HLA-DQ6 AND HLA-DQ8 TRANSGENIC MICE RESPOND TO RAGWEED ALLERGENS AND RECOGNIZE A DISTINCT SET OF EPITOPES ON SHORT AND GIANT RAGWEED GROUP 5 ANTIGENS

We have investigated the genetic and molecular basis of immune respons iveness to short ragweed (SRW) (Ambrosia artemisiifolia) extract, and group 5 allergens from short and giant (Ambrosia trifida) ragweed usin g transgenic mice expressing DQ6 (HLA-DQA10103, HLA-DQB1*0601) and DQ 8 (HLA-DQA10301, HLA-DQB1*0302) genes in class II knockout (APO) mice . Panels of overlapping peptides spanning the Amb a 5 and Amb t 5 Ags were synthesized. Mice were immunized with whole SRW extract or indivi dual peptides s.c. and lymph node cells (LNC) were challenged in vitro , Strong T cell responses to SRW extract were measured in both HLA-DQ transgenic mice, while control, HLA-DQ6(-)/DQ8(-/)H-2A beta(0), mice w ere unresponsive. IL-5 and IL-10 were the primary cytokines produced b y in vitro challenged LNC of SRW primed transgenic mice. HLA-DQ6-restr icted T cell responses were detected to all three peptides of Amb t 5 and two determinants (residues 1-20 and 11-30) on Amb a 5, In contrast , LNC of HLA-DQ8 mice did not recognize peptide 11-30 of Amb t 5 Ag, b ut recognized several Amb a 5 determinants. The immune response in tra nsgenic mice was dependent upon CD4(+) T cells and was HLA-DQ restrict ed. Primed with purified Amb t 5, both transgenics recognized peptide 21-40, and an additional DQ6-restricted epitope was found within resid ue 1-20, SRW-immunized HLA-DQ6 mice respond to peptide 11-30 of Amb a 5, while HLA-DQ8 mice strongly recognize peptide 1-20. These results d emonstrate the specificity of HLA class II polymorphism in allergen se nsitivity and pave the way for developing antagonistic peptides for de sensitization.