Epigenetic Inducible Treg Conversion for Transplant Immune Control
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Solution Overview
Problem
Current methods for generating regulatory T cells (Tregs) are inadequate, limiting their use in therapeutic applications such as suppressing immune responses in transplant recipients and treating autoimmune diseases.
Innovation Solution
A method is developed to convert non-regulatory T cells (non-Tregs) into inducible regulatory T cells (iTregs) using agents such as tryptophan catabolites, demethylating agents, and histone deacetylase inhibitors, in combination with TGFβ and bead-based expansion systems.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional methods are used to generate Tregs, then the process is simple, but the quantity and quality of Tregs produced is insufficient for therapeutic applications
Solution Approach 1:
The patent applies parameter changes by using chemical agents (demethylating agents, histone deacetylase inhibitors) and cytokine combinations (TGF-β, IL-2, IL-15) to transform non-Treg CD4+ T cells into iTregs. These chemical and biological parameters are systematically varied to optimize conversion efficiency and Treg stability, directly addressing the insufficiency of conventional Treg generation methods.
Solution Approach 2:
The invention employs composite treatment protocols combining multiple agents simultaneously: demethylating agents (e.g., 5-aza-2'-deoxycytidine), HDAC inhibitors (e.g., trichostatin A, suberoylanilide hydroxamic acid), and cytokine combinations (TGF-β with IL-2 and/or IL-15). This composite approach synergistically enhances Treg generation efficiency and functional stability.
2Productivity
If natural Treg cells are used, then they are stable and functional, but they are difficult to expand and maintain in sufficient numbers
Solution Approach 1:
The patent performs preliminary conversion of non-Treg CD4+ T cells into iTregs using demethylating agents and HDAC inhibitors before expansion. This preliminary epigenetic reprogramming primes the cells for stable Treg phenotype maintenance during subsequent expansion phases, allowing large-scale production while preserving functional stability.
Solution Approach 2:
The invention implements continuous treatment with TGF-β, IL-2, and IL-15 during the conversion and expansion process to maintain Treg stability throughout culture. This continuous cytokine support ensures sustained expression of Treg markers (CD25, FoxP3) and functional properties, enabling long-term expansion without phenotypic drift.
3Reliability
If immunosuppressive drugs are used to prevent rejection, then graft rejection is prevented, but the drugs have dangerous side effects and require lifelong maintenance
Solution Approach 1:
The patent creates functional copies of natural Treg cells through in vitro conversion of CD4+ T cells into iTregs using chemical and biological agents. These engineered iTregs replicate the immunosuppressive function of natural Tregs (preventing graft rejection and GVHD) without the harmful side effects of conventional immunosuppressive drugs, offering a cell-based therapeutic alternative.
Data Source
AI summary
The present invention provides methods and compositions for converting non-Tregs into Tregs. The converted Tregs are referred to as inducible Tregs (iTregs). The iTregs are useful for preventing, suppressing, blocking or inhibiting an immune response. For example the iTregs are useful for preventing rejection of a transplanted tissue in a human or other animal host, or protecting against graft vs host disease. The iTregs can also be used to treat autoimmune diseases.