Th1 and Th17 immunocompetence in humanized NOD/SCID/IL2rgammanull mice

We evaluated the immunocompetence of human T cells in humanized NOD-SCID interleukin (IL)-2r-gamma-null (hu-NSG) mice bearing a human thymic organoid, after multilineage reconstitution with isogeneic human leukocytes. Delayed type hypersensitivity (DTH) response was assessed by a direct footpad challenge of the immunized hu-NSG host, or by transfer of splenocytes from immunized hu-NSG, along with antigen, into footpads of C.B-17 scid mice (trans vivo [tv] DTH). Both methods revealed cellular immunity to tetanus toxoid (TT) or collagen type V (ColV). Immunohistochemical analysis of the swollen footpads revealed infiltration of human CD45(+) cells, including CD3(+) T cells, CD68(+) macrophages, and murine Ly6G(+) neutrophils. We observed a significant correlation between the percentage of circulating human CD4(+) cells and the direct DTH swelling response to TT. The tvDTH response to TT was inhibited by anti-interferon-gamma, whereas the tvDTH response to collagen V was inhibited by anti-IL-17 antibody, mimicking the cytokine bias of adult human T cells to these antigens. hu-NSG mice were also capable of mounting a B-cell response (primarily IgM) to TT antigen. The activation of either Th1- or Th17-dependent cellular immune response supports the utility of hu-NSG mice as a surrogate model of allograft rejection and autoimmunity.