Development of a Human Immune System from Hematopoietic Stem Cells in a Human/Mouse Xenogeneic Model




Melkus, Michael W.

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T cells play a central role in the development of immune responses. Patients lacking T cells due to genetic defects such as DiGeorge or Nezelof's syndrome and individuals infected with the human immunodeficiency virus are highly susceptible to infections and cancers. The lack of adequate in vivo models of T cell neogenesis has hindered the development and clinical implementation of effective therapeutic modalities aimed at treating these and other clinically important maladies. Transplantation of severe combined immunodeficient (SCID) mice with human hematopoietic stem cells results in long-term engraftment and systemic reconstitution with human progenitor, B and myeloid cells but curiously, human T cells are rarely present in any tissue. While the implantation of SCID mice with human fetal thymus and liver (SCID-hu thy/liv mice) allows for the development of abundant thymocytes that are localized to the human organoid implant, there is minimal systemic repopulation with human T cells. Here I present evidence that transplantation of autologous human hematopoietic fetal liver CD34+ cells into NOD/SCID mice previously implanted with fetal thymic and liver tissues results in long-term, systemic human T cell homeostasis. In addition to human T cells, these mice have systemic repopulation with human B cells, monocytes/macrophages and dendritic cells (DC). This mouse model of the human immune system has been designated as BLT for a Bone marrow transplant in fetal Liver and Thymus implanted mice. T cells in these mice generate human MHC Class I and Class II restricted adaptive immune responses to Epstein Barr virus infection and are activated by human DCs to mount potent T cell immune response to super antigens. Administration of the super-antigen toxic shock syndrome toxin-1 (TSST-1) resulted in the specific systemic expansion of human Vbeta 2+ T cells, release of human pro-inflammatory cytokines and localized specific activation and maturation of human CD11c+ dendritic cells. These results represent the first demonstration of long-term systemic human T cell reconstitution in vivo allowing for the manifestation of the differential response by human DCs to TSST-1.

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