Autoimmunity and lymphoma development based on Id-driven T-B collaboration.
Patients with autoimmunity have 15-50% higher risk of developing cancer compared to general population. The physiopathology of the cancer in autoimmune patients is less understood. Understanding this physiopathology is important in treating the patients. Preclinical models that spontaneously develop autoimmunity and then progress into lymphoma are rare. Also the role of T cells in this process is not known. We have developed a double transgenic mice NocturnXtg46, which harbor both Id+ B cells and Id specific T cells. In previous study in the lab (described in FOTS 12387), NocturnXtg46 mice develop autoimmunity at around 4 months and as a result of chronic T-B collaboration, it develops lymphoma after 1 years. It happens spontaneously over time. In this application we aim to understand the lymphoma development from autoimmune phase by using cutting edge technologies like next generation sequencing. We hypotheses that the chronic interaction of helper T cells with autoimmune B cells result in lymphoma development. We also aim to develop new treatment approaches in treating and preventing lymphoma that develops from autoimmunity by blocking this interaction. Normal B cell when it undergoes spontaneous mutation along with T cell help can develop into autoimmune B cell. Even a single mutation can result in development of autoimmunity in healthy individual. We have made a new mouse strain called 'Island', which differs from Nocturn by just one aminoacid. When crossed with tg46, IslandXtg46 will normal and it needs to mutate to FRN to collaborate with Id specific T cells and develop autoimmunity. In double transgenic IslandXtg46 mice, we would like to test if the chronic T cell help could induce the mutation and autoimmunity.
NocturnXtg46 mice develops normally even it develops autoimmunity. When it develops lymphoma it will have mild pain and weight loss. The immunodeficient mice which are used in the application are expected to have moderate pain due to enlargement of lymphoid organs. All the mice will be monitored regularly using the scoresheet to reduce the harm to the mice.
Value to society: we have developed an animal model with very high relevance to the disease process that links human autoimmune disease and lymphoma. Patients with autoimmunity have higher risk of developing cancer. Our mice model have developed auto-antibodies already at three months of age and spontaneously developed lymphoma with age. This model will be useful in understanding the disease progression and developing novel treatment methods.
We will use a total of 600 mice in this project. We will reduce the animals in experiments to the absolute lowest necessary. We will use the cell lines whereever possible to reduce the mice numbers. In addition, we will reduce the cell dose in the transfer experiments in immunodeficient mice, so that we avoid a much exaggerated disease course, which would put more strain on the animals. We will complement our studies with assays of invitro characterization and expansion of the lines in culture.
NocturnXtg46 mice develops normally even it develops autoimmunity. When it develops lymphoma it will have mild pain and weight loss. The immunodeficient mice which are used in the application are expected to have moderate pain due to enlargement of lymphoid organs. All the mice will be monitored regularly using the scoresheet to reduce the harm to the mice.
Value to society: we have developed an animal model with very high relevance to the disease process that links human autoimmune disease and lymphoma. Patients with autoimmunity have higher risk of developing cancer. Our mice model have developed auto-antibodies already at three months of age and spontaneously developed lymphoma with age. This model will be useful in understanding the disease progression and developing novel treatment methods.
We will use a total of 600 mice in this project. We will reduce the animals in experiments to the absolute lowest necessary. We will use the cell lines whereever possible to reduce the mice numbers. In addition, we will reduce the cell dose in the transfer experiments in immunodeficient mice, so that we avoid a much exaggerated disease course, which would put more strain on the animals. We will complement our studies with assays of invitro characterization and expansion of the lines in culture.