Managing and preventing allogeneic immune rejection of human embryonic stem cell-derived transplants
The use of human embryonic stem cells (hESCs) to regenerate damaged nervous system tissues is theoretically exciting but has practical obstacles. One major obstacle is allogeneic rejection, whereby recipient immune cells reject donor cells possessing foreign human leukocyte antigens (HLA). To manage allogeneic rejection, clinical HLA Labs have designated tests, such as cross-matching and HLA typing, to help organ transplant doctors match donor organs to recipients. These tests also help to create an immune suppression protocol to allow the foreign organ to survive immunologic destruction. Currently, there are no standard laboratory tests or protocols to manage the hESC transplant recipient. Since the immune system may view hESC-derived cells differently from solid organs, our proposed aims will develop clinical tests and protocols to facilitate the routine use of hESC-derived cells in allogeneic transplants for tissue regeneration. Specifically, we will adapt HLA Lab protocols to hESC-derived cells. Moreover, we will use a humanized mouse model whereby hESC-derived neural stem cells will be transplanted into the spinal cord or brain of mice with a human immune system. This model will allow us to investigate the mechanisms of allogeneic rejection of hESC-derived tissues while devising immune suppression protocols to prevent immune allogeneic rejection. If successful, our studies will hasten the use of stem cells in the treatment of diseases such as neurodegeneration.
By providing strategies to prevent and manage allogeneic rejection of transplanted tissues, our research will benefit patients in need of regenerative medicine. Our specific model uses neural stem cell transplants into humanized mice, and thus our studies stand to benefit patients with neurologic disease such as patients with Alzheimer’s disease, Parkinson’s disease, spinal cord traumatic disease, amyotrophic lateral sclerosis, chronic ischemic stroke, and perinatal neurologic dysfunction. Moreover, since the research will also explore mechanism of immunologic rejection of transplanted foreign tissues, the studies may benefit organ transplant recipients such as those with end-stage renal, liver, heart, pancreatic, or intestinal diseases. In fact, we envisage that any patient in need of a stem cell graft would benefit from the technology developed in our research. Aside from the enormous potential to enhance the health of California residents, our research could also lead to an economic impact for California. We expect huge savings in the cost of healthcare for these patients, since many of them suffer from chronic incurable diseases. Another economic boon from our proposed studies takes the form of licensing opportunities and start-up companies, which would augment the number of jobs in California while bringing in new revenue.