Genetically Modified Cells for Local Immunosuppression
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Solution Overview
Problem
Current methods for preventing immune rejection of transplanted cells, such as those derived from human embryonic stem (ES) cells or induced pluripotent stem (iPS) cells, are inadequate due to systemic immunosuppression and the need for lifelong drug administration, which comes with increased risks of cancer and infections.
Innovation Solution
Genetically modifying cells to express a set of transgenes that provide local immunosuppression at the transplant site, including PD-L1, HLA-G, Cd47, Cd200, FASLG, Ccl21, Mfge8, and Serpin B9, to mitigate antigen presenting cell activation, graft attacking leukocyte activity, and local inflammatory responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If systemic immune suppression is used to prevent immune rejection, then immune rejection is reduced, but the risk of cancer and infections increases
Solution Approach 1:
The patent divides the immunosuppression function into local segments at the transplant site rather than applying systemic immunosuppression throughout the body. Genetically modified cells express immunosuppressive molecules (PD-L1, HLA-G, FASLG, etc.) specifically at the transplantation site, creating localized immunosuppressive zones that protect the graft without suppressing the entire immune system.
Solution Approach 2:
The patent implements local quality by making the immunosuppression property localized to the transplant site through genetic modification of the transplanted cells themselves. These cells constitutively express immunosuppressive molecules that create a protective microenvironment only where needed, leaving the rest of the body's immune system fully functional.
2Reliability
If genetically modified cells with multiple transgenes are used, then local immunosuppression is achieved, but device complexity increases
Solution Approach 1:
The patent merges multiple immunosuppressive functions into a single genetically modified cell type. The transplanted cells simultaneously express multiple immunosuppressive molecules (PD-L1, HLA-G, FASLG, CD200, etc.), combining several protective mechanisms in one integrated solution rather than using separate treatments for each function.
Solution Approach 2:
The patent makes the transplanted cells universal and multi-functional by genetically modifying them to perform both their primary therapeutic function and multiple immunosuppressive functions simultaneously. The same cell population that provides the therapeutic benefit also creates the immunosuppressive microenvironment through constitutive expression of various immunosuppressive molecules.
Data Source
AI summary
A cell genetically modified to comprise at least one mechanism for providing a local immunosuppression at a transplant site when transplanted in an allogeneic host is, and methods for making and using the same is provided. The cell comprises a set of transgenes, each transgene encoding a gene product that is cytoplasmic, membrane bound, or local acting, and whose function is one or more of: to mitigate antigen presenting cell activation and function; to mitigate graft attacking leukocyte activity or cytolytic function; to mitigate macrophage cytolytic function and phagocytosis of allograft cells; to induce apoptosis in graft attacking leukocytes; to mitigate local inflammatory proteins; and to protect against leukocyte-mediated apoptosis.