For the promise of stem cell transplantation therapy to treat or cure human disease to be realized, the key problem of stem cell transplant rejection must be solved. Yet, despite over three decades of research in human embryonic stem cells, little is known about the factors involved in immune system tolerance to grafts derived from embryonic stem cells.

The goal of our CIRM Stem Cell Transplantation Immunology Award is to overcome this formidable hurdle by generating pre-clinical mouse models that have human immune systems. This cutting-edge model system will provide a testing platform to evaluate the importance of matching immune system components, known as human leukocyte antigens (HLAs), between the human embryonic stem (hES) cell-derived neural stem cell (NSC) graft and the patient. Because mouse and human immune systems are fundamentally different, these next-generation ‘humanized’ mice are currently the only animal models within which to conduct our stem cell brain transplant experiments. Such models rely on immunocompromised mice as recipients for human umbilical cord blood stem cells (HSCs). These mice go on to develop a human immune system, complete with HLAs, and can subsequently be used to engraft embryonic stem cell-derived brain cells that are either HLA matched or mismatched and to monitor for graft acceptance vs. rejection.

During this no-cost extension (year 4) of CIRM funding, we have addressed both Specific Aims 2 and 3, and have specifically answered the following questions: 1) is the HLA-A haplotype important to match in order to prevent brain stem cell rejection, and 2) what are the transcriptome profiles of mouse vs. human compartments? In response to question 1, we have determined that HLA-A is expressed at significantly higher levels in NSCs than the other HLA components, which makes this HLA type the critical player in immune system acceptance-rejection. As evidence of this, ‘humanized’ mice transplanted with NSCs expressing completely mismatched HLA-A elicited an immune response. Regarding question 2, we were able to accomplish a new technique utilizing RNA sequencing technology on brain sections from ‘humanized’ mice engrafted with human NSCs. Additionally, in collaboration with Dr. George Liu from Cedars-Sinai Medical Center, we utilized ‘humanized’ mice to successfully model another disease that has become a threat to Californians’ health: skin infection by Staphylococcus aureus. While mice are generally not susceptible to this ‘human selective’ disease, ‘humanized’ mice did respond to the infection, closely mimicking the skin lesions observed in humans. A manuscript has recently been submitted detailing this work to the Journal of Experimental Medicine.