This disclosure provides miRNA/mRNA pairs that can be used to increase the efficacy of T cells or to down-modulate T cell efficacy and restore equilibrium.

The present invention generally relates to the production of antigen-specific T regulatory cells (Tregs). Such cells can be used in therapy to minimize undesirable immune responses such as those observed in autoimmunity and hemophilia and other diseases as well as in the response to protein therapy for genetic diseases. Methods for producing antigen specific Tregs and conditions for preferential expansion of functionally stable, specific Tregs are also provided.

Methods and compositions are provided for combined transplantation of a solid organ and hematopoietic cells to a recipient, where tolerance to the graft is established through development of a persistent mixed chimerism. An individual with persistent mixed chimerism, usually for a period of at least six months, is able to withdraw from the use of immunosuppressive drugs after a period of time sufficient to establish tolerance.

Methods and compositions are provided for combined transplantation of a solid organ and hematopoietic cells to a recipient, where tolerance to the graft is established through development of a persistent mixed chimerism. An individual with persistent mixed chimerism, usually for a period of at least six months, is able to withdraw from the use of immunosuppressive drugs after a period of time sufficient to establish tolerance.

The present disclosure provides methods of hematopoietic stem cell transplantation (HSCT). In particular, the present disclosure provides a method of HSCT using a combination of an in-vivo T-cell depletion method, with an ex-vivo method of ?? T cell expansion and ?? T cell depletion. The in-vivo T-cell depletion method depletes (in-vivo) the alloreactive T cells that would otherwise increase the risk of GvHD.

A method of treating or preventing graft versus host disease (GVHD) in a subject receiving a graft comprising hematopoietic cells is provided. The method comprises contacting the graft ex vivo with an amount of a Myxoma Virus effective to inhibit proliferation of T lymphocytes in the graft and to treat or prevent GVHD in the host subject following infusion of the graft into the subject. After the contacting of the graft with the Myxoma Virus, the method comprises transplanting the virus-treated graft into the subject.

Disclosed are compositions and methods for preventing graft versus host disease (GVHD) in subjects receiving donor cells. In particular, chimeric antigen receptor (CAR) polypeptides are disclosed that can be used with adoptive cell transfer to suppress alloreactive donor cells. Therefore, also disclosed are methods of suppressing alloreactive donor cells in a subject receiving transplant donor cells that involves adoptive transfer of the disclosed regulatory T cells engineered to express the disclosed CARs. Also disclosed is a method of preventing rejection of off-the-shelf therapeutic immune effector cells, such as CAR-T cells, in a subject that involves administering to the subject an effective amount of a regulatory T cell genetically modified with a disclosed CD83-specific CAR.

The present disclosure provides distinct therapeutic populations of cells that form a pharmaceutical composition useful in hematopoietic stem/progenitor cell transplant. For example, the present disclosure provides a therapeutic population of cells, comprising an enriched population of hematopoietic stem/progenitor cells, memory T cells, regulatory T cells, and wherein the population of cells is depleted of na?ve conventional ??-T cells. The present disclosure further provides methods of treatment using the therapeutic population of cells. In other embodiments, the present disclosure provides methods of producing a therapeutic population of cells.

It is provided a method of expanding dendritic (DC) cells and/or natural killer (NK) cells in vivo in a patient comprising the steps of producing a graft of stem and progenitor cells cultured with UM171 or analogues therefrom and expanded before being administered to the patient. The expansion or increase in dendritic (DC) cells and/or natural killer (NK) cells population in the patient results in an increase immune response reducing transplant related mortality (TRM), severe graft-versus-host disease (GVHD), relapse, and/or severe viral infections.

It is provided a method of expanding dendritic (DC) cells and/or natural killer (NK) cells in vivo in a patient comprising the steps of producing a graft of stem and progenitor cells cultured with UM171 or analogues therefrom and expanded before being administered to the patient. The expansion or increase in dendritic (DC) cells and/or natural killer (NK) cells population in the patient results in an increase immune response reducing transplant related mortality (TRM), severe graft-versus-host disease (GVHD), relapse, and/or severe viral infections.