ABSTRACT
Neonatal exposure to autoantigen is believed to induce effective antigen-specific T-cell tolerance in experimental models of autoimmunity. We have identified 120 kDa alpha-fodrin autoantigen in an animal model for primary Sjögren's syndrome (SS), that has been determined as a candidate autoantigen in both an animal model and the patients with primary SS. We demonstrate here that neonatal injection of autoantigen induce relevant tolerance when treated with intravenous (i.v.) administration within 24 h after birth, but not with i.v. injection after the thymectomy or with intraperitoneal injection. Autoantigen-specific T-cell response was significantly reduced in mice induced neonatal tolerance, and the activation markers of splenic CD4+ T cells were down-regulated in mice treated with neonatal administration. Because we detected that neonatal i.v. injection of autoantigen prevented Th1 response, it is possible that the autoantigen administration within 24 h after birth induce regulatory T cells that had a protective effect against Th1-mediated autoimmune diseases. These results indicate that the prevention of the spontaneous anti-120 kDa alpha-fodrin response in vivo, by tolerization of the autoantigen-reactive T cells, blocked the development of autoimmune lesions in an animal model for primary SS.
Subject(s)
Animals, Newborn/immunology , Autoantigens/toxicity , Autoimmune Diseases/immunology , Carrier Proteins/toxicity , Disease Models, Animal , Immune Tolerance/immunology , Microfilament Proteins/toxicity , Sjogren's Syndrome/immunology , Animals , Antigens, CD/biosynthesis , Autoantigens/administration & dosage , Autoantigens/immunology , Autoimmune Diseases/etiology , Carrier Proteins/administration & dosage , Carrier Proteins/immunology , Cytokines/biosynthesis , Female , Injections, Intravenous , Lymphocyte Activation , Mice , Mice, Mutant Strains , Microfilament Proteins/administration & dosage , Microfilament Proteins/immunology , Recombinant Proteins/administration & dosage , Recombinant Proteins/immunology , Recombinant Proteins/toxicity , Sjogren's Syndrome/etiology , Specific Pathogen-Free Organisms , Th1 Cells/immunology , Th1 Cells/metabolism , ThymectomyABSTRACT
Cellular DNA fragmentation can be induced in many biological instances without plasma membrane damage. The fungal metabolite, cytochalasin B, is capable of modifying numerous cellular functions related to DNA synthesis. In this work it is demonstrated that cytochalasin B is capable of inducing DNA fragmentation in a number of cells lines. This DNA fragmentation occurs before plasma membrane lysis and over a period of hours. Cytochalasin E and villin, agents that act on the microfilaments, also induce DNA fragmentation. Phorbol dibutyrate, a diacylglyceral analog, is able to inhibit cytochalasin B-induced DNA fragmentation in a dose-dependent fashion. These findings support the interpretation that cytochalasin B is inducing DNA fragmentation via its effect on the actin filaments.
