CAR Treg Cells for Immune Rejection Prevention
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Solution Overview
Problem
Current methods for transplanting human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) face challenges due to immune rejection, requiring immunosuppressive drugs with adverse side effects, and the rarity of antigen-specific regulatory T cells (Tregs) that can induce immune tolerance.
Innovation Solution
The use of chimeric antigen receptor (CAR) T regulatory cells (Tregs) that recognize natural or artificial antigens not expressed on the implanted cells, tissues, or organs, but are present nearby or co-administered, to induce immune tolerance and prevent rejection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immunosuppressive drugs are used to prevent rejection of transplanted cells, then immune rejection is reduced, but adverse side effects increase
Solution Approach 1:
The patent introduces a third party - antigen-specific regulatory T cells - as an intermediary to mediate between the immune system and the transplanted cells. These Tregs specifically recognize antigens on the transplanted cells and suppress immune responses against them, replacing the need for non-specific immunosuppressive drugs that cause widespread adverse effects.
Solution Approach 2:
The invention employs antigen-specific regulatory T cells that provide localized, targeted immunosuppression only at the transplant site and against specific alloantigens, rather than systemic immunosuppression. This local quality approach allows immune protection of the graft without the broad adverse effects of conventional immunosuppressive drugs on the entire organism.
2Reliability
If antigen-specific regulatory T cells are used to induce immune tolerance, then immune rejection is reduced, but cell availability decreases due to rarity
Solution Approach 1:
The patent employs preliminary action by pre-expanding antigen-specific regulatory T cells ex vivo before transplantation. This allows rare antigen-specific Tregs to be cultured and multiplied in advance to achieve therapeutic doses, overcoming the limitation of their natural scarcity in the donor's bloodstream.
Solution Approach 2:
The invention uses copying by generating multiple copies of rare antigen-specific Tregs through ex vivo expansion. A small number of initial antigen-specific Tregs are isolated and then proliferated in culture to produce sufficient numbers for therapeutic administration, effectively copying the rare cell population to achieve required quantities.
3Reliability
If CAR Tregs are used to protect transplanted cells, then immune rejection is reduced, but risk of CAR Treg-mediated toxicity increases
Solution Approach 1:
The patent applies parameter changes by modifying the CAR Treg design to express inhibitory cytokines such as IL-10 or TGF-beta instead of cytotoxic molecules. This changes the functional parameters of the CAR Tregs from cytotoxic effector cells to immunosuppressive regulatory cells, protecting the graft while avoiding toxicity through altered molecular expression profiles.
Solution Approach 2:
The invention converts the potential harm of CAR Treg cytotoxicity into benefit by engineering the CAR Tregs to produce immunosuppressive cytokines. The same targeted recognition capability that could lead to toxicity is redirected to produce protective immunosuppression, turning a potential harmful mechanism into a beneficial therapeutic effect.
Data Source
AI summary
The present disclosure is directed to method for the generation and use of regulatory T cells (Tregs) in the prevention and treatment of graft/transplant rejection. In particular, the method employs engineered CAR Treg cells that protect transplanted materials from rejection.