number of CD91+ cells which paralleled development of new psoriatic lesions in the psoriasis mouse model and in established psoriatic plaques compared with symptomless prepsoriatic or healthy skin. Morphology as well as cell-specific markers showed that CD91 was predominantly expressed by dermal dendritic APCs characterized by activation of nuclear factor-kappaB signalling and the presence of tumour necrosis factor-alpha, an important proinflammatory cytokine in the immunopathogenesis of psoriasis. In addition, HSP70, a ligand for CD91, was increased in keratinocytes in close vicinity to CD91-bearing APCs in psoriatic lesions.
These findings indicate massive presence of CD91+ dendritic cells juxtaposed to lesional keratinocytes expressing HSP70, and suggest a novel pathophysiological pathway and therapeutic target for this chronic inflammatory skin disease.
British Journal of Dermatology 07/2005; 152(6):1211-8. · 3.67 Impact Factor
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ABSTRACT: Nephrogenic fibrosing dermopathy (NFD) is a recently described cutaneous fibrosing disorder associated with renal dysfunction. Patients present with thickened skin or oedematous skin with indurated papules and plaques involving extremities and trunk, and often associated with disabling contracture of the adjacent joints. The aetiology and pathogenesis remain largely unknown. As a consequence, therapeutic measures with proven efficacy are nonexistent to date.
To consider treatment with extracorporal photopheresis (ECP) in three patients. Patients We report three new cases of NFD with the characteristic clinical and pathological features. Two patients required haemodialysis due to end-stage renal failure, despite prior renal transplantation. One patient had renal dysfunction but was never on dialysis, nor had she been transplanted. ECP treatment was administered at intervals of 2-4 weeks.
All three patients showed a softening of the skin lesions and a marked improvement of the joint motility starting after four cycles of ECP. One patient developed a complete regression of her skin lesions after 16 cycles of ECP, and response to therapy was observed despite constantly elevated renal values.
These data indicate that ECP may represent a valuable therapeutic option for NFD.
British Journal of Dermatology 04/2005; 152(3):531-6. · 3.67 Impact Factor
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Ernst Schering Research Foundation workshop 02/2005;
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Vox Sanguinis 08/2004; 87 Suppl 2:112-4. · 2.86 Impact Factor
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ABSTRACT: An 82-year-old female patient presented with a large perianal hyperkeratotic tumor extending into the anal canal. Staging did not reveal any metastatic spread. Diagnosis of verrucous carcinoma or Buschke-Löwenstein tumor, respectively, was based on typical clinical and histologic features. Moreover, human papillomavirus 6b DNA sequences could be detected by PCR. Surgical excision could not be performed due to the general health status of the patient; thus, alternative therapy methods were necessary. Treatment with imiquimod cream 5% (Aldara), a topical immune response modifier applied once a day and left for 12 h, led to significant partial tumor regression and clear demarcation of the tumor. The remaining tumor, now feasible for treatment with CO2 laser, was removed in two sessions in local anesthesia. In a third session, tumor parts in the anal canal were vaporized. This case demonstrates that the combination of imiquimod and CO2 laser ablation is an effective treatment option for verrucous carcinoma.
Dermatology 02/2003; 207(1):119-22. · 2.05 Impact Factor
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F O Nestle
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ABSTRACT: Melanoma is one of the prototypic immunogenic tumors. Various immunotherapeutic approaches for melanoma have been developed in the past decades. Recent scientific progress includes the discovery of defined melanoma antigens, new tools for monitoring of an anti-cancer immune response and application of novel adjuvants for amplification of the immune response such as dendritic cells. These and other advances in the field of melanoma vaccines will be discussed.
Clinical and Experimental Dermatology 11/2002; 27(7):597-601. · 1.20 Impact Factor
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ABSTRACT: Nasal mucosa melanoma is a rare entity that may occur together with nasal melanosis. The histological and immunological features and loss of heterozygosity analysis of such lesions have not been reported to date. In the study presented here short-term cell cultures were established from the patient's melanoma and subsequent relapses. Histology, immunohistochemistry, reverse transcription-polymerase chain reaction enzyme-linked immunosorbent assay, human leukocyte antigen analysis, microdissection with subsequent polymerase chain reaction for analysis of loss of heterozygosity were used to characterize the tumour and other cells. Melanoma of the nasal cavity was found, with a surrounding proliferation of atypical melanocytes corresponding to nasal melanosis. Immunoreactivity was found for S-100, gp100, tyrosinase and MelanA protein. Loss of heterozygosity for a p16-flanking marker was found in the tumour and the melanotic cells. Short-term cell cultures expressed tyrosinase and MUC18 at the mRNA level and intercellular adhesion molecule-1 (ICAM-1) and interleukin-12 receptor at the protein level. This is the first time short-term cell cultures have been established and analysed from such a tumour. Melanoma-associated antigens were identified within the tumour. The melanoma and the melanotic cells showed loss of heterozygosity for the p16 gene, which is implicated in melanoma development. This points to a common origin in tumorigenesis. Pathways of tumour escape, such as expression of CD54 and interleukin-10, were observed. The clinical, immunological and molecular features suggest that nasal melanosis should be followed closely.
Melanoma Research 03/2002; 12(1):77-82. · 2.19 Impact Factor
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ABSTRACT: We report a 50-year-old male patient with a 15-year history of psoriasis including mutilating psoriatic arthritis, in whom the withdrawal of cyclosporin A induced a generalised pustular exacerbation and a aggravation of the joint condition. Two weekly injections of 25 mg of the tumour necrosis factor alpha inhibitor etanercept led to a rapid improvement of his psoriatic arthritis, as well as regression of the pustular eruption, while residual erythema was still present. The clinical response was reflected by an increase in circulating interleukin (IL) 10 and a decrease in IL-6 and IL-8 serum levels during treatment. We conclude that etanercept may be a safe and effective therapy not only in severe psoriatic arthritis, but also in cases of pustular rebound after withdrawal of immunosuppressive agents.
Dermatology 02/2002; 205(2):213-6. · 2.05 Impact Factor
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ABSTRACT: Lichenoid pigmented purpuric dermatitis of Gougerot-Blum belongs to a group of closely related disorders which are termed pigmented purpuric dermatoses. It clinically manifests itself with grouped lichenoid papules in association with purpuric lesions. We report a case of lichenoid pigmented purpuric dermatitis of Gougerot-Blum with a heavy band-like CD4-positive lymphocytic infiltrate and clonal rearrangements of the gamma-chain of the T cell receptors as detected by polymerase chain reaction/denaturing gradient gel electrophoresis. Monoclonal expansion of T cells in combination with certain histological features of mycosis fungoides (MF) might support a biological relationship between lichenoid pigmented purpuric dermatitis of Gougerot-Blum and MF. However, prompt clinical response to topical steroid therapy supports the benign clinical nature of our case.
Dermatology 02/2002; 205(2):191-3. · 2.05 Impact Factor
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Melanoma Research 11/2001; 11(5):549-50. · 2.19 Impact Factor
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ABSTRACT: Langerhans cells can originate in vitro from immature precursors stimulated with granulocyte macrophage-colony-stimulating factor (GM-CSF), tumour necrosis factor (TNF)-alpha and stem cell factor (SCF). We asked whether these cytokines also control the differentiation state of Langerhans cells within the epidermis and upon leaving this tissue. We harvested sheets of human epidermis by controlled dispase hydrolysis of keratomes, cultured them in RPMI and 10% fetal calf serum for 48 h and analysed the sheets and the cells migrated spontaneously into the medium, most of which were Langerhans cells containing Birbeck granules. By flow cytometry, the intensity of CD1a expression was reduced quite evenly among Langerhans cells migrated from sheets within 48 h. The cells in the sheets underwent loss of dendrites, with a significant reduction in the cell perimeter that was prevented by GM-CSF and TNF-alpha together. Either of these cytokines induced expression of CD18 by cells in the sheets and those in the medium. Moreover, TNF-alpha induced expression of CD54 by cells in the medium, but not by those retained in the sheets, whereas human SCF induced, dose dependently, expression of CD54 by cells in the sheets, but not from those in the medium. The proliferation of allogeneic lymphocytes was much higher when stimulating Langerhans cells were harvested from cultures with any cytokine, rather than from cultures without cytokines. We conclude the following: (i) GM-CSF and TNF-alpha help to maintain full differentiation of Langerhans cells within the epidermis; (ii) cytokine influence on Langerhans cells adhesiveness is in part context dependent; and (iii) pretreatment with cytokines influences positively the number or accessory activity of Langerhans cells on lymphocytes during subsequent mixed leucocyte reaction.
Journal of the European Academy of Dermatology and Venereology 10/2001; 15(5):433-40. · 2.98 Impact Factor
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ABSTRACT: As dendritic cells increasingly become the adjuvant of choice in new approaches to cancer immunotherapy, a degree of protocol standardization is required to aid future large-scale clinical trials.
Nature Medicine 08/2001; 7(7):761-5. · 22.46 Impact Factor
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[show abstract]
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ABSTRACT: Several pathogenetic factors such as peripheral neuropathy, vasculopathy and infection are responsible for the development of diabetic foot ulcerations. An important factor contributing to the high infection risk in diabetic patients is a defect in neutrophil granulocytes. Deficiencies in neutrophil chemotaxis, phagocytosis and respiratory burst activity with the decrease of the super- and peroxids are known to be associated with diabetes. Granulocyte-colony stimulating factor (G-CSF) increases the release of neutrophils from the bone marrow and improves neutrophil function. A 78-year old patient with non-insulin-dependent diabetes presented with ulcerations of both big toes and a malum perforans on the right sole. He also had generalized arteriosclerosis as well as a polyneuropathy with a dry foot and typical foot deformation as well as decreased in sensitivity. Intensive local care for 35 days led to no improvement of the ulcerations. Then G-CSF (Neupogen) was administered in a total dose of 165 million IU over 11 days; the daily dose varied between 15-30 million IU depending on the absolute leucocyte count. In addition 500 mg of oral ciprofloxacin (Ciproxin) was given b.i.d. This treatment led to a significant improvement of the lesions. Within 11 days cost analysis suggests G-CSF may be a cost-effective addition to antimicrobial therapy in diabetic foot infection.
Der Hautarzt 05/2001; 52(4):327-30. · 0.58 Impact Factor
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ABSTRACT: We describe a case of cicatricial pemphigoid in a 92-year-old female with extensive mucocutaneous involvement. She developed extensive hemorrhagic blistering with severely bleeding lesions, that healed with scarring. The conjunctivae showed extensive synechia. The diagnosis was based on clinical and histopathological features as well as immunofluorescence findings and immunoblot analysis. There was no clinical response to topical corticosteroids. The patient was given tetracycline and nicotinamid and showed rapid improvement of the mucocutaneous lesions within a few weeks. The clinical features, differential diagnosis and various treatment modalities of cicatricial pemphigoid are briefly reviewed, whereby the use of tetracycline and nicotinamide is discussed as an alternative effective and safe therapy for this potentially incapacitating condition.
Der Hautarzt 04/2001; 52(3):247-50. · 0.58 Impact Factor
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ABSTRACT: Dendritic cells (DC) are commonly viewed as the professional antigen-presenting cell. They capture antigens, migrate to appropriate lymphoid organs and initiate an antigen-specific CD4 and CD8 T cell response. Much is known about DC physiology, and it is now possible to culture, maintain and expand DC from different human sources, including hematopoietic progenitors in bone marrow and peripheral blood. Combined with the detection of an increasing number of tumor-associated antigens and T cell-recognized peptide epitopes, this has led to a new enthusiasm in the field of tumor immunotherapy and to various clinical applications in phase I/II studies on the treatment of different malignancies. This chapter will review the latest developments and give a brief update of the results obtained in studies of advanced melanoma, as well as provide a short overview of published results for other tumors.
Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer 02/2001; 158:236-48.
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ABSTRACT: Borrelia burgdorferi infection has been implicated in cutaneous B-cell lymphoma. We report a case of multilesional primary cutaneous large B-cell lymphoma without extracutaneous spread in a patient with elevated B. burgdorferi titers. After antibiotic therapy, clinical remission and a subsequent drop in B. burgdorferi antibody titers were obtained.
Dermatology 02/2001; 203(2):168-70. · 2.05 Impact Factor
