Engineered Support Cell Compositions for Localized Graft Tolerance
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Solution Overview
Problem
Current immunosuppressive therapies for organ transplantation are inadequate for long-term graft survival, leading to graft rejection and complications due to immune recognition, and there is a need for a universally compatible solution to expand the organ supply and reduce the reliance on lifelong immunosuppression.
Innovation Solution
Engineered support cells, such as fibroblasts and endothelial cells, expressing immunomodulatory proteins like PD-L1, provide localized immunotolerance through a controllable inducible system, decoupled from parenchymal cells, to inhibit immune responses and promote graft acceptance.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If systemic immunosuppressive medications are used to prevent graft rejection, then graft acceptance is improved, but the risk of infections and cardiovascular disease increases
Solution Approach 1:
The patent applies local quality by delivering immunosuppressive activity directly to the graft site through engineered support cells expressing PD-L1, rather than using systemic immunosuppressants. This localized approach provides graft acceptance protection while minimizing harmful effects to the rest of the body, such as increased infection and cardiovascular risk.
Solution Approach 2:
The patent uses an intermediary mechanism by employing engineered support cells as mediators between the graft and the immune system. These cells express PD-L1 to provide immunosuppressive activity locally, acting as a bridge that prevents rejection without requiring systemic medication.
2Duration of action of stationary object
If lifelong immunosuppression is maintained to prevent graft rejection, then graft survival is improved, but the quality of life and risk of complications increase
Solution Approach 1:
The patent applies self-service by designing a self-sustaining system where engineered support cells continuously express PD-L1 to provide long-term immunosuppression. The cells maintain their immunomodulatory function without requiring external intervention or lifelong medication, potentially enabling graft survival without compromising quality of life.
Solution Approach 2:
The patent ensures continuity of useful action by using engineered support cells that persist in the graft microenvironment and continuously provide PD-L1 expression. This continuous localized immunosuppression maintains graft survival over time without the need for intermittent or lifelong systemic medication.
3Adaptability or versatility
If allogeneic transplants are performed to expand organ supply, then the pool of available organs is improved, but the immune response against the graft increases
Solution Approach 1:
The patent applies universality by creating a universal approach that can be applied to various allogeneic and xenogeneic transplants. The engineered support cells expressing PD-L1 provide a universally compatible solution for immunosuppression across different graft types, expanding the pool of available organs without requiring HLA matching.
Solution Approach 2:
The patent inverts the traditional approach by instead of suppressing the entire immune system, it specifically targets and inhibits the immune response at the graft site through PD-L1 expression on support cells. This inverted strategy allows the rest of the immune system to remain functional while controlling rejection.
4Reliability
If parenchymal cells are engineered to provide immunosuppression, then localized immunotolerance is improved, but the manipulation complexity increases
Solution Approach 1:
The patent applies segmentation by separating the immunosuppressive function from the parenchymal cells. Instead of engineering the functional cells (parenchymal cells) to provide immunosuppression, the patent uses separate support cells (fibroblasts, endothelial cells) to express PD-L1. This segmentation simplifies the manipulation process as support cells are easier to engineer and maintain.
Solution Approach 2:
The patent uses support cells as intermediaries to provide the immunosuppressive function. These intermediary cells express PD-L1 and mediate the interaction between the immune system and the graft, simplifying the overall system by using cells that are easier to manipulate rather than the functional parenchymal cells.
Data Source
AI summary
Immunotolerant engineered human tissue constructs are provided that are suitable for implantation into subjects. In some embodiments, the immunotolerance is controllable by an inducible system. Methods of making and using the immunotolerant engineered tissue constructs are provided.