CD4+T cell recognition of a single discordant HLA-A2-transgenic molecule through the indirect antigen presentation pathway induces acute rejection ofmurine cardiac allografts

To further define the role of indirect allorecognition, cardiac allografts from HLA-A2-transgenic (HLA-A2+) C57BL/6 mice were heterotopically transpla nted into normal C57BL/6, CD4 T cell-knockout (KO) C57BL/6 mice, CD8 T cell -KO C57BL/6 mice, fully MHC-discordant BALB/c mice (allogeneic control), an d HLA-A2+ C57BL/6 mice (syngeneic control). HLA-A2+ grafts were acutely rej ected when transplanted into BALB/c mice (mean survival time: 10 +/-0.8 day s), normal C57BL/6 mice (mean survival time: 16.5 +/-2.1 days) as well as C D8-KO mice (mean survival time: 12.8 +/-1.3 days). Histopathological analys is revealed classical acute cellular rejection with moderate to severe diff use interstitial CD4+ and CD8+ cellular infiltrates and significant intra-g raft deposition of IgG and complement. In contrast, HLA-A2+ grafts were not rejected when transplanted into CD4-KO mice or HLA-A2+ mice. CD8-KO recipi ents treated with an anti-CD4 monoclonal antibody, but not with an anti-Mi monoclonal antibody, failed to reject their allografts with prolonged admin istration of antibody (30 days). Spleen cells from mice rejecting HLA-A2+ a llografts failed to lyse HLA-A2+ target cells indicating a lack of involvem ent of CD8+ T cells in the rejection process. In contrast, spleen cells fro m rejecting animals proliferated significantly to both HLA-A2+ cells and to a peptide derived from the HLA-A2 molecule. Development of anti-HLA-A2 ant ibodies was observed in all animals rejecting HLA-A2+ allografts. These res ults suggest that indirect allorecognition of donor MHC class I molecules l eads to rejection of cardiac allografts and development of alloantibodies i n this unique transplant model in which there is a single MHC discordance b etween donor and recipient.