HLA-E T Cell Down-Regulation for Transplant Tolerance

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Solution Overview

Problem

Current immunosuppressive therapies for transplant rejection require long-term medication, which is prone to failure and increases the risk of infection, and do not effectively differentiate between self and non-self antigens in the periphery.

Innovation Solution

Administering irradiated peripheral blood mononuclear cells and a monoclonal antibody binding CD40 ligand before transplantation, followed by an agent that enhances down-regulation of donor tissue-activated HLA-E+ T cells by HLA-E-restricted CD8+ T cells to prevent rejection without long-term immunosuppression.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional immunosuppressive therapy is used to prevent transplant rejection, then rejection is suppressed, but the risk of infection increases and long-term medication is required

Engineering Contradiction:

Improvetransplant acceptanceVSAvoidinfection risk

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention segments the T cell population by avidity, targeting only intermediate avidity T cells for down-regulation while preserving high avidity T cells that provide immunity to foreign pathogens. This selective approach is achieved through HLA-E restricted CD8+ T cells that specifically recognize and down-regulate intermediate avidity allo-reactive T cells, thereby preventing rejection while maintaining protective immunity and reducing infection risk

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention applies local quality by creating a differentiated response to different T cell subsets based on their avidity characteristics. High avidity T cells (protective immunity) are preserved, intermediate avidity T cells (pathogenic allo-reactive) are selectively down-regulated, and low avidity T cells are maintained. This localized differentiation allows selective tolerance induction without global immunosuppression

Inventive Principle:

Principle #3Local quality

2Reliability

If conventional immunosuppressive therapy is used to prevent transplant rejection, then rejection is suppressed, but long-term medication is required

Engineering Contradiction:

Improvetransplant acceptanceVSAvoidtreatment duration

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The invention performs preliminary action by inducing permanent tolerance through selective down-regulation of intermediate avidity T cells before the need for long-term maintenance therapy arises. The HLA-E restricted CD8+ T cells establish a regulatory mechanism that provides lasting protection against rejection, eliminating the need for continuous immunosuppressive medication

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The invention enables self-service by creating an autonomous regulatory system where HLA-E restricted CD8+ T cells continuously monitor and down-regulate intermediate avidity allo-reactive T cells. This self-regulating mechanism provides ongoing protection without external intervention, allowing the transplant recipient to achieve operational tolerance without long-term medication

Inventive Principle:

Principle #25Self-service

3Reliability

If conventional immunosuppressive therapy is used, then rejection is prevented, but differentiation between self and non-self antigens is not achieved

Engineering Contradiction:

Improvetransplant acceptanceVSAvoidself/non-self discrimination

Core Design Contradiction:

ReliabilityVSMeasurement precision

Solution Approach 1:

The invention changes the parameter of T cell avidity as the basis for discrimination between self and non-self. By targeting intermediate avidity T cells that recognize donor antigens with moderate strength, the system achieves precise discrimination without affecting high avidity T cells that provide protective immunity. This parameter-based differentiation enables selective tolerance induction

Inventive Principle:

Principle #35Parameter changes

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

This approach induces permanent tolerance to transplanted tissue by selectively down-regulating intermediate avidity T cells, reducing the risk of autoimmune responses while maintaining immunity to foreign pathogens, thereby eliminating the need for chronic immunosuppressive therapy.

Implementation Method 1

administering irradiated peripheral blood mononuclear cells

Methodology Applied

Scientific EffectRadiation: Radiation

Implementation Method 2

a monoclonal antibody which specifically binds CD40 ligand

Methodology Applied

Scientific EffectAntibody binding:

Implementation Method 3

an agent that enhances down-regulation of a donor tissue-activated HLA-E+ T cell by an HLA-E-restricted CD8+ T cell

Methodology Applied

Scientific EffectT cell down-regulation:

Data Source

PatentUS9597381B2Methods of preventing rejection of transplanted tissue by administering anti-CD40L antibody and HLA-E-bearing composition

Publication Date: 2017.03.21 THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK

AI summary

A method is provided for preventing rejection by an immune system of a recipient subject of a tissue transplanted from a donor subject into the recipient subject without the need for long-term administration of non-specific immunosuppressive drugs.