title: Comparison of three humanized mouse models for adoptive T cell transfer.
abstract: BACKGROUND
  Humanized mouse models for adoptive T cell transfer are important for preclinical efficacy and toxicity studies. However, common xenograft models using immunodeficient mice have so far failed to efficiently support the homing of human T cells to secondary lymphoid tissues.
  
  
  METHODS
  We established a new mouse model for the adoptive transfer of genetically-modified (gm) T cells using conditioned BALB/c mice. Conditioning involved cyclophosphamide injections, lethal irradiation and radioprotection with bone marrow from immunodeficient mice. We compared repopulation kinetics and the quality of grafts in these modified Trimera (mT3) mice with immunodeficient BALB/c Rag2(-/-) interleukin (IL)2 receptor gamma (rg) knockout (DKO) and NOD/LtSz-scid IL2rg(-/-) (NSG) recipient mouse strains.
  
  
  RESULTS
  DKO mice showed only marginal engraftment until onset of graft-versus-host disease, whereas mT3 and NSG were repopulated with comparable kinetics. However, T cell repertoire and human cytokine profiles suggest a xenoreactivity-driven gm T cell expansion in mT3 mice, whereas NSG mice were characterized by an initial homeostatic proliferation. Morphological analysis revealed high levels of human gm T cell infiltration in the spleen and liver of all three mouse strains. However, mT3 mice provided the strongest homing of human gm T cells to mucosal sites. Additionally, mT3 mice were the only model with macroscopically visible superficial inguinal lymph nodes. These lymph nodes strongly supported the homing of gm T cells.
  
  
  CONCLUSIONS
  In the present study, we give proof-of-concept that wild-type mice can accept gm T cell grafts while providing secondary lymphoid structures. Despite limitations, mT3 mice are a valid alternative for applications that specifically rely on improved secondary lymphoid structures.
authors: Georg-Speyer-Haus, Institute for Biomedical Research, Frankfurt, Germany.
authors: Andreas
authors: A
authors: Volk
authors: Sylvia
authors: S
authors: Hartmann
authors: Alexander
authors: A
authors: Muik
authors: Yvonne
authors: Y
authors: Geiss
authors: Christoph
authors: C
authors: Königs
authors: Ursula
authors: U
authors: Dietrich
authors: Dorothee
authors: D
authors: von Laer
authors: Janine
authors: J
authors: Kimpel
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D003520:Cyclophosphamide / Q000008:administration & dosage; D016207:Cytokines / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology; D000090023:Metallothionein 3; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D019172:Transplantation Conditioning; D014916:Whole-Body Irradiation
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; C507942:Il2rg protein, mouse; D007166:Immunosuppressive Agents; D053631:Interleukin Receptor Common gamma Subunit; D000090023:Metallothionein 3; C000715430:Mt3 protein, mouse; C499308:Rag2 protein, mouse; D011948:Receptors, Antigen, T-Cell; D003520:Cyclophosphamide; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human