Engineered Tissue Immune Evasion via MHC-I Knockout and HLA-E

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Solution Overview

Problem

Existing methods for producing engineered tissues from pluripotent stem cells face the challenge of transplant rejection due to allogeneic donor-derived tissues that are not histologically compatible, leading to immune responses and potential rejection.

Innovation Solution

The production of non-immunogenic engineered tissues from pluripotent stem cells deficient in MHC class I molecules and expressing an immunomodulatory protein, such as HLA-E, which are differentiated into essential cell types to form tissues that are not recognized as allogeneic by the recipient's immune system.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If pluripotent stem cells are used to produce engineered tissues, then the supply of tissues can be increased to meet medical demand, but the tissues are recognized as allogeneic by the recipient's immune system leading to rejection

Engineering Contradiction:

Improvesupply of engineered tissuesVSAvoidimmune rejection

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent extracts and removes MHC class I molecules from the surface of pluripotent stem cells through genetic modification (knockout of B2M gene and HLA-A, HLA-B, HLA-C loci). This extraction of immunogenic elements allows the cells to evade immune detection while maintaining their ability to differentiate into functional tissue, thus resolving the contradiction between increased tissue supply and immune rejection

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent introduces HLA-E molecules as an intermediary that provides protective function without triggering immune rejection. HLA-E acts as a mediator that interacts with natural killer cells to prevent lysis of the engineered tissue, while not being recognized as foreign by the recipient's adaptive immune system. This intermediary molecule enables the tissue to be both productive and immunologically compatible

Inventive Principle:

Principle #24Intermediary (Mediator)

2Adaptability or versatility

If allogeneic donor-derived tissues are used, then the availability of tissues for transplantation is improved, but histological incompatibility leads to immune responses and rejection

Engineering Contradiction:

Improveavailability of tissuesVSAvoidhistological compatibility

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent changes the immunological parameters of the stem cells by genetically modifying them to lack MHC class I molecules and express HLA-E. This parameter change transforms the cells from being histologically incompatible (allogeneic) to being effectively compatible (non-immunogenic), allowing widespread use of donor-derived tissues without rejection concerns

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20260015584A1Non-immunogenic engineered tissue and methods of producing and using the same

Publication Date: 2026.01.15 GERMEROTH LOTHAR

AI summary

The invention provides a method of producing a non-immunogenic (bio)engineered tissue from pluripotent stem cells or pluripotent stem cell derivatives, the respective cells being deficient of MHC class I molecules and comprising an immunomodulatory protein on their surface, wherein the method comprises inducing the differentiation of the pluripotent stem cells into a cell type that is essential for the function of the engineered tissue under conditions that also allow the formation of the engineered tissue, thereby rendering the engineered tissue to be non-immunogenic to a recipient of the engineered tissue. The present invention further relates to an engineered tissue, a pharmaceutical composition comprising the engineered tissue, medical treatments using the engineered tissue and uses of the engineered tissue.