Veto-ing the Rejection of Allogeneic HSCs

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DESCRIPTION (provided by applicant): The transplantation of allogeneic hematopoietic stem cells (HSC) has become an important treatment for malignant diseases. Allogeneic HSC transplantation (HSCT) is being used to provide cures for other hematological and also some metabolic diseases. Allogeneic HSCT represents the infusion of fully or partially histo-incompatible HSCs, which are rejected by the recipient's immune system. Harsh conditioning regimens of the recipient are used to overcome graft rejection in spite of numerous complications. New protocols are being sought that are less toxic and at best short-term; yet prevent rejection with similar if not improved efficacy. Isogenis' mission has been the development of innovative immune inhibitory agents that employ highly specific, yet effective immune suppression approaches. Isogenis based its technology on the natural veto immune inhibitory phenomenon. Rather than infusing donor-derived CD8+ T cells to suppress allogeneic immune responses, Isogenis' engineered veto uses the transfer of the CD8 a-chain to attach specific immune suppression activities to tissues with the goal to protect them from rejection. Isogenis' scientists established the overall feasibility of this veto approach. Engineered antibodies and different gene transfer vectors, veto vectors (VV), were used to demonstrate that surface expression of the CD8 a-chain inhibited T lymphocyte responses in vitro and in vivo and ultimately protected pancreatic islets from rejection in fully allogeneic recipient mice. Isogenis proposes to examine whether bone marrow (BM)-derived cells can be engineered into effective veto cells with the help of Isogenis' VVs. It will be investigated whether engineered veto cells prevent the rejection of allogeneic HSCs. If successful, this strategy will allow the transplantation of highly purified HSC preparations. The removal of donor-derived T cells will avoid graft-versus-host disease (GVHD) that are only detrimental in the case of HSCTs for non-malignant diseases, but will no longer result in increased graft failure rates. Isogenis also proposed to study whether BM-derived engineered veto cells can be used to protect donor-matched solid organs from rejection. If successful, Isogenis will only have to deal with a single cell population as regulated product rather than with each respective transplant organ. The transplantation of bone marrow from unrelated donors has become an important treatment for malignant diseases. Its also is being used to provide cures for other hematological and also some metabolic diseases. However, present immune suppression regimens used for organ transplantation are fraught with significant immediate and chronic side effects that make their use especially problematic for children. Isogenis is developing novel immune suppressive compounds that are less toxic, and are used short-term; yet prevent the rejection of transplanted tissue with similar if not improved efficacy.