No abstract

To investigate the differentiation and activation of monocytes, the combined effects of 1,25-dihydroxyvitamin D3 (D3) and IL-4 on human blood monocytes were examined with respect to expression of MHC class-II antigens, accessory activity, and phagocytic capacity. IL-4 was reported to upregulate the expression of MHC class-II antigens and accessory activity of monocytes. The experiments described here demonstrate that D3 inhibits the expression of all three subtypes of MHC class-II antigens (HLA-DR, -DP and -DQ) as well as the accessory activity of monocytes, both in a dose- and time-dependent manner. However, D3 enhances the immunoglobulin- and complement-dependent phagocytosis by monocytes in a dose- and time-dependent manner. When monocytes are treated with both IL-4 and D3, the effects of D3 are reverted by IL-4, suggesting that IL-4 induces the development of monocytes into accessory cells, whereas D3 stimulates differentiation of monocytes into classical macrophages. These findings provide further evidence for the contention that, depending on defined stimuli, monocytes may develop either into accessory cells or into classical macrophages.

Lichen planus is assumed to represent a delayed hypersensitivity reaction, in the course of which cytokines control the proliferation and differentiation of cytotoxic T lymphocytes which attack the epidermis and cause apoptosis of undifferentiated keratinocytes. Since interferon-gamma and interleukin 6 are known to be markedly generated in lichen planus, we investigated the cellular localization of these cytokines in affected skin/oral mucosa biopsy specimens using in situ hybridization for interferon-gamma and in situ reverse transcription-polymerase chain reaction for interleukin 6 mRNA. In the upper subepithelial connective tissue interferon-gamma mRNA was noted within proliferating CD3+ T lymphocytes. In this tissue compartment interleukin 6 mRNA was detected in infiltrating CD4+ and CD8+ T lymphocytes. In the epithelium, expression of interferon-gamma mRNA and interleukin 6 mRNA was observed in the basal and suprabasal keratinocytes of altered skin/oral mucosa. In contrast, normal skin did not reveal any interferon-gamma or interleukin 6 expression, although a few CD4+ and CD8+ T lymphocytes were noted in the dermis as well as the epidermis. These findings indicate that in lichen planus the proinflammatory cytokines interferon-gamma and interleukin 6 are produced not only by activated T lymphocytes but also by altered keratinocytes, and suggest that stimulated keratinocytes may amplify the course of lichen planus.

No abstract

Malignant melanoma has been shown to be susceptible to T cell-mediated immunity and, therefore, is a candidate for vaccination approaches. Clinical trials using dendritic cells (DC) loaded with peptides corresponding to tumor antigens are ongoing in several institutions, and some promising results have already been published. However, every single peptide-based vaccine can only be used in a patient with a given single HLA type, and this strategy is not appropriate for patients with rare HLA types or with tumors without defined antigens. A clinical pilot study in patients with disseminated melanoma refractory to standard therapy was initiated using a different approach. The authors generated autologous monocyte-derived DC and fused these DC with gamma-irradiated primary autologous tumor cells by incubation in polyethylene glycol. In previous experiments, the authors had shown that these fused cell products are potent inducers of a T-cell response in a mixed lymphocyte tumor cell culture. Seventeen patients were immunized with the cell product by s.c. injection in monthly intervals without any serious side effects. Of these patients, one had a partial response with decrease in size of all evaluable tumor manifestations. In one patient, some of the metastases were regressing despite an overall progressive disease, and one patient achieved disease stabilization for six months. In the responding patient, in parallel to tumor regression, circumscript hair depigmentation occurred. These data show, that a hybrid vaccine of DC and tumor cells can be safely applied and can induce tumor regressions, however, the clinical efficacy of the approach in its present form is insufficient.