TIME-DEPENDENT INDUCTION OF PROTECTIVE ANTIINFLUENZA IMMUNE-RESPONSESIN HUMAN PERIPHERAL-BLOOD LYMPHOCYTE SCID MICE

The human (hu) PBL/SCID mouse model has the potential to provide a pow erful tool for the study of human immune function, However, at peak en graftment (4-8 wk postinjection), recovered human T cells are largely unresponsive to foreign Ag and have converted to an activated/memory-t ype phenotype, Here we show that this conversion is not a prerequisite for engraftment because at early stages (2 wk) a substantial fraction of human T cells detected in SCID peripheral blood retains the unacti vated/naive phenotype of donor PBL. This early stage is also associate d with a TCR repertoire in both the CD4 and CD8 subsets that is simila r to that in the donor, Importantly, we show that strong HLA class I a llele- and peptide-specific cytotoxic T lymphocyte as well as humoral responses can be generated in this model when human cells encounter Ag (infection with influenza A) at early, but not late, stages in engraf tment, This early human response was also functional, as partial prote ction against influenza-induced pathology and death in SCIDs was obser ved, Taken together, these results demonstrate that the huPBL/SCID mod el can support the generation of potent and specific CTL and humoral r esponses provided that Ag is introduced early, presumably before the t ime-dependent generalized xenoactivation of engrafted human cells.