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W Dummer

Publications and source records attributed to W Dummer.

At least 19 recordsLinked to original sources
PubMed2004

T-cell modulation for the treatment of chronic plaque psoriasis with efalizumab (Raptiva): mechanisms of action.

Psoriasis is a chronic, incurable, auto-immune disorder with cutaneous manifestations. New evidence on the central role of the immune system in the pathogenesis of psoriasis increasingly provides insight into pathogenic steps that can be modulated to provide disease control. Numerous biological therapies are in various stages of clinical development, with expectation of providing enhanced safety and efficacy over currently available psoriasis therapies. Efalizumab, a recombinant humanized monoclonal IgG1 antibody, is a novel targeted T-cell modulator that inhibits multiple steps in the immune cascade that result in the production and maintenance of psoriatic plaques, including initial T-cell activation and T-cell trafficking into sites of inflammation, including psoriatic skin, with subsequent reactivation in these sites. This article reviews the pharmacodynamic, pharmacokinetic and clinical effects observed during phase I, II and III efalizumab trials in patients with moderate to severe chronic plaque psoriasis.

Adjuvants, Immunologic↗
PubMed2001

Role of cyclin kinase inhibitor p21 in systemic autoimmunity.

The cyclin kinase inhibitor protein p21 affects multiple processes relevant to the immune system, including cell cycle progression, replicative senescence, hemopoietic stem cell quiescence, and apoptosis. Therefore, malfunction of this protein may be a contributor to the pathogenesis of systemic autoimmunity. Here, we report that mixed background p21-deficient 129/Sv x C57BL/6 mice showed increased in vitro and in vivo T cell cycling and activation, moderate hypergammaglobulinemia and, at low penetrance, anti-chromatin autoantibodies. Homeostatic anti-self MHC/peptide ligand-induced proliferation of p21-deficient T cells was also enhanced. However, lymphoid organ enlargement was very mild, presumably due to increased apoptosis of the rapidly dividing cells. Moreover, the older p21-deficient mice had kidney pathology representing a similar, but slightly more advanced, state than that seen in the control mice. The timing and severity of the above serologic, cellular, and histologic manifestations in p21-deficient mice were unaffected by gender. Thus, p21 deficiency significantly enhances T cell activation and homeostatic proliferation, and can induce mild autoimmune manifestations at a low incidence without gender bias, but does not in itself generate the full spectrum of lupus-like disease.

Animals↗
PubMed2001

The role of alpha beta+ T cells and homeostatic T cell proliferation in Y-chromosome-associated murine lupus.

Male BXSB mice develop an early life, severe lupus-like disease largely attributed to an undefined Y-chromosome-associated autoimmunity accelerator, termed YAA: Although the exact disease pathogenesis is uncertain, indirect evidence suggests that T cells play an important role in the male BXSB disease. We have developed TCR alpha-chain gene-deleted BXSB mice to directly examine the role of alphabeta+ T cells and the mode by which Yaa promotes disease in this strain. All disease parameters, including hypergammaglobulinemia, autoantibody production, glomerulonephritis, and the unique monocytosis of BXSB males, were severely reduced or absent in the alphabeta+ T cell-deficient mice. Adoptively transferred CD4+ T cells of either male or female BXSB origin showed equal homeostatic proliferation in alphabeta+ T cell-deficient male recipients. Moreover, deficient male mice eventually developed equally severe lupus-like disease after adoptive transfer and homeostatic expansion of T cells from wild-type BXSB males or females. The results directly demonstrate that the Yaa-mediated disease requires alphabeta+ T cells that are not, in themselves, abnormal in either composition or properties, but are engaged by a Yaa-encoded abnormality in a non-T cell component. In addition, homeostatic anti-self proliferation of mature T cells derived from a small number of precursors can induce systemic autoimmunity in an appropriate background.

Adoptive Transfer↗
PubMed2001

Autologous regulation of naive T cell homeostasis within the T cell compartment.

Naive T cells undergo spontaneous slow proliferation on adoptive transfer into syngeneic T cell (T)-deficient hosts. Recent work has shown that such "homeostatic" T cell proliferation is driven by MHC molecules loaded with self-peptides rather than foreign peptides. Because naive T cells in normal T-sufficient hosts remain in interphase despite continuous contact with self-MHC/peptide ligands, T cells apparently inhibit homeostatic proliferation of neighboring T cells. To address this, we have investigated the requirements necessary for "bystander" T cells to inhibit homeostatic proliferation of other T cells. Three key findings are reported. First, homeostatic proliferation of T cells only occurs in specific microenvironments, namely the T cell compartment of the secondary lymphoid tissues. Second, direct entry into T cell compartments is also required for bystander inhibition of homeostatic proliferation. Third, bystander inhibition is mediated largely by naive rather than activated/memory T cells and does not require proliferation or TCR ligation. These findings suggest that homeostasis of naive T cells is unlikely to be regulated through competition for systemic soluble factors or for specific stimulatory self-MHC/peptide ligands. Rather, the data favor mechanisms that involve competition for local non-MHC stimulatory factors or direct cell-to-cell interactions between the T cells themselves within the T cell compartment.

Adoptive Transfer↗
PubMed2000

[Pemphigoid gestationis without blisters].

BACKGROUND AND OBJECTIVE: Pemphigoid gestationis (PG) is a rare pregnancy-associated autoimmune bullous disease characterized by autoantibodies to the 180 kD bullous pemphigoid antigen (BP180). The clinical spectrum of PG is polymorphic and for diagnostic purposes, a skin biopsy is usually taken demonstrating the deposition of autoantibodies. PATIENTS AND METHODS: From 2 patients, skin biopsies were obtained for histopathologic and immunofluorescence studies. Circulating autoantibodies were characterized by immunoblotting and ELISA using a recombinant form of the immunodominant BP180 NC16 A domain. RESULTS: The 2 PG patients described here did not show blisters but complained about severe itching. In the first case, PG presented in the first trimester of the second pregnancy as an erythema-multiforme-like disease. The second patient developed urticarial plaques a few days after delivery. PG was diagnosed by the detection of autoantibodies against recombinant BP180 NC16 A by immunoblot and ELISA analysis and confirmed by linear deposits of C3 at the cutaneous basement membrane zone on direct immunofluorescence microscopy. Skin lesions healed with oral prednisolone. CONCLUSIONS: In our two patients, non-bullous PG could be diagnosed by serological tests. Immunoblotting and ELISA might be sensitive and specific tools when screening sera of patients with pruritic skin lesions in pregnancy for the presence of autoantibodies to BP180. In some cases, these newer techniques may make a skin biopsy unnecessary.

Adult↗
PubMed2000

Role of self-major histocompatibility complex/peptide ligands in selection and maintenance of a diverse T cell repertoire.

Positive selection has long been thought to be a devise for producing a repertoire of T cells that can efficiently recognize foreign peptides in the context of self-major histocompatibility complex (MHC) molecules. However, in the light of recent evidence that long-term survival of mature T cells requires continuous contact with self-MHC molecules, the possibility for an additional role for positive selection has emerged: to generate a repertoire of T cells that can be maintained in the periphery through contact with self-MHC/peptide ligands. In support of this idea, our recent work suggests that positive selection is highly peptide specific and, more important, that mature T cells require extrathymic contact with the same MHC/peptide ligands that initially induced positive selection in the thymus in order for prolonged survival and to undergo homeostatic proliferation in response to T cell deficiency.

Animals↗
PubMed1999

[Model of a special consultation for patients with atopic eczema].

Due to its high prevalence, atopic dermatitis is an important problem in the dermatologic practice. The chronicity of the disease together with numerous triggering factors of varying individual impact create a complex situation which is difficult to manage under the current circumstances in our health care system. We describe the concept of an outpatient clinic especially for atopic dermatitis as established in our Department of Dermatology. A high degree of standardization is combined with a high measure of individual care. The aims of this clinic are an optimized outpatient management of atopic dermatitis, the gathering of epidemiologic data, the performance of controlled studies, and potentially the reduction of costs.

Ambulatory Care↗
PubMed1999

Differential expression of transforming growth factor beta 1 and interleukin 10 in progressing and regressing areas of primary melanoma.

The coexistence of tumor specific immunity with a progressing tumor remains a major paradox of tumor immunology. This enigma is most evident in partially regressing melanomas, where efficient eradication of tumor cells is closely linked to uncontrolled tumor growth. Mechanisms involved in this differential susceptibility of tumor cells to the host immune response may include altered production of immunosuppressive cytokines, i.e., transforming growth factor (TGF) beta or interleukin (IL) 10. Since only limited amounts of tissue samples are available from primary tumors, a semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) was established which allowed to estimate the amount of cytokine mRNA expressed in a small number of melanoma cells segregated by indirect immunomagnetic isolation. Thereby, we determined the expression of TGF-beta 1 and IL-10 mRNA in melanoma cells obtained from regressing and progressing areas of 9 primary tumors. TGF-beta 1 mRNA could be detected in all undiluted samples from progressing areas and in 7 samples from regression zones. Titration of the sample revealed that in 6 cases TGF-beta 1 mRNA could be detected at a significant higher titer in progressing than in regressing areas. IL-10 mRNA was present in 8 samples obtained from progressing and in 7 samples from regressing tumor areas. In 6 tumors IL-10 mRNA was detectable at a higher titer in the progression zones. Specificity of the PCR amplification was confirmed with a series of restriction enzyme digestions of the resulting PCR product. Based on these findings the hypothesis that immunosuppressive cytokines, such as TGF-beta 1 or IL-10, represent important factors for the melanoma cells to escape immune surveillance is supported.

Disease Progression↗
PubMed1998

Expression of CD30 on T helper cells in the inflammatory infiltrate of acute atopic dermatitis but not of allergic contact dermatitis.

The CD30 molecule has been proposed as a marker for a subset of CD4+CD45RO+ (memory) T cells with potent B cell helper activity producing IL-5 and IFN-gamma and as a specific marker for Th2 cells. Recently, an association has been demonstrated between elevated serum levels of soluble CD30, which is shed by CD30+ cells in vitro and in vivo, and atopic dermatitis but not respiratory atopic disorders or allergic contact dermatitis. We studied the expression of CD30 in the inflammatory infiltrate of atopic dermatitis compared with that of allergic contact dermatitis, with special regard to skin disease activity (acute vs subacute/ chronic). Biopsies were obtained from 16 patients suffering from atopic dermatitis (acute n = 6, subacute/ chronic n = 10), from 7 patients with acute allergic contact dermatitis and from 5 positive patch-test reactions. Paraffin-embedded as well as snap-frozen material was stained with anti-CD30 and anti-CD45RO mAbs according to standard procedures. Double-staining procedures for CD30CD3, CD30CD4, CD30CD45RO and CD30CD68 were also performed. Abundant CD45RO+ cells were detected both in atopic dermatitis and in allergic contact dermatitis lesions. We found scattered CD30+ cells in only one of six formalin-fixed paraffin-embedded acute atopic dermatitis biopsies, but in all of the respective snap-frozen specimens, possibly because CD30 expression on atopic dermatitis infiltrating cells is weak and sensitive to formalin fixation and paraffin embedding. CD30CD3 and CD30CD4 double staining identified CD30+ cells to be helper T lymphocytes. No significant CD30 expression (either in paraffin-embedded or in frozen material) could be found in subacute/chronic atopic dermatitis lesions or in any of the specimens of allergic contact dermatitis. The results suggest a specific regulatory function of CD30+ T cells in acute atopic dermatitis. With respect to the view that CD30 is a marker for Th2 cells, our observations confirm previous findings that Th2 cells predominate in the infiltrate particularly of acute atopic dermatitis. CD30 expression in acute atopic dermatitis but not in acute allergic contact dermatitis might be helpful in the histological differentiation of these disorders and in the further characterization of atopy patch testing.

Acute Disease↗
PubMed1998

Reliability of reverse transcription-polymerase chain reaction (RT-PCR)-based assays for the detection of circulating tumour cells: a quality-assurance initiative of the EORTC Melanoma Cooperative Group.

Reverse transcription-polymerase chain reaction (RT-PCR)-based assays detecting occult neoplastic cells are increasingly being used for the study of tumour dissemination and minimal residual disease. However, different methods are employed by various research groups and the results are heterogenous. We prospectively assessed the results from nine laboratories performing tyrosinase RT-PCR assays for the detection of melanoma cells on a series of blind samples. After complete analysis, the results were compared for sensitivity and specificity. All laboratories reported correct results for cDNA standards. Five laboratories attained acceptable specificity and a sensitivity detecting 10 cells in 10 ml of whole blood. Four laboratories had unacceptable specificity and/or sensitivity. This blind study highlights the difficulty of RT-PCR data interpretation and the need for quality assurance between laboratories. Measures to increase the reliability of RT-PCR assays are proposed, which have to be prospectively evaluated in future studies.

DNA, Neoplasm↗
PubMed1997

Elevated serum levels of soluble CD30 are associated with atopic dermatitis, but not with respiratory atopic disorders and allergic contact dermatitis.

Type 2 helper T-cell immune responses can be demonstrated in the human atopic disorders atopic dermatitis and allergic asthma/rhinoconjunctivitis. The CD30 (Ki-1) antigen, originally described on Hodgkin and Reed-Sternberg cells, has recently been proposed as a marker of T cells with potent B-cell helper activity producing IL-5 and gamma-IFN, as well as on CD4+ and CD8+ T cells with a Th2 cytokine profile. As a soluble form of CD30 (sCD30) is released by CD30+ cells in vivo, we studied its clinical significance in atopic disorders compared with allergic contact dermatitis and healthy controls. Elevated sCD 30 levels were associated with atopic dermatitis (P < 0.0001), but not with respiratory atopic disorders or allergic contact dermatitis. sCD30 levels in patients with atopic-dermatitis were independent of serum IgE. The particular occurrence of serum sCD30 in patients with atopic dermatitis indicates a special regulatory function of CD30+ cells in this disease.

Adolescent↗
PubMed1996

Interleukin-10 production in malignant melanoma: preferential detection of IL-10-secreting tumor cells in metastatic lesions.

IL-10 mRNA expression and protein production in established melanoma cell lines and freshly cultured primary and metastatic melanoma cells was examined. The in situ distribution of IL-10 in native melanoma tissue was also investigated by immunohistochemistry in primary tumors, metastases, benign melanocytic nevi and normal skin of healthy persons and melanoma patients. IL-10 mRNA, but not IL-10 protein in the culture supernatant, was found in 1 of 4 cultured melanoma cells of primary tumors, while 3 of 6 melanoma-metastasis-derived cultures expressed both IL-10 mRNA and protein. No IL-10 was detected in skin biopsies of healthy volunteers or in the healthy skin of melanoma patients; nor was IL-10 found in congenital melanocytic nevi. In only 1 of the 11 examined primary malignant melanomas was IL-10 immunoreactivity detected within the cytoplasm of cells in the tumor. On the other hand, 4 of 9 metastases clearly displayed scattered IL-1O+ cells. In all sections with IL-10-positive cells, the cells were positive for HMB-45. No co-expression of CD3 and IL-10 was observed. The data suggest that melanoma cells themselves are the main origin of IL-10 in tumor specimens in vivo. The preferential expression of IL-10 in metastatic lesions and in cultured cells from metastases might indicate an increased spreading potential of IL-10-secreting melanoma-cell clones.

Base Sequence↗
PubMed1996

Scalp necrosis in temporal (giant cell) arteritis:implications for the dermatologic surgeon.

Temporal arteritis, a variant of giant cell arteritis, is a systemic granulomatous vasculitis of large and medium-sized arteries. Usually the clinical features are dominated by ophthalmological and neurological complications. In rare instances, ischaemic necrosis, especially of the scalp, may lead patients to the dermatologist. We report a 76-year-old woman presenting with a unilateral scalp necrosis, accompanied by a dramatic ipsilateral impairment of vision. Immediately after duplex-sonography of the extracranial vessels and after initiation of corticosteroid therapy, the diagnosis of temporal arteritis was confirmed by temporal artery biopsy. One month later, because of insufficient secondary healing of the ulcer, the defect was covered by a mesh graft. The taking of the graft was delayed due to immunosuppressive therapy, but was complete. The patient unfortunately died as a result of complications related to surgical removal of an aspergilloma in the sphenoid cavity secondary to immunosuppressive therapy. We discuss the technique of artery biopsy and the possibility of surgical management of scalp necrosis in temporal arteritis.

Aged↗
PubMed1995

Elevated serum levels of interleukin-10 in patients with metastatic malignant melanoma.

Interleukin-10 (IL-10), originally described as a product of TH2 cell clones, has been recognized as a potential immunosuppressive cytokine. To investigate the relevance of IL-10 in melanoma patients in vivo, we studied IL-10 serum levels in 104 untreated patients in different stages of the disease; 20 healthy subjects and 22 patients with inflammatory dermatoses served as controls. Serum levels were measured by ELISA. Only one of 31 patients with stage I melanoma (3%) and one of 16 stage II patients (6%) showed detectable IL-10 levels. Interestingly, six of 17 patients with lymph node metastases (stage III, 35%) and 29 of 40 patients with widespread disease (stage IV, 73%) revealed IL-10 levels of 15-480 pg/ml. No healthy person and only one control patient had a detectable IL-10 serum level. The data suggest that IL-10 in melanoma patients may contribute to down-modulation of anti-tumour responses in vivo.

Adult↗
PubMed1995

Preoperative characterization of pigmented skin lesions by epiluminescence microscopy and high-frequency ultrasound.

BACKGROUND AND DESIGN: Previous studies have referred to the value of epiluminescence microscopy in the differential diagnosis of pigmented skin lesions and to the possibility of preoperative tumor thickness measurement in malignant melanoma by high-frequency ultrasound. Both noninvasive methods have been combined in this study. The question of improved diagnostic accuracy was discussed. Previously proposed epiluminescence microscopic characteristics of 508 melanocytic lesions and sonographic characteristics of 792 skin tumors were investigated for their sensitivity and specificity. The tumor thickness of 108 malignant melanomas was measured sonographically. RESULTS: Black dots, irregular pigment network, and grayish-blue areas have been shown to be the most sensitive characteristics, whereas pseudopods, grayish-blue areas, and a whitish veil have been shown to be the most specific epiluminescence microscopic features for malignant melanoma. Sonography alone cannot reliably distinguish between different skin tumors. Preoperatively, the tumor thickness of 85% of the melanomas was assessed correctly concerning the pT stage. CONCLUSIONS: A 20-MHz ultrasound, in addition to epiluminescence microscopy, may improve the diagnostic accuracy by delivering information about depth and topographic location of skin tumors, but cannot give highly specific information about tissue dignity. It is a reliable tool for tumor thickness measurement for surgical planning.

Adult↗