Year 2

In order for stem cell therapies to proceed, it will be essential that the regulation of immune responses to the stem cell derived tissues be achieved. While the function of the immune system in protection from Infections Is essential throughout life, some Immune reactions are undesirable. Illnesses due to autoimmunity, in which the immune system attacks one’s own body, instead of only germs that cause infection, are common. Examples of autoimmune diseases that are amenable to stem cell based therapies include Type I diabetes caused by abnormal immune responses directed against the Insulin producing cells and multiple sclerosis (MS) caused by Immune responses that attack the nervous system. Another type of undesirable immune response is the attack on transplanted tissues, leading to rejection. Control of immune reactions is the major impediment to successful organ transplantation, and is highly likely to be an obstacle to therapeutic uses of stem cells.

We are evaluating a stem cell based strategy to control the editing of the immune response to both treat autoimmunity and permit stem cell-derived tissues to be transplanted. Members of the International (California and Australia) team have collaborated on the Isolation of the stem cells that give rise to specialized thymic epithelial cells (TEC), which control immunity by editing the developing T cells in the thymus before they get released into the bloodstream. Therefore, we hypothesize that by transplanting new TEC, we can control the immune response by permitting different T cells to be produced. Because TEC are always being replaced, It has become necessary for us to focus on identifying TEC stem cells, which can produce new TEC continuously. The TEC stem cells continue to make new TEC for at least 6 months. We are now comparing two ways to isolate these TEC stem cells by either making them from embryonic stem cells or by isolating them from a donor thymus. We have also developed mouse models for MS and for stem cell rejection which can be controlled by modification or suppression of the immune system. We have tested a new antibody-based approach to control autoimmune reactions against nervous system tissue in a model of MS, and for control of rejection of transplanted stem cells. The antibody-based approach improved the course of experimental MS, but by itself was unable to protect stem cells from rejection. Therefore, we are now evaluating additional therapies to augment the effect of the antibody approach to control autoimmunity or rejection.