There is a need for pre-clinical models that could be used to evaluate manipulation of the human immune system. This is particularly important for the testing of vaccines such as those currently needed in the context of biowarfare. Conclusions from studies in mouse models cannot be directly extrapolated to humans because of biological differences as exemplified by the pattern of Toll receptors expression on dendritic cells (DCs) and/or by the CD1 antigen presentation system that are different between species. SCID mice represent an interesting candidate however, the use of SCID mice for evaluation of immune responses has not quite fulfilled all its promises. Thus, grafting of PBMCs leads to rather limited immune reconstitution that does not allow development of in vivo human immune responses, particularly priming and affinity maturation. Development of NOD-SCID has brought about an improvement in engraftment of both hematopoietic progenitors and PBL. Yet, many of the difficulties could be due to insufficient reconstitution of DCs, a parameter that has been overlooked in studies up to date. Our preliminary results show that NOD-SCID mice transplanted with human CD34+ HPCs develop all subsets of human dendritic cells (SCID-hu/DCs mice). Therefore, SCID-hu/DCs mice represents a novel model system to study the physiology of human DCs. We propose to assess the in vivo function of human DCs generated in SCID mice including their capacity to induce vaccine specific cellular (CD4 mediated) and humoral immune responses using Tetanus Toxoid as a model vaccine.
Two aims are designed: 1) To determine whether human DCs can induce proliferation of human allogeneic T cells in vivo, and 2) To determine whether human DCs can induce vaccine-specific immune responses in vivo. The experiments proposed here would lay ground for further use of SCID-hu/DCs mice to study other vaccines and demonstrate development of protective immunity upon in vivo rechallenge. ? ?
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