Antigen-Enriched Central Memory T-Cell Veto Cells for GvHD Control
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Solution Overview
Problem
Existing methods for generating veto cells to prevent graft versus host disease (GvHD) in transplantation are inadequate, as they fail to completely eliminate GvHD and often result in graft rejection, particularly in allogeneic settings.
Innovation Solution
A method to generate veto cells with a central memory T-lymphocyte (Tcm) phenotype by depleting CD4+, CD56+, and CD45RA+ cells from peripheral blood mononuclear cells (PBMCs), followed by antigen activation and culturing in the presence of cytokines like IL-21, IL-15, and IL-7 to enrich antigen-reactive cells, resulting in a population with reduced GvHD reactivity and enhanced tolerance-inducing capabilities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If CD45RA+ depleted PBMCs are used to generate veto cells, then GvHD reactivity is reduced, but graft rejection occurs
Solution Approach 1:
The patent changes the phenotypic parameters of T cells by depleting CD45RA+ naive T cells and enriching for CD45RA- memory T cells. This parameter change shifts the T cell population from naive to memory phenotype, which inherently has lower GvHD reactivity while maintaining engraftment capability through the retained memory T cell population.
Solution Approach 2:
The patent extracts and removes the harmful component (CD45RA+ naive T cells that cause GvHD) from the PBMC population. By selectively depleting this subset through CD45RA microbeads, the remaining population is enriched for memory T cells that do not cause GvHD, thereby solving the contradiction between reducing GvHD and maintaining engraftment.
2Object-affected harmful factors
If T cell depleted stem cell transplantation is used, then GvHD is reduced, but immune reconstitution is impaired
Solution Approach 1:
The patent employs memory T cells that are self-sufficient in providing protective immunity without requiring continuous external stimulation. These memory T cells can autonomously recognize and respond to pathogens, providing long-lasting immunity while not causing GvHD, thus achieving both GvHD reduction and effective immune reconstitution.
Solution Approach 2:
The patent performs preliminary depletion of CD45RA+ cells before transplantation to pre-establish a T cell population composed of memory T cells. This preliminary action ensures that the infused T cells have already been selected for their low GvHD potential and high engraftment capability, resolving the contradiction between GvHD reduction and immune reconstitution.
3Productivity
If CD45RA-depleted fraction is used, then engraftment is enhanced, but GvHD is not completely eliminated
Solution Approach 1:
The patent replaces the mechanical/physical depletion method (CD45RA microbead-based depletion) with a more sophisticated immunological selection approach. By using antigen-specific memory T cells that have been previously activated against third-party antigens, the system achieves more complete elimination of GvHD potential while maintaining engraftment, going beyond the limitations of simple CD45RA depletion.
Data Source
AI summary
A method of generating an isolated population of non graft versus host disease (GvHD) inducing cells comprising a central memory T-lymphocyte (Tcm) phenotype, the cells being tolerance inducing cells and/or endowed with anti-disease activity, and capable of homing to the lymph nodes following transplantation is disclosed. The method comprising: (a) providing a population of at least 70% memory T cells; (b) contacting the population of memory T cells with an antigen or antigens so as to allow enrichment of antigen reactive cells; and (c) culturing the cells resulting from step (b) in the presence of cytokines so as to allow proliferation of cells comprising the Tcm phenotype. Cells generated by the method, pharmaceutical compositions and methods of treatment are also disclosed.