Conditional HLA-I Downregulation for Allogeneic Cell Transplant Protection
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Solution Overview
Problem
Current methods for allogenic cell transplantation face challenges due to recognition of non-self HLA-I and HLA-II proteins, leading to transplant rejection and the need for immunosuppressive therapies that come with complications, and the risk of tumorigenesis with undifferentiated stem cells used in therapies.
Innovation Solution
A recombinant genetic construct that conditionally expresses immune checkpoint proteins and reduces HLA-I expression, providing selective immunoprotection to cells, thereby minimizing immune rejection and reducing the risk of tumorigenesis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-autologous donor cells are typed for HLA and matched to the transplant recipient, then transplant rejection is reduced, but the complexity of the transplantation process increases and complete matching is often not achievable
Solution Approach 1:
The patent extracts and removes HLA-I and HLA-II molecules from the donor cell surface, eliminating the primary antigens that trigger immune rejection. This approach bypasses the need for complex HLA typing and matching procedures while achieving transplant success without immunosuppression.
Solution Approach 2:
The patent changes the immunological parameters of donor cells by modulating HLA expression levels, specifically reducing or eliminating HLA-I and HLA-II surface expression. This parameter change allows cells to evade immune detection without requiring precise HLA matching between donor and recipient.
2Reliability
If allogenic transplant recipients are subjected to immunosuppressive therapy to prevent rejection, then transplant success is improved, but complications and morbidities from opportunistic infections increase
Solution Approach 1:
The patent converts the harmful effect of HLA molecules (which trigger immune rejection) into a benefit by selectively removing them. This allows the immune system to remain fully functional and protective against opportunistic infections while tolerating the transplanted cells that lack HLA expression.
3Adaptability or versatility
If undifferentiated stem cells are used in transplantation therapies, then cell replacement capability is enhanced, but the risk of tumorigenesis increases
Solution Approach 1:
The patent extracts HLA expression from undifferentiated stem cells, creating a state that protects against immune rejection while maintaining the cells' undifferentiated properties. This allows stem cells to engraft and differentiate in the host without requiring immunosuppression that could promote tumorigenesis.
4Reliability
If HLA-I and HLA-II expression is downregulated on donor cells to evade immune detection, then immune rejection is reduced, but the cells become susceptible to clearance by the innate immune system
Solution Approach 1:
The patent applies local quality by differentially modulating HLA expression: completely eliminating or significantly reducing HLA-I and HLA-II on donor cells to evade adaptive immune detection, while maintaining other cell surface properties that protect against innate immune clearance. This localized modification achieves selective immunoprotection.
Data Source
AI summary
The present disclosure is directed to preparation of one or more cells, wherein cells of the preparation are modified to conditionally express (i) increased levels of one or more immune checkpoint proteins as compared to corresponding wild-type cells, (ii) reduced levels of one or more HLA-I proteins as compared to corresponding wild-type cells, or a combination of (i) and (ii). The present disclosure is further directed to methods and constructs for producing the cell preparations as well as methods of administering the cell preparation to a subject in need thereof.