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,
*
Institute of Medical Science and
Department of Immunology, University of Toronto; and
Research Institute, Program in Infection, Immunity, Injury, and Repair, The Hospital for Sick Children, Toronto, Canada
Although HLA transgenic mice (HLA TgM) could provide a powerful
approach to investigate human MHC-specific T cell responsiveness, the
extent to which these molecules are recognized by the mouse immune
system remains unclear. We established TgM expressing HLA class I
alleles A2, B7, or B27 in
their fully native form (HLAnat) or as hybrid molecules
(HLAhyb) of the HLA 
1/2 domains linked to the
H-2Kb 3, transmembrane, and cytoplasmic domains (i.e.,
to maintain possible species-specific interactions). Comparison of each
as xeno- (i.e., by non-TgM) vs allo- (i.e., by TgM carrying an
alternate HLA allele) transplantation Ags revealed the following: 1)
Although HLAhyb molecules induced stronger
xeno-CD8+ T cell responses in vitro, additional effector
mechanisms must be active in vivo because HLAnat skin
grafts were rejected faster by non-TgM; 2) gene knockout recipients
showed that xenorejection of HLAnat and, unexpectedly,
HLAhyb grafts doesn’t depend on CD8+ or
CD4+ T cells or B cells; 3) each HLAhyb strain
developed tolerance to "self" but rejected allele-
(-B27 vs -B7) and locus-
(-B vs -A) mismatched grafts, the former
requiring CD8+ T cells, the latter by CD8+ T
cell-independent mechanisms. The finding that recognition of
xeno-HLAhyb does not require CD8+ T cells while
recognition of the identical molecule in a strictly allo context does,
demonstrates an 1/2 domain-dependent difference in effector
mechanism(s). Furthermore, the CD8+ T cell-independence of
locus-mismatched rejection suggests the degree of similarity between
self and non-self 1/2 determines the effector mechanism(s)
activated. The HLA Tg model provides a unique approach to characterize
these mechanisms and develop tolerance protocols in the context of
human transplantation Ags.
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