Tetrameric HLA class I-minor histocompatibility antigen peptide complexes demonstrate minor histocompatibility antigen-specific cytotoxic T lymphocytes in patients with graft-versus-host disease

Graft-versus-host disease (GvHD) is a chief complication of allogeneic bone marrow transplantation(1). In HLA-identical bone marrow transplantation, G vHD may be induced by disparities in minor histocompatibility antigens (mHa gs) between the donor and the recipient, with the antigen being present in the recipient and not in the donort(2). Cytotoxic T lymphocytes (CTLs) spec ific for mHags of the recipients can be isolated from the blood of recipien ts with severe GvHD (ref. 3). A retrospective study demonstrated an associa tion between mismatch for mHags HA-1, -2, -4 and -5 and the occurrence of G vHD in adult recipients of bone marrow from HLA genotypically identical don ors(4). Tetrameric HLA-peptide complexes have been used to visualize and qu antitate antigen-specific CTLs in HIV-infected individuals and during Epste in-Barr virus and lymphocytic choriomeningitis virus infections(5-8). Here we show the direct ex vivo visualization of mHag-specific CTLs during GvHD using tetrameric HLA-class and 1-mHag HA-1 and HY peptide complexes. In the peripheral blood of 17 HA-1 or HY mismatched marrow recipients, HA-1-and M Y-specific CTLs were detected as early as 14 days after bone marrow transpl antation. The tetrameric complexes demonstrated a significant increase in H A-1- and MY-specific CTLs during acute and chronic GvHD, which decreased af ter successful GvHD treatment. HLA class 1-mHag peptide tetramers may serve as clinical tools for the diagnosis and monitoring of GvHD patients.