DERIVATION OF HLA-A11 K-B TRANSGENIC MICE - FUNCTIONAL CTL REPERTOIREAND RECOGNITION OF HUMAN A11-RESTRICTED CTL EPITOPES/

Transgenic mice expressing chimeric human (alpha 1 and alpha 2 HLA-A11 domains) and murine (alpha 3, transmembrane, and cytoplasmic H-2K(b) domains) class I molecules were derived, These mice were used as a mod el system to study the immunogenicity of human CTL epitopes and also t o examine the aspects of Ag processing differences of mice vs man, Imm unization of these mice with seven known HLA-A11-restricted CTL epitop es emulsified in IFA resulted in vigorous specific CTL responses, A la rger panel of 45 A11-binding peptides was used to examine the relation ship between immunogenicity in the HLA-A11/K-b transgenic mice and HLA -A11 binding capacity, Twenty-one of 28 (75%) peptides with high bindi ng affinities (50% inhibitory concentration (IC50), 2-50 nM) and 7 of 13 (54%) intermediate binding peptides (IC50, 50-500 nM range) were im munogenic, In parallel, 19 of these peptides were used for in vitro pr imary immunizations of PBMC derived from HLA-A11 healthy human donors, It was found that 8 of 8 peptides that were able to elicit CTL in pri mary human in vitro cultures were also immunogenic in HLA-A11/K-b mice , Finally, HLA-A11/K-b transgenic mice were found to generate an A11/K -b restricted CTL response following immunization with influenza virus A/PR/8/34, suggesting that, at least to some extent, All epitopes are generated by transgenic mice as a result of natural in vivo processin g and presentation.