title: Dendritic cell-mediated immune humanization of mice: implications for allogeneic and xenogeneic stem cell transplantation.
abstract: De novo regeneration of immunity is a major problem after allogeneic hematopoietic stem cell transplantation (HCT). HCT modeling in severely compromised immune-deficient animals transplanted with human stem cells is currently limited because of incomplete maturation of lymphocytes and scarce adaptive responses. Dendritic cells (DC) are pivotal for the organization of lymph nodes and activation of naive T and B cells. Human DC function after HCT could be augmented with adoptively transferred donor-derived DC. In this study, we demonstrate that adoptive transfer of long-lived human DC coexpressing high levels of human IFN-α, human GM-CSF, and a clinically relevant Ag (CMV pp65 protein) promoted human lymphatic remodeling in immune-deficient NOD.Rag1(-/-).IL-2rγ(-/-) mice transplanted with human CD34(+) cells. After immunization, draining lymph nodes became replenished with terminally differentiated human follicular Th cells, plasma B cells, and memory helper and cytotoxic T cells. Human Igs against pp65 were detectable in plasma, demonstrating IgG class-switch recombination. Human T cells recovered from mice showed functional reactivity against pp65. Adoptive immunotherapy with engineered DC provides a novel strategy for de novo immune reconstitution after human HCT and a practical and effective tool for studying human lymphatic regeneration in vivo in immune deficient xenograft hosts.
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany;
authors.forename: Gustavo
authors.initials: G
authors.lastname: Salguero
authors.forename: Anusara
authors.initials: A
authors.lastname: Daenthanasanmak
authors.forename: Christian
authors.initials: C
authors.lastname: Münz
authors.forename: Ana
authors.initials: A
authors.lastname: Raykova
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Guzmán
authors.forename: Peggy
authors.initials: P
authors.lastname: Riese
authors.forename: Constanca
authors.initials: C
authors.lastname: Figueiredo
authors.forename: Florian
authors.initials: F
authors.lastname: Länger
authors.forename: Andreas
authors.initials: A
authors.lastname: Schneider
authors.forename: Laura
authors.initials: L
authors.lastname: Macke
authors.forename: Bala Sai
authors.initials: BS
authors.lastname: Sundarasetty
authors.forename: Torsten
authors.initials: T
authors.lastname: Witte
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Renata
authors.initials: R
authors.lastname: Stripecke
mesh_terms: D019264:Adoptive Transfer; D064591:Allografts; D000818:Animals; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D064593:Heterografts; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology; D018183:Transplantation Chimera / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D016898:Interferon-alpha; D010750:Phosphoproteins; D014409:Tumor Necrosis Factor-alpha; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D016178:Granulocyte-Macrophage Colony-Stimulating Factor