ABROGATION OF EXPERIMENTAL AUTOIMMUNE GASTRITIS IN A DOUBLE TRANSGENIC MOUSE MODEL

Mark Biondo, Ban Hock Toh and Frank Alderuccio

Department of Pathology and Immunology, Monash University Medical School, Melbourne, Victoria, 3181

Autoimmune gastritis is a CD4+ T cell mediated disease directed against the gastric parietal cell associated H/K ATPase. The H/K ATPase beta-subunit has been identified as the initiating autoantigen as expression within the thymus renders mice (IE-H/Kb tg) resistant to EAG induction. To determine if local inflammatory signals within the stomach are capable of inducing autoimmune response, we have generated transgenic mice expressing GM-CSF under the control of the gastric H/K ATPase beta-subunit promoter (PC-GMCSF tg). These mice develop EAG complete with autoantibodies and a T cell response to the gastric H/K ATPase. In this study we have crossed disease prone PC-GMCSF and resistant IE-H/Kb tg mice and assessed mice for the development of EAG. PC-GMCSF X IE-H/Kb double transgenic mice do not develop disease, lacking parietal cell autoantibodies and cellular destruction within the gastric mucosa. They do however maintain a cellular infiltrate within the gastric mucosa, which is composed mainly of macrophages and dendritic cells. Therefore, even in the presence of an inflammatory signal capable of inducing autoimmunity, the lack of effector cells renders the individual resistant to disease induction.

THE "HOLY GRAIL" OF AUTOIMMUNITY

Ban.Hock. Toh, Kim. Murphy, Mark. Biondo and Frank Alderuccio

Department of Pathology and Immunology, Monash University Medical School, Melbourne, Victoria, 3181

The "Holy Grail" of autoimmunity is a "targeted therapy that would specifically destroy the pathogenic clones responsible for autoimmune damage" (Mackay and Rose, 1998). A prÈcised understanding of the pathogenesis of autoimmunity and in particular the identification of the causative autoantigen is essential for achieving this goal. In the case of autoimmune gastritis, we have identified the gastric H/K ATPase beta-subunit as the causative autoantigen targeted by the pathogenic CD4 T cells. We showed that transgenic mice that expressed the initiating autoantigen in the thymus driven by a MHC class II promoter were completely resistant to induction of gastric autoimmunity. Further, we showed that tolerance to autoantigen was established in thymus. These experiments have prompted us to attempt to realise the "holy grail" by transplanting bone marrow cells from these transgenic mice to appropriately pre-conditioned mice with autoimmune gastritis. The rationale of these experiments is that the bone marrow stem cells can be expected to seed the thymus and develop into T cells and tolerogenic dendritic cells that express the causative autoantigen. For these experiments, we have produced a second set of transgenic mice that spontaneously develop autoimmune gastritis following expression of GM-CSF in the stomach driven by a stomach-specific promoter. This is a particularly rigorous model to test the validity of our approach since the environmental trigger for autoimmunity (GM-CSF in this model) is ever present in the stomach. Before bone marrow transfer, the mice were pre-conditioned by total body irradiation to deplete lymphocytes from the thymus and periphery and to make "space" in the bone marrow for engraftment by donor bone marrow cells. The mice were also treated with depleting anti-CD4 antibody to "clear" the periphery of pathogenic CD4 T cells before bone marrow transfer.