CD73 Expression in DP8α Tregs for Acute GvHD Risk Prediction
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Solution Overview
Problem
Current treatments for acute graft-versus-host disease (aGvHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) are inadequate, with steroids being the first-line treatment but associated with complications, and there is a need for non-invasive and reliable methods to predict and treat aGvHD.
Innovation Solution
Identify and measure the CD73 expression level of a novel T regulatory cell subset, DP8α Tregs, characterized by a CD3+/CD4+/CD8α LOW/CCR6+/CXCR6+ phenotype, to predict aGvHD risk and treat it by modulating their activity through immunosuppressive agents or infusions of DP8α Tregs and their target antigens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If allogeneic hematopoietic stem cell transplantation is performed to treat hematologic malignancies, then curative potential is improved, but graft-versus-host disease risk increases
Solution Approach 1:
The patent extracts and removes regulatory T cells from the donor stem cell population before transplantation. This selective removal eliminates the suppressive function that protects target organs from graft-versus-host disease, thereby reducing the risk of GVHD while preserving the anti-tumor activity of the remaining T cells
Solution Approach 2:
The patent introduces a novel ex vivo culture system as an intermediary processing step between donor cell collection and patient transplantation. This culture system uses specific growth factors and conditions to selectively eliminate regulatory T cells while enriching for effector T cells, serving as a mediator that transforms the cell composition to reduce GVHD risk
2Object-affected harmful factors
If regulatory T cells are present in donor stem cells to protect against graft-versus-host disease, then safety is improved, but anti-tumor activity decreases
Solution Approach 1:
The patent selectively extracts regulatory T cells from the donor cell population through ex vivo culture. This removal eliminates the harmful suppressive effect on anti-tumor T cells while maintaining the protective function against GVHD through other mechanisms in the modified cell product
Solution Approach 2:
The patent changes the functional parameters of the T cell population by culture conditions that selectively eliminate regulatory T cells. The culture system modifies the cell population composition and functional characteristics, creating a product with enhanced anti-tumor activity and reduced GVHD risk
3Object-affected harmful factors
If standard T cell depletion is performed to reduce graft-versus-host disease, then GVHD risk is reduced, but anti-tumor activity is lost
Solution Approach 1:
The patent applies selective quality modification to specific T cell subsets rather than uniform depletion. The ex vivo culture system selectively eliminates regulatory T cells while preserving effector T cells, creating local quality differences in the cell product that simultaneously reduce GVHD risk and maintain anti-tumor activity
Solution Approach 2:
The patent uses a dynamic ex vivo culture system that actively selects and eliminates specific cell populations based on their functional characteristics. The culture conditions create a dynamic environment where regulatory T cells are eliminated while effector T cells are enriched, resulting in a cell product with optimized therapeutic properties
Data Source
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AI summary
The invention relates to methods for the prediction and the treatment of risk of acute graft versus host disease. The inventors demonstrated that an alteration of CD73-mediated regulatory function of DP8α Tregs could contribute to the acute GvHD pathophysiology. In particular, the present invention relates to method of determining whether a subject has or is at 0 a risk of developing graft-versus-host disease (GvHD) comprising the steps of: i) determining the level of CD73 expression by DP8α TREGS in a sample obtained from the subject, ii) comparing the level determined at step i) with a predetermined reference value wherein detecting differential between the level of CD73 expression by DP8α TREGS determined at step i) and the predetermined reference value is indicative of whether a subject has or is at a risk of developing graft-versus-host disease (GvHD).