GVT and GVHD targets in alloreactivity. (A) Donor and recipient are fully HLA identical. Polymorphic nonself peptides (MiHA) selectively expressed on hematopoietic cells provoke hematopoiesis-specific GVT responses. Polymorphic nonself peptides (MiHA) derived from broadly expressed genes can provoke combined GVT and GVHD. (B) CD8 T cells recognizing peptides presented in the context of nonself HLA class I molecules can mediate combined GVT and GVHD reactivity. CD4 T cells recognizing peptides in the context of HLA class II molecules mediate specific GVT responses under noninflammatory circumstances when HLA class II molecules are not expressed on nonhematopoietic tissues. Under inflammatory circumstances, upregulation of HLA class II on nonhematopoietic tissues causes combined GVT and GVHD by alloreactive CD4 T cells.