Inhibition of cytokine-induced expression of T-cell cytokines by antihistamines.

OBJECTIVE: To investigate immunomodulatory properties of 4 antihistamines available in Japan. METHOD: Isolated peripheral blood T cells from healthy volunteers were preincubated with cetirizine, loratadine, olopatadine, or fexofenadine for 30 minutes and then stimulated with interleukin (IL)-1 2 or IL-4 to skew immune response towards type 1 or type 2 helper T cells. RNA was extracted 6 hours later and semiquantitative reverse transcription polymerase chain reaction (RT-PCR) was performed using primers for IL-5 and interferon (IFN) gamma. Supernatants were collected 24 hours after stimulation, and cytokine production was quantified by enzyme-linked immunosorbent assay (ELISA). RESULTS: RT-PCR revealed that IL-12-induced expression of IFN-gamma was partially suppressed by loratadine and fexofenadine and that all 4 agents tested inhibited IL-4-induced expression of IL-5. ELISA demonstrated that IL-12-induced IFN-gamma production was significantly suppressed by cetirizine and fexofenadine and IL-4-induced IL-5 production was downregulated by three agents with the exception of cetirizine. This study demonstrates that antihistamines have varying immunomodulatory properties, suggesting treatment choice for atopic dermatitis can be directed by disease signs and symptoms.

Immunohistochemical detection for nuclear beta-catenin in sporadic basal cell carcinoma.

BACKGROUND: Despite the increasing incidence of basal cell carcinoma (BCC), its pathogenesis has remained largely unknown. Recently, it was reported that genes involved in tissue morphogenesis, such as sonic hedgehog or patched, were found to be mutated in BCC, suggesting the involvement of those molecules in the pathogenesis of this tumour. Furthermore, there is evidence that the Wnt-mediated signalling pathway may be one of the downstream targets of sonic hedgehog-mediated signalling, which has led us to focus on molecular events on the Wnt pathway in BCC. Among the signal transducers involved in the Wnt pathway, it is clear that beta-catenin plays a pivotal role in the promotion of morphogenesis and cell growth. In respect to this, it has been reported that, in particular circumstances, as in colorectal cancers, beta-catenin migrates to the nuclei, where it exerts an ability to activate the transcription of various genes. OBJECTIVES: To investigate the cellular distribution of beta-catenin in skin tumours, in particular, in BCC. METHODS: Twenty skin biopsy specimens derived from BCC, 10 from inflammatory skin diseases and five from squamous cell carcinomas were immunostained with an antibody directed against beta-catenin. RESULTS: Fourteen of the 20 BCC samples tested showed nuclear localization of beta-catenin, while none of the other samples gave rise to positive nuclear staining. CONCLUSIONS: Nuclear localization of beta-catenin is a characteristic feature of BCC; this suggests its tumorigenic role in this tumour. This gives us a further insight into the molecular pathogenesis of BCC.

A case of acral lentginous melanoma: the correlation between CD95L expression on melanoma cells and apoptosis of tumor infiltrating lymphocytes.

There is an increasing amount of evidence that melanoma cells express the ligand for CD95 (CD95L), a potent inducer of apoptosis which contributes to creating the immune privileged circumstances of tumor sites. However, it still remains to be demonstrated whether the capacity of melanoma cells to express CD95L is acquired during the progression. We addressed this question with a case of acral lentiginous melanoma by employing immunostaining using an antibody directed against CD95L as well as by in situ TUNEL staining. H&E-staining of tumor specimens revealed that there were two different growth patterns. The central part of the tumor showed a deeper invasion into the dermis (Breslow thickness >4 -mm). The horizontally growing edge of the tumor proliferated more superficially (Breslow thickness<3-mm). Relatively fewer lymphocytes were observed around the melanoma nests in central areas, which expressed detectable amounts of CD95L. In contrast, more lymphocytes were observed among the melanoma cells in the peripheral lesion, where CD95L was not detected. To evaluate the relevance of the CD95L expression, in situ TUNEL staining was performed. This indicated a significant correlation of lymphocyte apoptosis with CD95L expression on melanoma cells. Together the data suggest that expression of CD95L is turned on depending on the level of melanoma, and that it may tribute to creating immune privileged circumstances by initiating apoptosis of tumor filrating lymphocytes.

Detection of HTLV-I proviral DNA in sarcoidosis.

'Sarcoidosis-lymphoma syndrome' is known as an association of sarcoidosis with malignant lymphoma. We report a 56-year-old woman with systemic sarcoidosis who was seropositive for antibody against human T cell lymphoma/leukemia virus type I (HTLV-I). This patient showed integration of HTLV-I proviral DNA within cutaneous sarcoid nodules, but not in peripheral blood mononuclear cells. Neither atypical lymphocytes nor a T cell receptor beta1 gene rearrangement were observed in peripheral blood mononuclear cells or in cutaneous nodules, indicating that the patient did not have a smouldering type of adult T cell lymphoma/leukemia. Detection of integration of HTLV-I proviral DNA in cutaneous sarcoid nodules could suggest that the sarcoid nodules might have been generated as a protective response to chronic stimuli of HTLV-I.

Disseminated scleroderma of a Japanese patient successfully treated with bath PUVA photochemotherapy.

BACKGROUND: Localized scleroderma is known to be resistant to therapies. Recently, it has been reported that bath PUVA photochemotherapy is effective for treating this dermatosis. OBJECTIVES: Although according in earlier reports mainly white populations have been treated successfully with bath PUVA therapy, there is little knowledge of whether it is effective in treating colored populations. We treated a 64-year-old Japanese woman suffering from disseminated scleroderma with bath PUVA photochemotherapy to see its effects. CONCLUSION: Although rather high cumulative UVA doses were required for this patient compared with those needed in earlier reports, no adverse effects were observed. The lesions were markedly improved, suggesting that this therapeutic modality is well-tolerated and useful for colored patients such as the Japanese. Furthermore, it turns out that the thermographical assessment is useful to estimate clinical improvement of this sclerosing skin disorder.

The successful treatment of diffuse neonatal hemangiomatosis with flashlamp pulsed dye laser.

Diffuse neonatal hemangiomatosis is a rare disease with the distinctive features of multiple hemangiomas of the skin and visceral organs. These lesions have been treated with systemic corticosteroids, interferon-alpha, and their combination. We report a patient with diffuse neonatal hemangiomatosis who had multiple cutaneous and hepatic hemangiomas. Single therapy with the flashlamp pulsed dye laser was effective for cutaneous hemangiomas, whereas the hemangiomas of the liver remained stable and no liver dysfunction or hemorrhage has occurred so far, even with no treatment.

Pyoderma gangrenosum associated with biphenotypic acute leukemia.

Pyoderma gangrenosum is a neutrophilic dermatosis that may be associated with myeloid malignancies. Less information is available about the association of pyoderma gangrenosum with lymphoid malignancies. We present, to our knowledge, the first case of pyoderma gangrenosum associated with biphenotypic acute leukemia wherein the malignant cells show a phenotype specific for myelogenic and lymphocytic leukemia. Histopathologic examination revealed rather nonspecific features without involvement of leukemic cells in the skin lesions. Treatment with systemic steroids was followed by characteristically rapid healing of the skin lesion.

Inhibition of growth of melanoma cells by CD95 (Fas/APO-1) gene transfer in vivo.

Interaction of CD95 ligand with its cognate receptor CD95 induces apoptotic cell death. Alterations in this pathway within tumor cells can result in escape from apoptosis and from immune surveillance. Melanoma cells recently were found to escape an immune attack via high expression of CD95 ligand, thereby inducing apoptosis of activated T lymphocytes. When screening four human melanoma cell lines for expression of CD95 and CD95 ligand, respectively, an inverse correlation was found, i.e., cells expressing high levels for CD95 ligand (CD95L(high)) were almost negative for CD95 and vice versa. Since coexpression of CD95 and CD95 ligand may lead to apoptosis by autocrine suicide or fratricide, it was tested whether overexpression of CD95 in CD95L(high) melanoma cells results in apoptotic cell death. Upon transfection with a cytomegalovirus-promoter-driven expression vector encoding the CD95 gene, CD95L(high) melanoma cells underwent apoptosis at a much higher level than CD95L(low) melanoma cells. Apoptosis appeared to be due to the activation of CD95 as cell death was inhibited by cotransfection with a dominant negative mutant for the CD95 signaling protein, Fas-associated protein with death domain. Tumor progression of CD95L(high) melanoma cells transplanted into nude mice was significantly reduced when recipient animals were injected with liposomes containing the CD95 expression vector. As demonstrated by immunohistochemistry and TUNEL staining, in vivo transfected tumor cells expressed CD95 and underwent apoptotic cell death. Hence, this study indicates that delivery of the CD95 gene inhibits tumor growth in vivo and thus might be a therapeutic strategy to treat tumor cells that express high levels of CD95 ligand. J Invest Dermatol 115:1008-1014 2000