Treatment of Post‐Transfusion Graft‐versus‐Host Disease with Nafmostat Mesilate, a Serine Protease Inhibitor

Abstract

Abstract Background: Cytotoxic T lymphocytes from donors are thought to injure the target organs in post‐transfusion graft‐versus‐host disease (PT‐GVHD) through perforingranzyme‐ 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‐CD3. 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.