Stem Cell Transplantation using Psoralen treated T-lymphocytes

Funding Type: 
Transplantation Immunology
Grant Number: 
RM1-01715
Investigator: 
ICOC Funds Committed: 
$0
Public Abstract: 
While stem cell transplants of bone marrow have cured many patients, immune rejection of stem cell grafts, as well as the development of graft versus host disease remains a challenge. Immunosuppressive therapies have led to significant improvement in the survival of these patients, as well as patients receiving solid organs from donors. However, these treatments are non-specific and increase the risks for long term negative outcome. We propose a novel approach for inducing robust, and sustained tolerance of stem cell transplants, with the potential to be of major benefit not only for bone marrow stem cell replacement therapies, but also for regenerative medicine of other tissues. Our research has shown that we were able to overcome matching requirements in bone marrow transplants in the mouse, when we added miss-matched white blood cells (T-cells) treated with a chemical called psoralen to stem cells. This approach promoted stable engraftment of both bone marrow and cordblood derived stem cells, and avoided graft versus host disease. Our current data suggests that our protocols modulate the properties of the immune system in the recipient. In this proposal we aim to clarify the mechanisms that govern these changes. We speculate that modulation of the immune system by partially replacing bone marrow using our protocols may induce specific tolerance towards donor stem cells. This in turn may lead to graft acceptance, may modulate auto-immunity, and open a new opportunity for the successful cell therapy of a variety of diseases, as it leads to stable engraftment rather than rejection. These studies will have a major impact on clinical transplantation in sickle cell anemia as it addresses the acute lack of suitable donors. Partly mismatched units can overcome current compatibility barriers, prevent GVHD, and promote donor engraftment. Our proposed research will use human and murine stem cells in combination with psoralen treated T-cell add-back technology to: • Improve protocols to facilitate hematopoietic stem cell transplant in poorly matched donor-recipient pairs, with full T- and B- cell reconstitution. • Define the reprogramming of the host immune system to accept stem cell grafts, and optimize tolerance induction to stem cell derived grafts via hematopoietic and/or thymic chimerism. Our proposed studies will render a better understanding of the development of immune tolerance of pluripotent stem cell derivatives, the potential correction of autoimmunity, and will form the basis for a novel approach to improve clinical stem cell transplantation.
Statement of Benefit to California: 
While stem cell transplants of bone marrow have cured many patients, immune rejection of stem cell grafts, as well as the development of graft versus host disease remains a challenge. Immunosuppressive therapies have led to significant improvement in the survival of these patients, as well as patients receiving solid organs from donors. However, these treatments are non-specific and increase the risks for long term negative outcome. A better understanding of the mechanisms that lead to stable engraftment of stem cells to replace or restore tissues lost to injury or disease represents one of the most promising outcomes of regenerative medicine. We propose a novel approach for inducing robust, and sustained tolerance of stem cell transplants, with the potential to be of major benefit not only for bone marrow stem cell replacement therapies, but also for regenerative medicine of other tissues. Our research has shown that we were able to overcome matching requirements in bone marrow transplants in the mouse, when we added miss-matched white blood cells (T-cells) treated with a chemical called psoralen to stem cells. This approach promoted stable engraftment of both bone marrow and cordblood derived stem cells, and avoided graft versus host disease. Our current data suggests that our protocols modulate the properties of the immune system in the recipient. In this proposal we aim to clarify the mechanisms that govern these changes. We speculate that modulation of the immune system by partially replacing bone marrow using our protocols may induce specific tolerance towards donor stem cells. This in turn may lead to graft acceptance, may modulate auto-immunity, and open a new opportunity for the successful cell therapy of a variety of diseases, as it leads to stable engraftment rather than rejection. These studies will have a major impact on clinical transplantation in a variety of diseases that affect the residents of California. One such example with immediate benefit are patients with the sickle cell anemia as our study addresses the acute lack of suitable donors. Partly mismatched units can overcome current compatibility barriers, prevent GVHD, and promote donor engraftment. Our proposed research will use human and murine stem cells in combination with psoralen treated T-cell add-back technology to: • Improve protocols to facilitate hematopoietic stem cell transplant in poorly matched donor-recipient pairs, with full T- and B- cell reconstitution. • Define the reprogramming of the host immune system to accept stem cell grafts, and optimize tolerance induction to stem cell derived grafts via hematopoietic and/or thymic chimerism. Our proposed studies will render a better understanding of the development of immune tolerance of pluripotent stem cell derivatives, the potential correction of autoimmunity, and will form the basis for a novel approach to improve clinical stem cell transplantation.

© 2013 California Institute for Regenerative Medicine