Previous studies led us to demonstrate in pathological situations that the fibroblast, not the macrophage, was the terminal maturation step of the HLA-DR monocyte and that the entire process came under T-lymphocyte control. Fibrosis which developed under immunosuppressive treatment (cyclosporin) after organ transplantation is an illustration of these in vitro observations. The present in vitro study was undertaken in order to investigate whether or not this transformation process takes place under physiological conditions and if so, the nature of the T-lymphocyte control. We report that normal HLA-DR monocytes/macrophages are able to secrete type 1 collagen and to differentiate into neo-fibroblasts. However, contrarily to what happened in pathology, only a few neo-fibroblasts developed transiently. The addition of conditioned medium (CM) from activated T-lymphocytes greatly enhanced the transformation process. Counteracting this CM effect, cell-to-cell contact between neo-fibroblasts and T-cells resulted in the loss of fibroblastic shape. The 'end-result' macrophage engulfed numerous lymphocytes giving rise to a multinucleated cell. This giant cell no longer adhered to the slide and died. The question is raised as to whether the process observed in vitro is involved in vivo in tissue repair. We also report that HLA-DR monocytes and the neo-fibroblasts which derive from them are able to secrete, in addition to type 1 collagen, a variety of proteins such as uromodulin, amyloid-beta peptide, alpha-fetoprotein and carcinoembryonic antigen. In cystic fibrosis we previously reported a high level of uromodulin production by HLA-DR monocytes differentiating towards the fibroblastic phenotype. Pathologies characterized by excessive production of either alpha-feto-protein, carcinoembryonic antigen, beta-amyloid protein (Alzheimer's disease) should be investigated, taking into account the involvement of HLA-DR monocytes and their possible uncontrolled differentiation into neo-fibroblasts.