Abstract. The ability of cultured human fibroblasts to reorganize and contract three dimensional collagen I gels is regarded as an in vitro model for the reorganization of connective tissue during wound healing. We investigated whether adhesion receptors of the integrin family are involved . It was found that synthesis and transcription of the a2ß1 integrin (but not of a,ß, or a3ß1) is selectively upregulated when fibroblasts are seeded into type I collagen gels . Time course experiments revealed that high synthetic levels of a2ß, parallel the gel contraction process and return to "baseline" levels after the contraction has subsided . Furthermore, function-blocking mAbs directed to the a2 and ß, chain of integrins inhibited gel contraction.Remodelling of connective tissue can be important for tumor cells during invasion and formation of metastases . Therefore, we tested human melanoma cell T HE reorganization of collagen by fibroblasts is an important function in wound healing which leads to wound contraction and finally helps to reestablish organ integrity. The ability ofcultured fibroblasts to reorganize and contract three-dimensional collagen I gels (Bell et al., 1979) is considered as an in vitro model for wound contraction. Previous studies have described in detail the influence of cytokines (Gullberg et al., 1990), the requirement of protein synthesis and of an intact cytoskeleton for this process (Mauch, 1986 ; Guidry and Grinnell, 1985) . Seeding of fibroblasts into a three-dimensional collagen lattice results in major changes oftheir morphology (Tomasek et al., 1982), their protein and collagen metabolism (Mauch et al., 1988) as well as in their response to cytokines (Nagakawa et al., 1989). However, little is known, so far, about the role of extracellular matrix (ECM)1 receptors on the fibroblast surface for this function. Recently, evidence has been provided lines for this function . Five out of nine melanoma lines contracted collagen gels in vitro. Among these, two highly aggressive melanoma cell lines (MV3 and BLM) most efficiently contracted gels almost reaching the rate of normal adult fibroblasts. In these cells, synthesis of a2ß, was also significantly upregulated when seeded into collagen I gels . Moreover, function blocking anti-a2 in conjunction with anti-ßt chain mAbs completely inhibited gel contraction for several days.Other melanoma cells (530) with lower metastatic potential which were not able to contract gels, showed no induction of a2ß1 synthesis in gel culture. Our results suggest an important role of integrin a2ß, in the contraction of collagen I by normal diploid fibroblasts during wound healing and in the reorganization of collagen matrices by highly aggressive human melanoma cells.
No abstract
Psoriasis is a chronic skin disease affecting about 2% of the Caucasian population, characterized by co-existing inflammation and epidermal hyperproliferation. A T-lymphocyte-mediated autoimmune reaction induced by bacterial superantigens might be central in its pathogenesis. To model psoriasiform inflammation, we transplanted clinically uninvolved skin from psoriatic patients onto SCID mice. Repetitive intradermal injections with a bacterial superantigen and simultaneous intraperitoneal injections with the patients superantigen-stimulated peripheral mononuclear blood cells resulted in an inflammatory reaction exhibiting some of the hallmarks of psoriasis, e.g. epidermal hyperproliferation, papillomatosis, focal neo-expression of ICAMI, and an exocytotic T-lymphocytic infiltrate characterized by the expression of the cutaneous lymphocyte-associated antigen. These observations document the potential of superantigens to trigger psoriasiform dermatitis and provide a model to study lymphocyte homing.
Preferential usage of certain T-cell receptors by the lymphocytic infiltrate in psoriasis might indicate the involvement of an antigen in the pathogenesis of this disease. However, to date there are no data on the complete T-cell-receptor V alpha and V beta repertoire in psoriatic patients. We therefore compared the usage of T-cell-receptor variable regions in blood and skin of 10 patients with chronic plaque-stage psoriasis by means of semiquantitative polymerase chain reaction. Additionally, HLA class II alleles were analyzed by means of sequence-specific oligonucleotide typing. A considerable restriction of the T-cell-receptor repertoire was observed in the skin, where up to 20% of the variable regions present in the blood were not detectable. This was true for both alpha- and beta-chains. However, no interindividually constant pattern of T-cell-receptor restriction was deducible. Inconsistently, a certain preferential usage of some beta chains occurred within the cutaneous compartment. This report on the complete T-cell-receptor V alpha and V beta repertoire in psoriasis documents the restricted receptor repertoire of infiltrating T cells and a lack of enrichment of superantigen-associated V beta regions. Thus superantigens seem not to play a pathogenetically relevant role in chronic plaque-stage psoriasis.
Although the etiology of alopecia areata is still unknown, evidence has accumulated to support an autoimmune pathogenesis for this disease. To evaluate the role of T cells in alopecia areata the T-cell receptor VB-repertoire was investigated in lesional skin and blood of 5 patients by means of a semiquantitative technique based on the reverse transcriptase polymerase chain reaction. Three patients with androgenetic alopecia served as controls. Amplification products were screened for clonality by temperature gradient gel electrophoresis. Four of 5 patients with alopecia areata exhibited a lesional T-cell receptor-repertoire characterized by an almost exclusive utilization of variable regions beta 2, 4, and 13. Temperature gradient gel electrophoresis revealed the oligoclonal constitution of the infiltrate. The restricted nature of the lesional T-lymphocytic infiltrate in alopecia areata strongly suggests that an antigen-specific T-cell response plays an important role in the pathogenesis of this disease.
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