HLA-DR DQ TRANSGENIC, CLASS-II DEFICIENT MICE AS A NOVEL MODEL TO SELECT FOR HSP T-CELL EPITOPES WITH IMMUNOTHERAPEUTIC OR PREVENTATIVE VACCINE POTENTIAL/

Protective immunity against mycobacteria is dependent on antigen/MHC c lass II specific, CD4(+) Th1 cells. HLA-DR3-restricted Th1 cells respo nd to a subset of mycobacterial antigens, including the immunodominant hsp65, and recognize a single epitope in hsp65, notably p1-20. Altere d peptide ligands (APL) of p1-20 can inhibit p1-20/hsp65-induced proli feration of DR3-restricted T cells in an allele specific manner in vit ro. In order to develop a preclinical model in which p1-20 APL can be tested in vivo in the context of HLA, we have used murine class II def icient, HLA transgenic (Ab(0)) mice, in which all CD4(+) T cells are r estricted by the tg KLA molecule. BCG-immunized DR3.Ab(0) and DQ8.Ab(0 ) mice both responded well to hsp65. Furthermore, DR3.Ab(0) mice recog nized precisely the same p1-20 epitope as DR3-restricted human T cells , whereas DQ8.Ab(0) mice responded to a different set of hsp65 peptide s. This shows that (i) the same immunodominant protein and peptide epi tope are recognized by T cells from DR3.Ab(0) mice and DR3(+) humans a nd (ii) indicates the major role of HLA polymorphism in controlling th e human T cell response to mycobacterial antigens. Thus, HLA-transgeni c, Ab(0) mice provide a novel, preclinical model system to analyze APL and vaccines in the context of HLA polymorphism.