Use of PDL1 expressing cells to convert T cells into regulatory T cells
Inventors
Riley, James L. • Fowler, Daniel H. • Amarnath, Shoba
Assignees
University of Pennsylvania Penn • US Department of Health and Human Services
Publication Number
US-10808225-B2
Publication Date
2020-10-20
Expiration Date
2032-11-20
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Abstract
The present invention provides methods and compositions for converting a T cell into a cell that exhibits at least one regulatory T cell phenotype. The converted T cell is generated by contacting a T cell with a cell that is modified to comprise an agent capable of activating PD1 signaling in a T cell. The converted T cell is useful for preventing, suppressing, blocking or inhibiting an immune response. For example the converted T cell is useful for preventing rejection of a transplanted tissue in a human or other animal host, or protecting against graft versus host disease. The converted T cell can also be used to treat autoimmune diseases.
Core Innovation
The invention provides methods and compositions for converting a T cell into a cell that exhibits at least one regulatory T cell phenotype by contacting the T cell with a cell modified to comprise an agent capable of activating PD1 signaling in the T cell. The converted T cell exhibits features such as expression of Foxp3 and suppression of effector T cell activation, which are indicative of a regulatory T cell phenotype.
The agent capable of activating PD1 signaling includes molecules such as PDL1, PDL2, PD1 ligand, or an anti-PD1 antibody, often expressed on cells like modified K562 cells. The method applies to various T cells including non-regulatory T cells, Th1, Th2, and Th17 cells, and involves conversion through direct cell contact, potentially using irradiated K562 cells expressing these agents.
The problem addressed by the invention concerns the need for compositions and methods to modulate and differentiate T cell subsets, specifically converting Th1 cells—which are critical for immune responses but can also contribute to autoimmunity and graft-versus-host disease—into regulatory T cells. Prior to this invention, there were no reports suggesting that PD1/PDL1 interactions could modulate Th1 cell plasticity to achieve such conversion.
Claims Coverage
The patent features six independent claims focusing on methods to generate immunosuppressive effects, prevent alloresponse, and treat transplant recipients by administering modified K562 cells expressing agents that activate PD1 signaling.
Use of K562 cells modified to activate PD1 signaling
Administering K562 cells modified to express agents selected from PDL1, PDL2, or anti-PD1 antibodies to activate PD1 signaling in T cells to generate immunosuppression or prevent immune responses.
Methods to prevent alloresponse in mammals
Administering modified K562 cells expressing PD1 activating agents that inhibit immune responses such as graft rejection through modulation of PD1 signaling.
Treatment to reduce immune response in transplant recipients
Administering cells including modified K562 cells expressing PD1 ligands and possibly T cells (Th1, Th2, Th17) or regulatory T cells to reduce immune response against transplanted tissues.
Inclusion of regulatory T cell phenotypes in administered cell population
Use of cell populations comprising cells with regulatory T cell phenotypes exhibiting Foxp3 expression and suppression of effector T cell activation in conjunction with K562 cells modified to activate PD1 signaling.
Incorporation of multiple T cell types with modified K562 cells
Administering a combination of modified K562 cells with T cells selected from Th1, Th2, Th17 subsets to achieve immunosuppressive or preventative effects.
The independent claims primarily cover methods of administering modified K562 cells expressing PD1 activating agents alone or in combination with various T cell types or regulatory T cells to generate immunosuppressive effects, prevent alloresponses, and treat transplant-related immune reactions by converting or modulating T cells through PD1 signaling.
Stated Advantages
The invention provides a method to convert Th1 cells into regulatory T cells expressing Foxp3, which can suppress effector T cell activation and prevent lethal graft-versus-host disease (GVHD).
PDL1-expressing cells modulate Th1 cells by inducing differentiation plasticity and shifting them to a regulatory phenotype, thereby contributing to immune tolerance and suppression.
Blocking PD1 or inhibiting downstream SHP1/2 signaling can stabilize Th1 cells and restore their effector function, providing potential therapeutic strategies for enhancing T cell immunity.
Genetic engineering of T cells to express PDL1 mimics regulatory T cell therapy and can be used to inhibit Th1 cell-mediated pathology, offering a versatile approach for immunosuppressive treatments.
Documented Applications
Preventing rejection of transplanted tissue in human or animal hosts by converting T cells into regulatory T cells that suppress immune responses.
Protecting against graft-versus-host disease (GVHD) through administration of converted regulatory T cells or PDL1-modified cells.
Treatment of autoimmune diseases by using converted regulatory T cells generated through PD1 signaling activation.
Inhibiting alloreactive T cells and cytotoxic T-lymphocyte activity to achieve immunosuppression in transplantation or autoimmune contexts.
Reducing immune responses against transplants via administration of modified cells expressing agents capable of activating PD1 signaling in T cells.
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