Expanding Double Negative Regulatory T Cells Using Irradiated PBMCs
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Solution Overview
Problem
Current methods for expanding human double negative regulatory T cells (DN Tregs) are limited in scale and effectiveness, hindering their clinical application in treating diseases such as cancer, allograft rejection, and autoimmune disorders.
Innovation Solution
A method for large-scale ex vivo expansion of human CD4−CD8− regulatory T cells (DN Tregs) is developed by culturing them with antigen-presenting cells (APCs), specifically αβ-TCR+, CD56−, or γδ-TCR+, which enhances their suppressive function and cytotoxicity against cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If DN Tregs are cultured with allogeneic monocyte-derived dendritic cells, then DN Tregs can be generated, but the number of DN Tregs generated is very limited
Solution Approach 1:
The patent changes the culturing parameters by using irradiated allogeneic peripheral blood mononuclear cells (PBMCs) instead of monocyte-derived dendritic cells, and by adding specific cytokines (IL-2, IL-7, IL-15) to the culture medium. These parameter changes enable large-scale expansion of DN Tregs while maintaining their regulatory function, resolving the contradiction between generating DN Tregs and producing sufficient numbers for clinical use.
2Quantity of substance
If DN Tregs are expanded for clinical use, then therapeutic numbers can be produced, but the method must maintain safety by not inducing GVHD or harming normal cells
Solution Approach 1:
The patent utilizes the presence of irradiated allogeneic PBMCs, which would normally be harmful and induce GVHD, as a beneficial tool for expanding DN Tregs. The irradiation prevents these cells from causing harm while their antigen-presenting capacity promotes DN Treg expansion. This converts a potentially harmful factor into a beneficial expansion tool, allowing large-scale production of therapeutic DN Tregs without inducing GVHD or harming normal hematopoietic cells.
Data Source
AI summary
There is provided herein a method for expanding human CD4−CD8− regulatory T cells (DN Tregs) from a population of cells comprising DN Tregs, comprising: culturing the population of cells with artificial antigen presenting cells (APCs), preferably the DN Tregs are αβ-TCR+CD56− or alternatively γδ-TCR+.