Managing and preventing allogeneic immune rejection of human embryonic stem cell-derived transplants
New Faculty Physician Scientist
$3 096 000
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.
Statement of Benefit to California:
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.
Executive Summary Allogeneic transplantation of neural stem cells (NSCs) derived from human pluripotent stem cell lines is a promising therapeutic approach for treating neurodegenerative disorders and spinal cord injury. However, there are several barriers to the successful implementation of this type of therapy. The focus of this proposal is overcoming one of the principle bottlenecks: the ability of NSCs to escape allogeneic immune detection. The applicant intends to develop a set of assays to measure in vitro alloreactivity and utilize a humanized mouse model to evaluate in vivo immune rejection of NSC lines, study the duration and intensity of immune suppression required for successful engraftment of NSCs, and test new immune suppression strategies that may induce local tolerance to transplanted NSCs. The ultimate goal is to develop tailored immune suppression protocols based on immune reactivity of grafts and to minimize the immunogenicity of the grafts in order to reduce the immune suppression burden. Research Plan - The proposed research is based on sound scientific rationale, focuses on an important and poorly understood bottleneck to therapeutic cell transplantation, and has a logical but not overly ambitious research plan. - The primary concern is the lack of sophistication of the immunology. The approaches to address this bottleneck and the tools the applicant proposes to develop do not represent the state of the art in transplantation biology, and the assays proposed are unlikely to be sensitive enough to produce information that could be used clinically to minimize the immunogenicity of the cell grafts. - The applicant does not propose a sufficiently detailed analysis of the immune response. - The proposed animal model is not a replica of the human system, and it is unlikely that the type of assessments proposed in the model will successfully predict the human situation and inform the type and duration of immune suppression that should be used in the clinical setting. - Reviewers like the inclusion of elements of the immune response that might be present in diseased, but not healthy patients. - The applicant has the appropriate resources in place to complete the described research. Principal Investigator - This candidate is firmly established in his/her area of expertise with an excellent publication and funding track record. This proposal represents a change of direction into a new area of expertise, and the career development plan does not adequately describe how the candidate will develop his/her career in this new area. - It is not clear from the mentoring plan how the existing relationship with the mentor would be enhanced by this award. Institutional Commitment - The institution has made an appropriate commitment to this candidate, and there is excellent collaborative potential in the environment. - The institution has an outstanding track record in promoting physician scientists and is firmly committed to the future of translational stem cell research. Responsiveness - The scope of the proposed research is clearly responsive to the RFA, but the candidate minimally meets the criteria for a new investigator. This seems more like a well-established investigator using this RFA to expand his/her expertise into a new area rather than advancing the career of an early stage investigator.