title: Perforin-independent rejection of transplanted human stem cells.
abstract: The NOD/SCID mouse model is one of the most established model systems for the analysis of human stem cells in vivo. The lack of mature B and T cells renders NOD/SCID mice susceptible to transplantable human stem and progenitor cells. One remaining functional component of the immune system in NOD/SCID mice is natural killer (NK) cells. We rationalized that by eliminating NK cell-mediated cytotoxicity in this model system engraftment of human haematopoietic stem cells could be improved. Thus perforin-deficient NOD/SCID mice (PNOD/SCID) were generated, which display a complete lack of NK cell-mediated cytotoxicity. To test the engraftment potential of human stem cells in PNOD/SCID mice, we compared the repopulating potential of human haematopoietic stem cells in these mice with the repopulating potential in NOD/SCID mice. Upon injection with varying numbers of mononuclear cells from human cord blood, the number of engrafted PNOD/SCID mice was lower (34.8%) than the number of engrafted NOD/SCID mice (64.7%). Similarly, injection of purified CD34(+) human cord blood cells led to engraftment in 32.3% PNOD/SCID versus 60% in NOD/SCID mice. Surprisingly, these results show that the inactivation of cytotoxic activity of NK cells in PNOD/SCID mice did not result in better engraftment with human haematopoietic stem cells. A potential reason for this observation could be that compensatory activation of NK cells in PNOD/SCID mice induces high levels of soluble factors resulting in an environment unfavourable for human stem cell engraftment.
authors.affiliation: Schweizerhall Management AG, Zürich, Switzerland. stefankaiser2@gmx.de
authors.forename: S
authors.initials: S
authors.lastname: Kaiser
authors.forename: D
authors.initials: D
authors.lastname: Kägi
authors.forename: G
authors.initials: G
authors.lastname: Ihorst
authors.forename: U
authors.initials: U
authors.lastname: Kapp
mesh_terms: D000818:Animals; D005434:Flow Cytometry / Q000379:methods; D006084:Graft Rejection; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007694:Killer Cells, Natural / Q000276:immunology; D008212:Lymphocyte Depletion; D008562:Membrane Glycoproteins / Q000172:deficiency*; D051379:Mice; D016513:Mice, SCID; D023421:Models, Animal; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D014183:Transplantation, Heterologous
chemical_list: D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin