Year 1

In order 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 governing immune system tolerance to grafts derived from these 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 next-generation model system will provide a testing platform to evaluate the importance of matching immune system components known as human leukocyte antigens (HLAs). Because mouse and human immune systems are fundamentally different, these cutting-edge ‘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 first year of CIRM funding, we have accomplished three main goals leading to completion of Specific Aim 1: To establish mouse models with human immune systems (year 1). Firstly, we have increased purity of HSCs from 75% to 93%. This has enabled us to complete our second goal of generating 10 mice bearing 50% or more human immune cells. Thirdly, we have characterized the human adaptive immune systems of these mice and have found presence of 40-60% of human T lymphocytes in lymphoid organs of ‘humanized’ mice.