PFA-Fixed Dendritic Cell Composition for CD8+ Treg Correction
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Solution Overview
Problem
Current methods for treating autoimmune diseases like type 1 diabetes (T1D) are ineffective due to the instability of dendritic cells loaded with human heat shock protein 60 signal peptide (hHsp60sp) and the inability to reliably identify and correct defective HLA-E restricted CD8+ Treg cells in individuals, making precise antigen-specific tolerance induction unfeasible.
Innovation Solution
Stabilizing dendritic cells with paraformaldehyde (PFA) to load them with hHsp60sp, creating pDC(H)s, and using novel cell lines to identify and correct defective HLA-E restricted CD8+ Treg cells, thereby treating autoimmune diseases like T1D.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If dendritic cells are loaded with hHsp60sp to induce antigen-specific tolerance, then therapeutic effectiveness is improved, but the stability of the dendritic cells deteriorates
Solution Approach 1:
The dendritic cells are pre-loaded with hHsp60sp peptide before administration to ensure stable antigen presentation. This preliminary loading of the therapeutic antigen ensures that the cells maintain their therapeutic function throughout the treatment process, resolving the contradiction between therapeutic effectiveness and stability.
2Measurement precision
If precise MHC/peptide complex identification is performed for each patient, then antigen-specific tolerance precision is improved, but the complexity and burden of the treatment process increases
Solution Approach 1:
The patent uses HLA-E, a universal MHC class I molecule that presents a conserved set of peptides including hHsp60sp, rather than patient-specific MHC/peptide complexes. This universal approach allows the same dendritic cell loading strategy to work across multiple patients without requiring individualized antigen identification, thereby reducing treatment complexity while maintaining therapeutic precision for autoimmune diseases.
3Adaptability or versatility
If HLA-E restricted CD8+ Treg cells are used to regulate self-reactive T cells, then the scope of disease coverage is improved, but the difficulty of identifying defective cells increases
Solution Approach 1:
The patent uses dendritic cells loaded with hHsp60sp as an intermediary to activate and correct defective HLA-E restricted CD8+ Treg cells. These dendritic cells serve as a mediator that can identify and stimulate the Treg cells in patients, making the detection and correction of defective cells more feasible while maintaining the broad disease coverage capability of HLA-E restricted Tregs.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The stabilized pDC(H)s effectively restore CD8 Treg function, improve biological indicators, and reduce insulin intake in T1D patients, while correcting defective HLA-E restricted CD8+ Treg cells in various autoimmune diseases.
Implementation Method 1
Stabilizing dendritic cells with paraformaldehyde (PFA) to load them with hHsp60sp
Data Source
AI summary
The present invention provides a composition comprising dendritic cells loaded with hHsp60sp, which dendritic cells are from a subject and have been fixed with paraformaldehyde (PFA). The subject may suffer from an autoimmune disease. Also provided are a method for preparing the composition; recombinant human cells comprising a heterologous gene encoding a fusion protein of HLA-E and hHsp60sp or B7sp, and expressing the fusion protein on the surface of the cells; a method for determining a percentage of maximum inhibition of testing the function of the HLA-E restricted CD8+ Treg cells from a subject, determining whether HLA-E restricted CD8+ Treg cells freshly isolated from a subject are defective, or determining whether defective HLA-E restricted CD8+ Treg cells from a subject are correctable; and a method for correcting defective HLA-E restricted CD8+ Treg cells, treating type 1 diabetes (T1D), or treating multiple sclerosis (MS).