HLA-DR4 (DRB1*0401) Transgenic Mice

Reference #:

1997-071

Inventors/Contributors

Chella S. David, Ph.D.

Description

We generated an HLA-DR4ß(NT) transgene construct in which positions 110 and 139 were altered to resemble endogenous mouse H2 Aß molecules. This construct was introduced into (B10 x SWR) embryos, and DR4ß(NT) transgenic mice were produced. The transgene was transferred into B10.RFB3 (Eß0 Ealphap) mice. The transgene-encoded DR4ß molecules paired with endogenous Ealpha chains to form stable DR4ß/Ealpha dimers expressed on the cell surface. The hybrid dimers showed similar Ag-binding specificity to HLA-DR4 molecules and positively selected CD4+ T cells in vivo. Immunization of HLA-DR4ß(NT) transgenic mice with DR4-restricted peptides induced T cell proliferation in vitro. While the purified T cells from DR4ß(NT) transgenic mice responded strongly to the HA(307–319) presented by M12C3 transfectants expressing altered DR4ß/Ealpha heterodimers, the response to the same peptides presented by transfectants expressing wild-type DR4ß/Ealpha molecules was substantially reduced. Taken together, these data confirmed in vitro studies on the importance of these residues in CD4-MHC class II interaction. The altered HLA-DR4ß transgenic mice were able to overcome the species barrier and generate efficient HLA-DR4-restricted CD4-specific immune responses.

Patent Status

None