T Regulatory Cell Generation via Thymic Microenvironment Recapitulation
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Solution Overview
Problem
Current protocols for generating T regulatory cells (Tregs) in vitro do not produce clinically relevant numbers of Treg cells and often result in loss of suppressive activity, making them inadequate for clinical use.
Innovation Solution
The method involves obtaining pluripotent stem cells and exposing them to thymic medullary epithelial cells, followed by culturing and providing conditions for differentiation and expansion of T regulatory cells, thereby recapitulating the normal developmental process of Treg cells in vitro.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If current protocols for Treg expansion are used, then Treg cells can be generated, but the numbers produced are insufficient for clinical use and suppressive activity is lost
Solution Approach 1:
The patent applies preliminary action by pre-establishing the thymic microenvironment with thymic medullary epithelial cells, thymic stromal cells, and thymic dendritic cells before introducing pluripotent stem cells. This pre-prepared thymic niche enables proper Treg differentiation and maintains suppressive activity, resolving the contradiction between generating sufficient Treg numbers and preserving their functional potency.
Solution Approach 2:
The patent uses thymic medullary epithelial cells, thymic stromal cells, and thymic dendritic cells as intermediary cells that mediate the differentiation and functional development of Treg cells from pluripotent stem cells. These intermediary cells provide the necessary signals and microenvironment to generate clinically relevant numbers of Tregs while maintaining suppressive activity.
2Productivity
If protocols are used to hyperaccelerate Treg generation, then the number of Treg cells increases, but suppressive activity is lost
Solution Approach 1:
The patent applies parameter changes by optimizing the thymic microenvironment parameters including the ratio of thymic medullary epithelial cells to stromal cells, the presence of specific cytokines (TGF-beta, IL-7, IL-15), and the developmental stage of thymic dendritic cells. These parameter optimizations enable efficient Treg generation while preserving suppressive activity, avoiding the loss of function that occurs with hyperacceleration protocols.
Data Source
AI summary
Compositions of matter and means useful for treatment of autoimmunity and/or transplant rejection through generation of T regulatory cells in a manner that recapitulates thymic development. Methods of seeding thymic medullary epithelial cells with pluripotent stem cells such as inducible pluripotent stem cells, followed by exposure to conditions allowing for selective growth and expansion of T regulatory cells. T regulatory cells can be scaled for clinical utilization through the use of three-dimensional adhesive growth matrices as well as addition of FoxP3 inducing cytokines such as interleukin-2.