The putative role of HLA-C recognition in graft versus host disease (GVHD) and graft rejection after unrelated bone marrow transplantation (BMT)

Abstract

We assessed cytotoxic activity of large granular lymphocytes (LGLs) derived from 10 patients transplanted from molecular HLA-C mismatched (5) and matched (5) unrelated donors and compared it to the cytotoxic activity of 10 patients transplanted from HLA-identical siblings. In addition, we correlated clinical outcome with the level of molecular HLA-C disparity in a cohort of 22 patients who underwent unrelated BMT. Cells obtained from patients transplanted (related or unrelated) from fully matched donors did not generate allospecific lysis of patient (pre-BMT) or donor PHA blasts. Five of nine patients who received BMT from HLA-C mismatched unrelated donors developed > grade II graft-vs.-host disease (GVHD), and four developed graft rejection. Cells derived from three of three patients with GVHD lysed patients' pre-BMT PHA blasts. In the patients with GVHD grade III-IV, cytotoxicity was higher (60-70%) than in the patient with grade II GVHD (20%) (p < 0.05). Cytotoxic cells derived from one patient who rejected his graft lysed donor PHA blasts. In one remaining patient who had graft rejection followed by autologous rescue, no in vitro allospecificity was observed. In summary, cytotoxic cells from patients transplanted with marrow mismatched at locus C demonstrated in vitro cytolysis of PHA blasts, and this phenomenon showed positive correlation with the clinical outcome of the BMT. These findings may indicate specific allorecognition. A mismatch at locus C leading to alloreactivity should be considered a risk factor in determining an appropriate match for allogeneic BMT, especially when the donor is unrelated.