CD8+ Regulatory T Cells for Autoimmune Self-Tolerance
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Solution Overview
Problem
Current methods are inadequate in achieving a balance between inducing protective immunity against pathogens and maintaining self-tolerance, leading to incomplete removal of self-reactive T cells and an increased risk of autoimmune disorders, such as lupus and rheumatoid arthritis.
Innovation Solution
The discovery and utilization of a subpopulation of CD8+ regulatory T cells, specifically CD44+CD122+Kir+ Treg cells, which are essential for maintaining self-tolerance and preventing autoimmune diseases, through methods involving IL-15R agonists and the administration of CD44+CD122+Kir+ CD8+ Treg cells enriched in culture media with IL-15 and IL-21.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If negative selection in the thymus is used to remove self-reactive T cells, then self-tolerance is improved, but the process is incomplete and autoimmune disorders still occur
Solution Approach 1:
The patent employs negative selection in the thymus as a preliminary action to remove self-reactive T cells before they enter the peripheral immune system. While this preliminary action reduces autoimmunity, it is intentionally designed to be incomplete, allowing some self-reactive cells to escape and be controlled by peripheral mechanisms including the discovered CD8+ regulatory T cells.
Solution Approach 2:
The patent identifies CD8+ regulatory T cells as intermediary elements that mediate suppression of self-reactive CD4+ T cells in the periphery. These intermediary cells provide an additional layer of control that complements the thymic negative selection, ensuring complete self-tolerance through a multi-stage regulatory system.
2Reliability
If effector T cells are allowed to respond to self-peptide-MHC complexes, then protective immunity is improved, but autoimmune disorders increase
Solution Approach 1:
The patent distinguishes between different functional qualities of T cells: effector T cells with high responsiveness to self-peptide-MHC complexes provide protective immunity, while a separate subpopulation with regulatory phenotype (CD8+ Treg cells expressing FoxP3, CTLA-4, and other regulatory markers) provides suppression. This local quality differentiation allows simultaneous maintenance of immunity and tolerance.
Solution Approach 2:
The patent identifies specific phenotypic parameters (expression of regulatory markers, cytokine profiles, functional responses) that distinguish suppressive CD8+ T cells from conventional effector T cells. By characterizing these parameter changes, the patent enables identification and manipulation of the regulatory subset to control autoimmune responses while preserving protective immunity.
3Reliability
If regulatory T cells are used to suppress immune response, then self-tolerance is improved, but the mechanism is not fully understood and treatment options are limited
Solution Approach 1:
The patent segments the T cell population into distinct functional subsets, specifically identifying CD8+ regulatory T cells as a separate segment with unique suppressive functions. This segmentation allows independent study and manipulation of the regulatory subset, simplifying the complex immune system into manageable components for therapeutic development.
Solution Approach 2:
The patent discovers that CD8+ regulatory T cells naturally express high levels of IL-15Rα, making them inherently responsive to IL-15 stimulation. This self-service characteristic allows these cells to autonomously expand and enhance their suppressive function when exposed to IL-15, providing a built-in mechanism for therapeutic activation without requiring complex external manipulation.
Data Source
AI summary
A method to treat an autoimmune disease is provided. The method involves administration of interleukin-15 receptor (IL-15R) agonists in an amount effective to ameliorate a symptom of the autoimmune disease. The invention also involves a method to treat an autoimmune disease by ex-vivo expansion of CD44+CD122+Kir+ CD8+ Treg cells and administration of the CD44+CD122+Kir+ CD8+ Treg cells. Compositions comprising CD44+CD122+Kir+ CD8+ Treg cells are also provided. Methods for stimulating an immune response to an antigen are also provided.