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Background  To date very few systems have been described for preclinical investigations of human cellular therapeutics  in vivo . However, the ability to carry out comparisons of new cellular vaccines  in vivo  would be of substantial interest for design of clinical studies. Here we describe a humanized mouse model to assess the efficacy of various human dendritic cell (DC) preparations. Two reconstitution regimes of NOD/scid IL2Rg null  (NSG) mice with adult human peripheral blood mononuclear cells (PBMC) were evaluated for engraftment using 4-week and 9-week schedules. This led to selection of a simple and rapid protocol for engraftment and vaccine evaluation that encompassed 4 weeks.    Methods  NSG recipients of human PBMC were engrafted over 14 days and then vaccinated twice with autologous DC via intravenous injection. Three DC vaccine formulations were compared that varied generation time  in vitro  (3 days versus 7 days) and signals for maturation (with or without Toll-like receptor (TLR)3 and TLR7/8 agonists) using MART-1 as a surrogate antigen, by electroporating mature DC with  in vitro  transcribed RNA encoding full length protein. After two weekly vaccinations, the splenocyte populations containing human lymphocytes were recovered 7 days later and assessed for MART-1-specific immune responses using MHC-multimer-binding assays and functional assessment of specific killing of melanoma tumor cell lines.    Results  Human monocyte-derived DC generated  in vitro  in 3 days induced better MART-1-specific immune responses in the autologous donor T cells present in the humanized NSG mice. Moreover, consistent with our  in vitro  observations, vaccination using mature DC activated with TLR3 and TLR7/8 agonists resulted in enhanced immune responses  in vivo . These findings led to a ranking of the DC vaccine effects  in vivo  that reflected the hierarchy previously found for these mature DC variations  in vitro .    Conclusions  This humanized mouse model system enables comparisons among different DC vaccine types to be rapidly assessed  in vivo . In addition,  ex vivo  analyses of human CD3 +  T cells recovered from the spleens of these mice are also possible, including studies on lymphocyte subsets, Th1/Th2 polarization, presence of regulatory T cells and the impact of DC vaccination on their functions.

NOD/scid IL-2Rgnull mice: a preclinical model system to evaluate human dendritic cell-based vaccine strategies in vivo