Treatment of post-transfusion graft-versus-host disease with nafmostat mesilate, a serine protease inhibitor

Background: Cytotoxic T lymphocytes from donors are thought to injure the target organs in post-transfusion graft-versus-host disease (PT-GVHD) through perforin-granzyme- and Fas-dependent cell killings. The protease involved is a serine protease, and nafmostat mesilate (NM), a serine protease inhibitor, has been found to inhibit the in vitro allocytotoxicity of the T cell clone established from a patient with PT-GVHD, thus suggesting the usefulness of NM for treatment of PT-GVHD. Case Report: A 47-year-old male with esophageal cancer, who received 3 units of packed red cells and 20 units of platelet concentrates from 5 unrelated donors, was diagnosed as having PT-GVHD on the basis of typical clinical features, HLA typing of the patient and the responsible donor, and a mixed chimera of CD8+ lymphocytes on microsatellite DNA polymorphism analysis. NM was administered to inhibit the activity of the serine proteases, thought to be granzymes; a liver dysfunction and thrombocytopenia with leukocytopenia simultaneously improved. Subsequently, a high-dose methylprednisolone pulse therapy and monoclonal anti-CD3 were administered to reduce the donor's proliferating lymphocytes, which resulted in lymphopenia accompanied by elimination of the donor's lymphocytes and normalization of the CD4/CD8 ratio. However, recurrence of the proliferation of the responsible donor's lymphocytes developed after cessation of NM administration, probably because of excessive immunosuppression caused by steroids and the monoclonal anti-CDS. Conclusion: This case indicates that administration of a serine protease inhibitor may improve PT-GVHD symptoms by inhibiting cytotoxic T-cell-mediated killing of target cells in fatal PT-GVHD. Steroids and monoclonal anti-CD3 were probably responsible for the transient clinical improvements. More studies are required, however, on mechanisms to eliminate the donor's lymphocytes.