Alloantigen-Specific Treg Expansion via CD40-Activated B Cells
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Solution Overview
Problem
Current methods for generating human antigen-specific regulatory T cells (Treg) on a large scale are hindered by the limitations of dendritic cells, including rarity, heterogeneity, and high costs, with no effective way to expand them in vitro, and existing protocols often result in global immune suppression and non-specificity.
Innovation Solution
A novel method using co-culture of naïve CD4+CD25− T cells with human allogeneic CD40-activated B cells without exogenous cytokines to induce and expand alloantigen-specific Treg, which are CD45RO+ and CCR7− memory cells expressing CD25 and Foxp3, facilitating their use in clinical immunotherapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If dendritic cells are used to expand antigen-specific Treg on large scale, then Treg induction can be achieved, but the process is hindered by rarity, heterogeneity, high costs, and inability to expand DCs in vitro
Solution Approach 1:
The patent replaces the original dendritic cell system with a copied alternative system using B cells that have been engineered to express dendritic cell markers and functions. This copying approach allows Treg expansion without the limitations of primary DCs, achieving large-scale production while maintaining the desired immunological effects.
Solution Approach 2:
The patent fundamentally changes the cell type parameter from dendritic cells to B cells, while modifying the B cells to acquire dendritic cell-like properties through marker expression. This parameter change enables scalable Treg production by using a cell type that can be expanded in vitro without the rarity and cost issues of DCs.
2Productivity
If polyclonal Treg are expanded with repeated stimulation by CD3 and CD28 mAbs or artificial APCs, then large numbers of Treg can be produced, but global immune suppression occurs
Solution Approach 1:
The patent applies local quality by making the Treg expansion antigen-specific rather than polyclonal. The B cells present specific alloantigens to T cells, inducing Treg that are specific to those antigens. This localized, specific approach avoids the global immune suppression caused by polyclonal expansion while maintaining sufficient Treg quantities for therapeutic effect.
3Manufacturing precision
If antigen-specific Treg are induced by co-culture with allogeneic monocyte-derived DCs, then antigen specificity can be achieved, but the process is expensive and laborious
Solution Approach 1:
The patent replaces expensive, laborious monocyte-derived DC production with a cheaper, simpler B cell system. The B cells can be expanded in vitro without the complex differentiation protocols required for DCs, reducing both cost and labor while maintaining antigen-specific Treg induction capability.
Data Source
AI summary
Methods for inducing, expanding, and/or generating alloantigen-specific regulatory T cells. Alloantigen-specific regulatory T cells can be induced, expanded, and/or generated from naive CD4+CD25− T cells by using CD40-activated B cells. The regulatory T cells can be human T cells. In one embodiment, the alloantigen-specific human regulatory T cells can be CD4highCD25+Foxp3+ regulatory T cells.