Tolerance induction using fetal multilineage hematopoietic stem cells
The human immune system is usually considered to act defensively, recognizing and reacting against invading elements from the outside world. Although such a protective response is often required (for instance, to defend against the entry and spread of infectious agents), it can also prevent the engraftment of foreign cells that might otherwise provide help (for instance, stem cells from an unrelated donor that could be provided as part of a therapy). The goal of this proposal is to find a way to permit such transplants to be tolerated and accepted when necessary. Our experimental strategy is instructed by the single occasion during each of our lives when we must tolerate the presence of “foreign” cells: the time when we are in the womb, in close contact with our related but genetically distinct mother. In recent experiments, we have discovered that this is a time when our immune systems include large numbers of so-called “regulatory T cells,” or Tregs. These cells are generated so that they can suppress the immune response of the fetus against the mother, allowing for a full-term pregnancy to take place without problems. Importantly, we have found that such Tregs are derived from a blood-forming stem cell in the fetus that is distinct from the one that is found after birth. Thus, the fetal stem cell gives rise to an immune system that confers tolerance and prevents an immune response against the mother, whereas the adult stem cell gives rise to an immune system that reacts against anything that is foreign (including cells from the mother). We wish to learn how to isolate the fetal stem cell, preferably from discarded umbilical cord blood, and to learn how to use it after birth so that tolerance to foreign stem cell grafts can be conferred. Two investigators and their respective teams with long experience in human immunology and in stem cell biology, as well as in the use of preclinical models to study stem cell transplantation, will collaborate on these studies. Using resources from CIRM as well as those leveraged from their existing programs, this team will carry out a milestone-driven program to test the feasibility of this approach. Should it work, the next step will be to optimize and to bring this novel approach to the clinic so that it might benefit those in need of stem cell grafts from unrelated donors for a myriad of currently untreatable diseases.
The proposed research will benefit the State of California and its citizens in three ways:
• It will immediately leverage existing resources to support a multidisciplinary, multi-site, in-State collaboration that is likely to discover new knowledge in an efficient manner. Such collaborations form the basis for bench-to-bedside research and are best facilitated by goal-oriented programs such as that envisioned by the CIRM request for applications.
• Pursuit of this project may move a novel strategy for inducing tolerance to stem cell grants to the clinic, thereby expanding the use of such grafts to a much larger population of patients in need. In particular, our proposed approach could open the door to the development of multiple new stem cell therapies that might be carried out in the absence of lifelong immunosuppression. This step, in turn, would likely encourage creative new applications of stem cells for an even broader constellation of human diseases than previously imagined.
• Finally, the knowledge that is obtained could form the basis of a preclinical effort that would garner the input of additional support from non-State (e.g., venture capital) sources while also generating new jobs and taxable income for those in the State. If, for instance, preliminary data from this series of studies appear promising, a much larger infusion of resources would be required to realize the full potential of the proposed strategy. Since our approach will be applicable to all forms of allogeneic stem cell transplantation into humans, the potential demand for its use would be large and the chances for successful pursuit of additional resources should be correspondingly high. To the extent that such resources are forthcoming, new jobs and additional taxable revenues for the State will follow.