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Biomedical subjects

L R Braathen

Publications and source records attributed to L R Braathen.

At least 19 recordsLinked to original sources
PubMed2001

A comparative study of the expression of cytotoxic proteins in allergic contact dermatitis and psoriasis: spongiotic skin lesions in allergic contact dermatitis are highly infiltrated by T cells expressing perforin and granzyme B.

Recent reports indicate that cytotoxic T cells are critically involved in contact hypersensitivity reactions in animals. In this study we sought to investigate the in vivo expression of cytotoxic granule proteins in the elicitation phase of allergic contact dermatitis in humans. Skin biopsy specimens were obtained from patients with allergic contact dermatitis (n = 8) and psoriasis (n = 6) and from controls with normal skin (n = 6). Expression of perforin and granzyme B was investigated by in situ hybridization and immunohistochemistry. In contrast to normal skin and psoriasis, a significant enhancement of perforin and granzyme B gene expression and immunoreactivity was observed in the mononuclear cell infiltrate of allergic contact dermatitis. Immunoreactivity for perforin and granzyme B was mainly found in the cytoplasm of lymphocytic cells, which were located in the dense perivascular infiltrate as well as at sites of marked spongiosis in the epidermis. Double immunostaining revealed that both CD4+ and CD8+ T cells are capable of expressing perforin and granzyme B. In conclusion, our data suggest that T-cell-mediated mechanisms involving cytotoxic granule proteins may elicit epidermal cell injury in vivo and thereby strongly contribute to the development of allergic contact dermatitis in humans.

Adult↗
PubMed2001

Successful induction of immune responses against mutant ras in melanoma patients using intradermal injection of peptides and GM-CSF as adjuvant.

The rapidly increasing incidence and mortality rate of malignant melanoma, together with the lack of efficient treatment of the late stages, makes it a serious threat to public health. Innovative new treatments are needed. The proteins of the ras-family of proto-oncogenes, functioning as relay switches for signalling pathways between cell surface and nucleus, are involved in cell proliferation, differentiation, apoptosis and transformation. If over-expressed or mutated they can induce and/or maintain a transformed state of a cell. Codon 61 mutations of N-ras seem to be involved in melanoma development on sun exposed sites. In order to induce an immune response towards mutated N-ras proteins we performed a phase 1 feasibility study. Ten melanoma patients were immunized intradermally 6 times with N-ras peptides (residue 49-73) with 4 codon 61 mutations using GM-CSF as adjuvant. HLA typing was not used as an inclusion criterion. Eight patients responded with strong delayed type hypersensitivity reactions. In 2 of the patients an in vitro response to the vaccine could also be detected. The specificity of the reaction could be confirmed by cloning of peptide-specific CD4 positive T cells from peripheral blood of the patients. Intradermal injection of ras peptides using GM-CSF as adjuvant is simple to perform and seems to be efficient in inducing cellular immune responses. Since a majority of the patients showed positive skin reactions and 2 of the patients analysed showed a T-helper response to this melanoma specific antigen, these promiscuous HLA class II binding mutant ras peptides may be candidates for inclusion into vaccine cocktails containing various established CTL epitopes.

Adjuvants, Immunologic↗
PubMed2001

Perforin and granzyme B may contribute to skin inflammation in atopic dermatitis and psoriasis.

BACKGROUND: Infiltration of the skin by pathogenic T cells is regarded as a key factor in the development of inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis. OBJECTIVES: To investigate whether T cells containing cytotoxic proteins may contribute to the generation of skin inflammation in these skin diseases. METHODS: Skin biopsy specimens were obtained from non-lesional and lesional skin of patients with chronic AD (n = 8) and psoriasis (n = 6), and from non-atopic controls with normal skin (n = 6). Expression of perforin and granzyme B was investigated by immunohistochemistry. RESULTS: A significant enhancement of perforin and granzyme B expression was observed in lesional AD skin as compared with normal skin, non-lesional AD skin and psoriasis. Expression of these cytotoxic proteins was also increased in psoriasis as compared with normal skin and non-lesional psoriatic skin. Immunoreactivity for perforin and granzyme B was mainly found in the cytoplasm of lymphocytic cells located in the perivascular infiltrate. In AD increased numbers of positive cells were also observed focally at sites of spongiosis in the epidermis. Double immunostaining revealed that both CD4+ and CD8+ T cells are capable of expressing perforin and granzyme B. CONCLUSIONS: Our data suggest that cytotoxic CD4+ and CD8+ T cells containing perforin and granzyme B may play an integral part in eliciting cutaneous inflammation in AD.

Adolescent↗
PubMed2001

Ulcerative sarcoidosis successfully treated with apligraf.

The case of a 73-year-old female patient is reported with a 25-year-long history of widespread cutaneous sarcoidosis without any known extracutaneous manifestations. The skin manifestations started with erythematous and plaque-like lesions that had ulcerated on the legs for the last half-year. A relevant venous insufficiency or other etiology of the ulcers could not be found. Histology from lesions of the trunk and from the surroundings of the ulcers revealed the typical noncaseating granulomas. A systemic involvement could not be observed; leukopenia and a slightly elevated angiotensin-converting enzyme level in the serum were found. Topical steroids did not prove successful on the ulcers. Apligraf, a bilayered skin equivalent, was transplanted twice on the ulcers leading to complete closure within 3 months. A therapy with systemic steroids could thus be avoided.

Aged↗
PubMed2000

Human afferent lymph from normal skin contains an increased number of mainly memory / effector CD4(+) T cells expressing activation, adhesion and co-stimulatory molecules.

We investigated the T cell population in the afferent lymph and the peripheral blood with regard to expression of activation, adhesion and co-stimulatory molecules and cytokine profile by immunohistochemistry and flow cytometry. The majority of the lymphoid cell population in the afferent lymph were CD4(+), CD45RO(+) T cells expressing the alpha beta TCR. An increased percentage of the T cells expressed activation molecules like HLA-DR, CD25, CD26, CD69 as well as adhesion and co-stimulatory molecules like CD54, CD154 / 40 ligand. Furthermore, T cells in the afferent lymph predominantly expressed the type 1 cytokine IFN-gamma, whereas type 2 cytokines such as IL-4, IL-5, IL-10 were not or barely detectable. Interestingly, dendritic cells expressing IL-12 were also found in close association with some lymphocytes, indicating that these contacts may be important in promoting Th 1 cells. In conclusion, an increased number of mainly CD4(+) memory / effector T cells, expressing activation, adhesion and co-stimulatory molecules migrate through the afferent skin-derived lymph in humans. Furthermore, our data demonstrate the dominance of a type 1 cytokine profile in these T cells and suggest that they have an important function in the immune surveillance against pathogens or other antigens in the skin and its associated lymphoid tissue.

Antigens, CD↗
PubMed2000

[Transitory acantholytic dermatosis (Grover disease). An analysis of the clinical spectrum based on 21 histologically assessed cases].

BACKGROUND AND OBJECTIVE: In 1970 Ralph W. Grover described a clinicopathologic entity characterized by pruritic keratotic papules and papulovesicles predominantly on the trunk, disappearing spontaneously after a few weeks or months and demonstrating the histological features of epidermal acantholysis. The etiology remains unknown; sweating, heat and sunlight are suspected trigger factors. In our survey the clinical spectrum of the disease will be examined. PATIENTS AND METHODS: We have analyzed 21 cases of Grover's disease histologically diagnosed in Berne in 1997 and 1998. RESULTS: In most cases we observed isolated papules disseminated on the trunk. The predominant histological type was the Darier-type; presumably there is no correlation between histological type and clinical features. At the time of diagnosis the skin disorder had been present on average for 83 months. There was a strong association with sweating and heat. Topical steroids were successful in 50% of patients. CONCLUSIONS: Our 21 cases reflect in general the literature. Nevertheless, the long persistence of the skin lesions was striking perhaps making the term transient somewhat inaccurate.

Acantholysis↗
PubMed2000

[Ibuprofen-induced, transient ANA- and anti-histone positive leukocytoclastic vasculitis].

Drug-induced leukocytoclastic vasculitis is clinically characterised by inflammation of small vessels and skin alterations, typically palpable purpura. Often the vasculitis is accompanied by fever, myalgia and malaise. All ages and sexes are equally affected. Besides the mentioned clinical features it may also present as macules, papules, vesicules, bullae, subcutaneous nodules or intermittent or chronic urticarial eruptions. Other organ systems may be affected. The patient's history is helpful in identifying the etiologic agent. If a drug is suspected as etiologic agent, a positive lymphocyte transformation test (LTT) supports the hypothesis. A 55 year old female patient developed an ANA and anti-histone antibody positive leukocytoclastic vasculitis with probable concomittant renal involvement after three weeks treatment with ibuprofen. Three months after discontinuation of the medication, the patient is without complaints and has a normal urine sedimentation and normalized immuno-autoantibodies.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Antigen-presenting cells and keratinocytes express interleukin-12 in allergic contact dermatitis.

Interleukin-12 (IL-12) has previously been suggested as playing a major rôle in the activation of cytotoxic lymphocytes. Recent reports indicate that cytotoxic CD8+ cells are critically involved in the elicitation phase of contact hypersensitivity reactions. In this study, the in situ expression of IL-12 was investigated in normal human skin and in allergic contact dermatitis by immunohistochemistry. Skin biopsy specimens were obtained from allergic patch test reactions after 3 days, and from normal skin in 8 subjects. In contrast to normal skin, a strong enhancement of IL-12 immunoreactivity was observed in the mononuclear cell infiltrate of allergic contact dermatitis. IL-12 immunoreactivity was mainly located in the cytoplasm of dermal dendritic cells and macrophages as well as of some Langerhans cells. IL-12-positive cells were often found in close apposition to lymphocytes. Furthermore, positive immunostaining was also detected in keratinocytes at sites of marked exocytosis and spongiosis in the epidermis. In conclusion, the enhanced in situ expression of IL-12 may contribute to the activation of cytotoxic lymphocytes and thereby represent an important factor in the pathogenesis of contact hypersensitivity reactions in humans.

Adult↗
PubMed2000

Infiltration of cytotoxic T cells in drug-induced cutaneous eruptions.

BACKGROUND: Previous in vitro data indicate that perforin containing drug-specific cytotoxic T cells are involved in cutaneous drug reactions. OBJECTIVE: The aim of this study was to investigate the in situ expression of perforin and granzyme B together with the nature of the inflammatory infiltrate in acute drug-induced exanthem. Furthermore, expression of interleukin (IL)-12 and interferon (IFN)-gamma, which are known to stimulate cytotoxic T cells, was investigated. METHODS: Skin biopsy specimens were obtained from 10 patients with a generalized maculopapular exanthem and from nine controls with normal skin. Expression of CD3, CD4, CD8, CD56, CD1a, CD68, CD25, HLA-DR, CD54, perforin, granzyme B, IL-12 and IFNgamma was analysed using immunohistochemistry. RESULTS: In contrast to the controls, the skin of patients with an exanthem was mainly infiltrated by T cells (CD4 > CD8) and showed a marked enhancement of perforin and granzyme B immunostaining. Double immunostaining revealed that perforin and granzyme B were expressed in both CD4+ and CD8+ cells, which were partly located at the dermoepidermal junction and in the epidermis. In addition, strong immunreactivity for IL-12 and IFNgamma was observed in the mononuclear cells infiltrate, indicating that these cytokines may be important in activation of these cytotoxic T cells. CONCLUSION: The increased numbers of perforin and granzyme B containing T cells infiltrating the dermoepidermal junction may contribute to the damage of epidermal cells, which is frequently observed as a typical feature of interface dermatitis in drug-induced exanthem. Our data provide further evidence that cytotoxic T cells play an essential role in cutaneous drug reactions.

Adult↗
PubMed2000

Role of the initiator element in the regulation of the melanoma cell adhesion molecule gene.

The melanoma cell adhesion molecule is a membrane glycoprotein whose expression is associated with tumor progression and the development of metastatic potential. The mechanisms for upregulation of the melanoma cell adhesion molecule during melanoma progression are still poorly understood. In this study, we show further evidence that melanoma cell adhesion molecule expression is tightly regulated at the transcriptional level. Using a combination of chloramphenicol acetyl transferase reporter assays and DNA mobility shift experiments, we investigated the role played by three putative melanoma cell adhesion molecule regulatory elements, namely the initiator sequence, the SCA element, and the ASp element. The SCA and the ASp boxes can potentially interact with the transcription factors Sp1 and AP-2. Sp1 binding to both sites was confirmed, but only the SCA sequence could form a complex with AP-2. AP-2-driven downregulation of the melanoma cell adhesion molecule promoter, however, did not depend only on a functional SCA element. The pyrimidine-rich CTCACTTG initiator, which overlaps the RNA start site, was essential for promoter function and was shown to interact with proteins related to basic helix-loop-helix transcription factors. Binding in nonmetastatic melanoma cells was induced by cAMP. In metastatic cells, however, binding was constitutive, but could be markedly decreased upon treatment with phorbol esters. As melanoma cell adhesion molecule expression is modulated by cAMP and phorbol ester signaling, these results suggest that the initiator is the central element that mediates cAMP and phorbol ester sensitivity and initiates melanoma cell adhesion molecule overexpression in melanomas.

Animals↗
PubMed2000

T cells isolated from positive epicutaneous test reactions to amoxicillin and ceftriaxone are drug specific and cytotoxic.

In order to investigate the function of T cells in cutaneous adverse drug reactions, skin-derived T cells were analyzed in two patients with a drug-induced exanthem. Skin biopsy specimens were obtained from positive epicutaneous test reactions to amoxicillin and ceftriaxone. Immunohistochemical analysis revealed that the majority of the cell infiltrate in both biopsy specimens was composed of activated T cells, of which some expressed perforin. By limiting dilution 36 amoxicillin-specific and 10 ceftriaxone-specific T cell clones were raised. All of these T cell clones expressed CD4/T cell receptor alphabeta. Cytokine analysis after antigen stimulation of the seven best proliferating T cell clones (four specific for amoxicillin and three for ceftriaxone) revealed that these cells secrete high amounts of interleukin-5 and mostly lower or no amounts of tumor necrosis factor alpha, interleukin-4, and interferon-gamma. A part of these CD4+ T cell clones were cytotoxic, i.e., two selected ceftriaxone-specific T cell clones killed target cells after antigen stimulation. The amoxicillin-specific T cell clones failed to show drug-specific cytotoxicity, but killed target cells in the presence of concanavalin A, indicating a principal ability to be cytolytic. In correlation with the in situ expression of perforin on T cells, the ceftriaxone-specific T cell clones also expressed perforin in vitro. In conclusion, a substantial part of the T cells in drug-induced epicutaneous test reactions are drug specific and are composed of a heterogeneous cell population. Drug-specific T cells producing interleukin-5 may contribute to eosinophilia, whereas cytotoxic CD4+ T cells may account for tissue damage. These data underline the role of T cells in delayed-type cutaneous adverse drug eruptions and drug-induced epicutaneous test reactions.

Adult↗
PubMed2000

[Immunotherapy in malignant melanoma].

The malignant melanoma is because of its ability to form metastasis even at early stages of disease the deadliest of all skin tumors. Its incidence rises faster than that of any other human tumor. Today, treatment of melanoma is based on surgical removal, and depending on the stage, chemotherapy and/or biological response modifiers. The response and cure rates are, however, not satisfactory and there is, therefore, ongoing research for other approaches. The identification of melanoma antigenic peptides like Melan-A, gp100 and ras peptides has opened new possibilities in the treatment of malignant melanoma. The research on generating mainly T cell mediated immune responses against malignant melanoma using many different approaches like injection of dendritic cells pulsed with melanoma specific peptides, injection of in vitro with cytokines stimulated T cells, immunization with peptides in the presence of different adjuvants, immunization with genetically modified melanoma cells etc. has produced many encouraging results. However, the future of tumor-vaccine development still lies in generation of more potent vaccination protocols.

Humans↗
PubMed2000

Down-regulation of IL-12 by topical corticosteroids in chronic atopic dermatitis.

BACKGROUND: Previous reports indicate that IL-12 may be involved in the development of chronic atopic dermatitis. However, the cellular source of this cytokine in the skin and its expression during successful treatment of the skin lesions are not known. OBJECTIVE: Our purpose was to delineate the precise in situ localization of IL-12 and its modulation under topical treatment with corticosteroids. METHODS: Skin biopsy specimens were obtained from nonlesional, lesional, and treated skin of patients with atopic dermatitis and from healthy skin of nonatopic control subjects. IL-12 was investigated by real-time quantitative reverse transcriptase-PCR and immunohistochemistry. RESULTS: Expression of IL-12 p40 mRNA was significantly enhanced in lesional skin from atopic dermatitis and strongly down-regulated after treatment with topical corticosteroids for 9 to 10 days. In contrast, similar levels of IL-12 p35 transcripts were found in all the samples without any significant differences after treatment. In addition, a strong enhancement of IL-12 immunoreactivity was observed on the mononuclear cell infiltrate in the lesional skin samples, which was also markedly reduced after treatment. IL-12 immunoreactivity was mainly located in the cytoplasm of dermal dendritic cells and macrophages as well as some Langerhans cells. CONCLUSION: Our data suggest that the enhanced local production of IL-12 in dendritic cells and macrophages may be responsible for up-regulating production of IFN-gamma in chronic lesions and strengthen the idea that IL-12 may have a pivotal role in promoting inflammation in atopic dermatitis.

Administration, Topical↗
PubMed2000

Evidence for a role for IL-5 and eotaxin in activating and recruiting eosinophils in drug-induced cutaneous eruptions.

BACKGROUND: Cutaneous drug reactions may be associated with increased numbers of eosinophils in the blood and tissue. However, the factors leading to the generation of eosinophilia have not been fully delineated. OBJECTIVE: The aim of this study was to investigate the in situ expression of IL-5, eotaxin, RANTES, monocyte chemoattractant protein 3, and IL-8 together with the appearance of eosinophils in acute cutaneous drug reactions. METHODS: Skin biopsy specimens were obtained from drug-induced maculopapular exanthems (n = 9), from normal skin of control subjects (n = 9), and from the skin of patients with psoriasis (n = 8). The in situ expression of IL-5, eotaxin, RANTES, monocyte chemoattractant protein 3, and IL-8 was analyzed by using immunohistochemistry. Furthermore, the corresponding numbers of eosinophils were determined in the blood and skin sections. RESULTS: Compared with normal skin and psoriatic skin, a significantly higher number of eosinophils was found both in the blood and tissue of patients with a drug-induced exanthem. In comparison with normal skin, immunoreactivity for IL-5 and all the chemokines was also significantly enhanced in drug-induced exanthem, whereas significant differences in psoriatic were only observed for IL-5 and eotaxin. CONCLUSION: Our data indicate that IL-5 and eotaxin may particularly contribute to the activation and recruitment of eosinophils and thereby play an important pathogenic part in the development of skin inflammation in drug-induced maculopapular exanthems.

Chemokine CCL11↗
PubMed2000

Primary cutaneous cryptococcosis in a patient with systemic immunosuppression after liver transplantation.

We report a 36-year-old woman who slowly developed an ulceration on the left thigh 2 years after transplantation for Budd-Chiari syndrome. At this time point, the patient was treated with prednisone, tacrolimus and azathioprine for immunosuppression and with phenprocoumon and low-dose aspirin for anticoagulation in the presence of polycythemia vera. A biopsy of the skin lesion was obtained and revealed encapsulated yeast that was identified by microbiological and serological methods as Cryptococcus neoformans serotype D. The patient had no signs of systemic infection and a therapy with fluconazole (200 mg/day) was started. The lesion healed within 8 weeks and fluconazole was stopped after 3 months. Due to interactions between fluconazole, tacrolimus and phenprocoumon, the latter drugs were decreased to prevent toxicity. So far, 1 month after stopping fluconazole, no recurrence of skin lesions has been observed.

Adult↗
PubMed2000

Apligraf--a living human skin equivalent for the treatment of chronic wounds.

Apligraf, a manufactured living human skin equivalent, was the first true composite tissue analog to become commercially available. It has been approved by the FDA for the treatment of venous leg ulcers and diabetic foot ulcers. The tissue engineered bi-layered skin equivalent has both an epidermis and a dermis, which consist of keratinocytes and fibroblasts derived from neonatal foreskin and bovine collagen. The skin equivalent produces a great number of cytokines and growth factors and is immunologically well tolerated. The product is easy to handle in clinical use and can be applied in an outpatient setting.

Collagen↗
PubMed1999

[Erythema following malnutrition and exposure to sunlight].

We report the case of a 19-year-old female patient with a history of anorexia nervosa. The patient suffered from a burning, symmetrical and well defined erythematous rash with hyperpigmentation on light-exposed skin areas and pressure points. The patient's nutritional assessment revealed severe malnutrition with a low-protein and corn-based diet. The history of vitamin and protein deficiency, together with the typical cutaneous findings, confirmed the diagnosis of pellagra. The clinical features and pathogenesis of the disease are discussed.

Adult↗