Toward Development and Production of Human T Cells in Swine for Potential Use in Adoptive T Cell Immunotherapy

Abstract

Immunotherapy and vaccination for cancer or infection are generally approached by administration of antigen or stimulation of antigen-presenting cells or both. These measures may fail if the treated individual lacks T cells specific for the immunogen(s). We tested another strategy-the generation of new T cells from hematopoietic stem cells that might be used for adoptive immunotherapy. To test this concept, we introduced T cell-depleted human bone marrow cells into fetal swine and tested the swine for human T cells at various times after birth. Human T cells were detected in the thymus and blood of the treated swine. These cells were generated de novo as they contained human T cell receptor excision circles not present in the T cell-depleted bone marrow. The human T cells were highly diverse and included novel specificities capable of responding to antigen presented by human antigen-presenting cells. Our findings constitute a first step in a new promising approach to immunotherapy in which tumor-or virus-specific T cell clones lacking in an individual might be generated in a surrogate host from hematopoietic stem cells of the individual to be treated.

Novel engraftment and T cell differentiation of human hematopoietic cells inArt-/-IL2RG-/SCID pigs

“…51 and Ogle et al . 42 show that the swine thymus can support engraftment and differentiation of human T cells. The lack thymic development in a SCID pig fetus may negatively impact the ability of human cells to develop, which may warrant transplantation of human thymic tissue after birth.…”

Porcine signal regulatory protein alpha binds to human CD47 to inhibit phagocytosis: Implications for human hematopoietic stem cell transplantation into severe combined immunodeficient pigs

“…Non‐SCID lambs and piglets can support the development of human T, B, NK, and myeloid lineages when HSC cells were injected in the fetal intraperitoneal space via in utero injection s with human HSCs . Additionally, the pig thymus can support the development of a wide range of human T cells . The development of human immune cell subsets suggests that porcine cytokines can support the development of human immune cells.…”

Toward a solution for cardiac failure in the newborn

“…Administration of hematopoietic stem cells from a xenogeneic source to a fetus can induce source-specific immune non-responsiveness that endures long after birth (e.g. human hematopoietic stem cells administered to a pig fetus induces non-responsiveness to APC of the stem cell donor with no loss of responsiveness to third-party APC in pigs tested a year after birth) (38, 39). However, the mechanisms that enable a fetus to accept grafts of foreign cells that a mature individual would reject may (40) or may not (41) include tolerance and success in early clinical efforts has been limited, at best (42).…”