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-9644179-B2
Publication Date
2017-05-09
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. The conversion is achieved by contacting a T cell with a cell modified to comprise an agent capable of activating PD1 signaling in the T cell, such as a K562 myeloid tumor cell overexpressing programmed death ligand-1 (PDL1), programmed death ligand-2 (PDL2), or an anti-PD1 antibody. The converted T cell exhibits characteristics such as expression of Foxp3 and suppression of effector T cell activation, and is useful for preventing, suppressing, or inhibiting immune responses.
The problem addressed by the invention is the lack of known methods and compositions for modulating Th1 cell plasticity through PD1/PDL1 interactions to induce regulatory T cell phenotypes. Th1 cells are critical in immune defense but contribute to autoimmunity and graft-versus-host disease (GVHD), and existing mechanisms do not adequately enable conversion of Th1 cells to regulatory T cells. The invention fills this need by providing a means to convert pathogenic T cells into regulatory T cells, thereby preventing deleterious immune responses such as rejection of transplanted tissues or autoimmune disease manifestations.
Claims Coverage
The patent includes one independent claim that covers a method for converting pathogenic T cells into regulatory T cells using modified K562 cells expressing PD1-activating agents.
Method of converting pathogenic T cells into regulatory T cells using modified K562 cells
A method comprising contacting a pathogenic T cell with a K562 cell modified to express an agent selected from the group consisting of PDL1, PDL2, and an anti-PD1 antibody, thereby converting the pathogenic T cell into a cell exhibiting a regulatory T cell phenotype.
Pathogenic T cell selection
The pathogenic T cell subjected to conversion is a non-regulatory T cell selected from CD4+, CD4+CD25−, or CD4+CD25−45RA+ cells.
Pathogenic T cell subtype
The pathogenic T cell can be of a subtype including Th1, Th2, Th17, or any combination thereof.
Converted regulatory T cell phenotype
The converted regulatory T cell exhibits characteristics such as expression of Foxp3, suppression of effector T cell activation, or both.
Use of irradiated modified K562 cells
The K562 cells modified to express the PD1-activating agent may be irradiated prior to use.
Targeting pathogenic T cells involved in GVHD
The pathogenic T cell to be converted induces graft versus host disease (GVHD).
The independent claim describes a method for converting pathogenic T cells, including Th1, Th2, and Th17 subtypes, into regulatory T cells with Foxp3 expression and suppressed effector function by contacting them with irradiated K562 cells expressing PDL1, PDL2, or anti-PD1 antibodies, aiming particularly at T cells involved in graft versus host disease.
Stated Advantages
Converted regulatory T cells can suppress lethality in xenogeneic graft-versus-host disease models.
PDL1-expressing cells mimic regulatory T cell therapy by preventing Th1 cell-mediated immune responses and graft rejection.
The method provides a novel means to modulate Th1 cell differentiation and plasticity via PD1 signaling.
Blocking PD1 signaling or SHP1/2 phosphatase activity prevents conversion and restores Th1 effector function, providing therapeutic targets.
Documented Applications
Preventing rejection of transplanted tissue in human or animal hosts.
Protecting against graft versus host disease (GVHD).
Treatment of autoimmune diseases by suppressing undesirable immune responses.
Generation of immunosuppressive effects in mammals having alloresponses or autoimmune responses.
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