Cross-Reactive Epitope Mapping for Multiple Sclerosis T-Cell Targeting
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Solution Overview
Problem
Conventional treatments for autoimmune diseases, such as multiple sclerosis, are non-antigen-specific, leading to undesirable side effects and immune suppression of whole immune system populations, while highly selective, antigen-specific therapies remain elusive.
Innovation Solution
Identification of cross-reactive peptides, such as ATFTSYRSWYLA and variants, that activate MS pathogenic T cells, allowing for specific therapeutic and diagnostic interventions by targeting these peptides and their associated TCRs, including antibodies and tolerization strategies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional non-antigen-specific immunosuppression is used, then immune suppression is achieved, but side effects increase and whole immune system populations are suppressed
Solution Approach 1:
The invention segments the immune suppression effect by identifying and targeting specific pathogenic T cell clones through their unique TCRs, rather than suppressing the entire immune system. This is achieved by screening and identifying specific TCR sequences from pathogenic T cells and developing therapies that selectively target these identified clones.
Solution Approach 2:
The invention applies local quality by making the immunosuppression therapy antigen-specific and T cell clone-specific. Instead of uniform suppression across all immune cells, the therapy is tailored to target only the specific pathogenic T cell clones identified through TCR screening, thereby suppressing disease-causing cells while preserving healthy immune function.
2Object-affected harmful factors
If more selective modification of the immune system is used, then side effects are reduced, but immune suppression of whole class of responses still occurs
Solution Approach 1:
The invention changes the parameter of selectivity by moving from class-specific suppression (affecting all T cells or B cells) to clone-specific suppression (affecting only the specific pathogenic T cell clone). This is achieved by identifying the specific TCR sequences of pathogenic clones and developing therapies that target only those specific receptors, thereby achieving high selectivity.
Solution Approach 2:
The invention introduces dynamics by adapting the therapy to the specific TCR repertoire of each patient's pathogenic cells. Through screening and identification of patient-specific TCR sequences, the therapy can be dynamically tailored to target the exact pathogenic clones present in each individual, rather than using a fixed, non-specific approach.
3Reliability
If antigen-specific therapies are developed, then treatment efficacy is improved, but identification of initiating antigens remains challenging
Solution Approach 1:
The invention uses TCR sequences as an intermediary to bridge the gap between pathogenic T cells and their target antigens. By screening and identifying TCR sequences from pathogenic T cells, the invention creates a measurable intermediate that can then be used to develop therapies targeting the specific T cell clones, bypassing the need to directly identify the initiating antigens.
Solution Approach 2:
The invention replaces the mechanical approach of directly identifying and targeting antigens with a molecular approach of identifying and targeting TCR sequences. Instead of trying to find the antigen through complex biochemical methods, the invention screens for the TCR sequences of pathogenic cells and uses those sequences as the therapeutic target, simplifying the approach.
Data Source
AI summary
Provided herein are methods and compositions for diagnosis and treatment of multiple sclerosis. Compositions and methods are provided, relating to novel peptides involved in autoimmune disease. In the experiments described herein, an unbiased approach was used to screen pathogenic CD4+ T cells from patients with multiple sclerosis (MS), and to determine the antigenic specificity of the T cell receptors (TCR) expressed by these pathogenic cells.