Human Immune System Mouse models as preclinical platforms for stem cell derived grafts

A major obstacle to stem cell based therapies is the immune response of the patient to stem cell derived tissue, which can be recognized as foreign and attacked by the patient's immune system. Humanized mouse models have considerable potential as test beds for exploring different therapeutic approaches, because they allow for human cells to be observed and manipulated experimentally. This proposal takes advantage of the most recent innovations in microscopic imaging to probe the interactions between developing T cells and their support cells in living 3D tissues, and thus inform therapeutic strategies to promote the acceptance of stem cell grafts. In the first year of funding we have examined human T cell development in living thymus tissue, and have begun characterization of T cell development in humanized mice in which human thymocytes develop with mouse support cells.

A major obstacle to stem cell based therapies is the immune response of the patient to stem cell derived tissue, which can be recognized as foreign and attacked by the patient's immune system. T cells orchestrate immune responses and are "educated" about self versus foreign in an organ called the thymus. It may be possible to educate T cells in a patient to avoid attacking stem cell derived grafts by "re-educating" them in a thymus that contains the same material as the graft. Humanized mouse models have considerable potential as test beds for exploring different therapeutic approaches, including thymic re-education approaches because they allow for human cells to be observed and manipulated experimentally. This proposal aims to refine humanized mouse models to allow for different therapeutic strategies to promote the acceptance of stem cell grafts by a patient's immune system to be modeled and tested. This proposal takes advantage of the most recent innovations in microscopic imaging to probe the interactions between developing T cells and their support cells in living 3D tissues. In addition to probing thymic development, in the future these approaches could be further adapted to reveal the cellular events that occur when stem cell derived grafts are accepted or rejected, and to allow for preclinical testing of drugs. The successful completion of this project will bring us closer to realizing the benefits of stem cell research by providing a viable humanized immune system mouse model for preclinical testing of stem cell-based therapies.

A major obstacle to stem cell based therapies is the immune response of the patient to stem cell derived tissue, which can be recognized as foreign and attacked by the patient's immune system. T cells orchestrate immune responses and are "educated" about self versus foreign antigen in an organ called the thymus. It may be possible to educate T cells in a patient to avoid attacking stem cell derived grafts by "re-educating" them in a thymus that contains the same material as the graft. To better understand how human T cells develop and improve the systems we currently use to mimic this process in the laboratory, we examined two complementary models of human thymocyte development: humanized immune system (HIS) mice and human thymic slices. Taking advantage of the most recent innovations in microscopic imaging, we examined and manipulated the interactions between developing human T cells and their support cells in living 3D tissues. Using small molecule inhibitors in our slice model, we identified signals immature T cells use to find their way in the thymus. Comparing our HIS model to human samples, we also found differences in non-conventional T cell development. In sum, our models provide a platform for dissecting the signals necessary for selection of diverse T cell lineages.