Induction of immune tolerance to FasL-expressing ES cell

Mc Lean Hospital (Belmont, Ma), Belmont MA

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Abstract

DESCRIPTION (provided by applicant): The potential of pluripotent embryonic stem (ES) cells to develop into functional mature cells or tissue has high implication in finding new treatments for diseases including neurodegenerative disorders. This includes the potential use of ES cells as cell replacement therapy in neurological diseases, such as Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS) and ischemia. However, survival of call grafts requires systemic immunosuppression, which severely compromises the entire host immune system leading to complications in clinical transplantation. An optimal therapy would be, therefore, the induction of specific tolerance to the donor cells by otherwise preserving functional immune responses. Fas ligand (FasL, CD178, or CD95L) is a type II membrane protein and is expressed in activated lymphocytes and cells in "immune-privileged" sites such as the testis, the eye, and the CNS. Its receptor Fas (CD95 or Apo-1), a type I membrane protein and a member of the TNF receptor family, is expressed on various immune-reactive hematopoietic cell types including activated NK and T calls, non-lymphoid calls such as immature myeloid cells, monocytes, and polymorphic mononucleocytes. Fas-expressing cells undergo apoptosis upon interaction with FasL, a process that is involved in regulating cellular immunity and it has been shown that FasL can be used as an immunomodulatory tool to protect allogeneic or xenogeneic cells against cellular immune responses. Here, I hypothesize that ES cell grafts in the brain, which express FasL, are protected against the host cellular immune response abolishing the need for systemic immunosuppressive drug treatment. For this, I will genetically engineer mouse ES cells to express FasL and test their survival ability in the host brain of rats without further immunosuppression. Furthermore, I will analyze the effects of FasL expression on transplanted cells towards modulating the host immune response. Results from this work will have implications for immunomodulation of ES cell grafts in both allogeneic and xenogeneic transplantation settings.