TERT as immunological barrier to iPS derivatives transplantation
Embryonic stem cells have the remarkable potential to develop into many different cell types in the body during early life and growth. Unlike their mature descendants, stem cells have two important characteristics. First, they can give rise to many different cell types through cell division (self renewal), sometimes after long periods of inactivity. Second, under certain conditions, they can be induced to become tissue- or organ-specific cells, which themselves can then be used to repair and replace worn out or damaged tissues. Their use for clinical purposes is generally referred to as cell-based therapies. In 2006, researchers discovered the conditions that would allow specialized adult cells to be "reprogrammed" genetically to assume an embryonic stem cell-like state. This new type of stem cell is called induced pluripotent stem (iPS) cells.
Like any transplant, an immune reaction against iPS cell derivatives is a realistic obstacle to their numerous medical applications. For this reason it is important to understand the immunobiology of stem cell therapy (i.e., transplantation) in clinically relevant terms, that is to understand and control simultaneously the immunology of iPS cell derivatives and that of the immune system of a putative recipient.
A common trait to stem and iPS cells is that in order to sustain self-renewal, they depend on the activity of a nuclear enzyme called telomerase. Telomerase is gatekeeper of the integrity of chromosomes during cell replication. However, telomerase also contributes to the immortality trait of cancer cells. A component of this enzyme, the telomerase reverse transcriptase (TERT), is a cancer rejection antigen, meaning that cells of the immune system can recognize TERT expressed on cancer cells, resulting in their elimination (rejection).
In this proposal we posit that transplants of iPS cell derivatives in immunocompetent recipients may be subjected to immunological rejection through TERT. Herein, our goal is twofold. One is to validate the hypothesis that TERT serves as a rejection element in iPS cell derivatives. The other is to test a series of immunological maneuvers to specifically prevent or attenuate potentially adverse effects associated with immunological rejection after transplantation.
The two participant laboratories, [REDACTED] and [REDACTED], provide the project with formidable expertise in immunology and iPS cell biology, respectively. They will synergize with unique strength (1) to test the new hypothesis “TERT as a barrier to stem cell-based therapies”, and (2) to develop methods to abrogate or attenuate rejection following transplantation. This synergy is an important key feature of this application. We hope that the results from this study will not only uncover a heretofore-unknown aspect of stem cell immunology but also contribute to the future clinical applications of iPS cell-based therapies in humans.
The California Institute for Regenerative Medicine (CIRM) was established in 2004 with the passage of Proposition 71, which provided $3 billion in funding for stem cell research at California universities and research institutions to advance stem cell research and regenerative medicine, and discover and develop cures, therapies, diagnostics and research technologies to relieve human suffering from chronic disease and injury.
Not uncharacteristically CIRM’s start was plague by controversies and rocky times. Its first Request for Application (RFA) in May 2005 was to fund pre-doctoral students, post-doctoral students, and clinical fellows in California's universities, non-profit academic and research institutions, in stem cell research, clearly spelled the mission and a new philosophy. Five years later, whether or not measurable progress has been made, the creation of a culture for the Medicine of the 21st century is already clear indication of success.
The idea of connecting basic discoveries in stem cell research to clinical applications is new and unique to the California initiative. California is the primary beneficiary of this philosophical and technological investment. We see two direct, major positive effects for Californians. (1) California patients will be privileged once actual stem cell therapies are developed and ready to move to the bedside. This will create a positive wave in the general perception and awareness as to the position of California vis-à-vis the new Medicine at its medical institutions. (2) California will witness the growth of its technological/industrial infrastructure to develop new forms of treatment on the wave of new basic discoveries. This combination is powerful and dividends will be generated in due time in the form of revenues from health care delivery and intellectual property.
A 2008 editorial in Nature Stem Cell Biology asked "Isn't the California Institute of Regenerative Medicine (CIRM) out of business now that the Yamanaka and Thomson papers show human fibroblasts can be induced to pluripotency?”
Our position is that curing diseases and perfecting technologies that enable the cures, while protecting patients from harmful effects, will measure success. That time is still ahead and the possibly largest investment in medical research infrastructure in the history of California has yet to come to full fruition. The present RFA on the Stem Cell Transplantation Immunology is an example of the far reaching objectives of CIRM’s initiative, a way of embracing other life science disciplines into a comprehensive program to speed up knowledge and control over future therapies. California will be the first beneficiary of this process.