The Immunobiology of Stem Cell Transplantation

2006 proved to be an important turning point in the history of the UK since, for the first time, the number of people retired exceeded the number of children at school. While such a landmark may appear subtle, it heralds a new era in modern medicine necessary to deal with the increasing prevalence of diseases commonly associated with old age, such as macular degeneration, diabetes and Parkinson!
s disease. Given that embryonic stem cells (ESC) have the capacity to spawn any one of the 200 or so types of cells that make up the human body, they have been widely acclaimed to be the answer to the shortage of organs and tissues for transplantation, needed to deal with this rising tide of degenerative diseases. Nevertheless, their use poses some of the same problems that have confounded whole organ transplantation over the past 30 years, while raising further problems besides. As is the case for an organ from either a living or deceased donor, tissues grown from ESC will be recognised as foreign and vigorously rejected by the host!
s immune system. Unlike conventional tissues, however, ESC are closely related to cancer cells and may, therefore, pose an additional risk of turning into tumours once implanted into patients. Furthermore, the intervention required to prevent rejection and ensure survival of the tissue may substantially increase the risk of a patient developing cancer. Our recent research has uncovered a previously unappreciated property of tissues differentiated from ESC: their capacity to actively repel an immune response targeted against them. While these findings are good news for helping to outwit the host!
s immune response, they may also prevent the immune system from identifying and destroying any cells hidden within the tissue that are on the verge of turning cancerous. The purpose of our current research is, therefore, to quantify the risks involved by constructing tissues for grafting known to contain defined numbers of these rouge cells and investigating whether or not they can be sought out and destroyed by the host!
s immune system. The outcome of this project will be critical for informing strategies for the use of ESC-derived tissues that will maximise the therapeutic value for patients while minimising the risks involved.

Proposals to embark on the first Phase I clinical trials of cell replacement therapy (CRT) using tissues differentiated from human embryonic stem cells (ESC) have brought into sharp focus the technological barriers that still need to be addressed to maximise efficacy and minimise any risks to patients. In particular, the immunogenicity of tissues differentiated from allogeneic ESC remains a significant obstacle which threatens to undermine the likely benefits of regenerative medicine. Furthermore, the potential for rare cells, contained within the graft, to become tumorigenic remains a substantial concern. Our previous work, funded by the MRC, is of relevance to both of these issues, since it demonstrated unequivocally that tissues differentiated from mouse ESC display a fragile propensity for immune privilege due, in part, to their constitutive expression of TGF-?O2, capable of polarising infiltrating T cells towards a Treg phenotype in an antigen-specific fashion. Although the privileged status of these tissues is only sufficient to repel an immune response across a minor histocompatibility barrier, it is important for several reasons: we have, for instance, demonstrated how it is possible to exploit these natural properties to establish transplantation tolerance across far greater immunological barriers, including a full MHC disparity. Conversely, by affording a microenvironment conducive the regulation, tissues derived from ESC may protect any transformed cells they harbour from immune surveillance and immunological destruction: indeed, the induction of tolerance required to secure acceptance of the very tissue itself may paradoxically increase the risk of tumorigenesis. Here we propose to exploit well-established models of CRT, together with a comprehensive panel of mouse ESC, first derived through MRC funding, to quantify the risks involved and to compare the ability of two strategies for tolerance induction to spare immune responses to immunogenic antigens sequestered within the tissue. Furthermore, we propose to determine whether the properties we have uncovered for mouse ESC are shared by induced pluripotent stem cells (iPSC), thereby predisposing them towards tolerance induction but conferring on them the capacity to nurture tumour growth. Finally, in anticipation of the need for clinical translation of these findings, we propose to adapt our preclinical models to investigate the immune privileged properties of ESC and iPSC of human origin.