Injection of bleomycin in newborn mice induces autoimmune sialitis that is transferred by CD4 T cells

Abstract

Bleomycin (BLM) induces cellular apoptosis or necrosis by producing reactive oxygen species, and has been used to induce scleroderma in adult mice. We wondered whether BLM induces the same pathological phenotype in newborn mice as in adult mice. BLM was subcutaneously administrated to newborn BALB/c mice. At 1 month of age, BLM-treated mice showed severe destruction of salivary glands with enlargement of nearby lymph nodes. These nodes contained CD4 + T cells and B220 + cells with high expression of MHC class II molecules. In addition, autoantibodies were detected by HEp-2 staining and western blotting. The cell transfer experiments were performed to evaluate the role of autoimmune phenomena in these pathological changes. Following the transfer of enriched CD4 + T cells to 1-month-old BALB/c nude mice, the salivary glands were severely damaged with CD4 + T cell and B220 + cells infiltrations. The number of T-cell antigen receptor Vb 8.3 + CD4 + T cells was significantly increased in BLM-treated murine spleen. These findings will provide new insights into the causal factors of environment in autoimmunity and the relationship between autoreactive CD4 + T cells and autoantibodies.

Inhibition of bleomycin-induced pulmonary fibrosis through pre-treatment with collagen type V

“…42 The formation of fibrosis is associated with autoimmune mechanisms in bleomycin-induced experimental systemic sclerosis. 43,44 Autoimmunity to collagen has also been reported in IPF patients and after bleomycin treatment. 11,45,46 Bleomycin may provoke and aggravate inflammatory responses, which is supported by the finding that bleomycin amplifies the inflammatory response induced by pneumonectomy and promotes severe lung fibrosis.…”

A genetic approach to the prediction of drug side effects: bleomycin induces concordant phenotypes in mice of the collaborative cross

“…More recently, in addition to lung fibrosis, it is now recognized that subcutaneously injected bleomycin can cause a scleroderma-like condition with autoimmune attributes 17,18. This model of human systemic scleroderma suggests that an early step in the catabolism of bleomycin results in the generation of reactive oxygen species in vascular endothelial cells and smooth muscle causing these cells to die by apoptosis or necrosis 19. Dead or dying cells liberate hyaluronan and HMGB-1 protein that can activate B-cells, CD4 T cells, and possibly macrophages via toll receptors TLR2 and TLR4 to produce profibrogenic cytokines such as IL-6 and TGF-β, resulting in local fibrosis.…”