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.


METHODS
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.


CONCLUSIONS
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.
Division of Blood Transfusion, Kobe University Hospital, Japan. tyo@med.kobe-u.ac.jp
R
R
Ryo
K
K
Saigo
M
M
Hashimoto
M
M
Kohsaki
M
M
Yasufuku
N
N
Watanabe
M
M
Okada
K
K
Tadokoro
T
T
Juji
D001550:Benzamidines; D001782:Blood Donors; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D004247:DNA / Q000235:genetics; D017707:Erythrocyte Transfusion / Q000009:adverse effects; D004938:Esophageal Neoplasms / Q000628:therapy; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000209:etiology*; D006146:Guanidines / Q000627:therapeutic use*; D006680:HLA Antigens / Q000097:blood; D006650:Histocompatibility Testing; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000502:physiology; D008875:Middle Aged; D017713:Platelet Transfusion / Q000009:adverse effects; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D065227:Transfusion Reaction
D001550:Benzamidines; D006146:Guanidines; D006680:HLA Antigens; D015842:Serine Proteinase Inhibitors; D004247:DNA; C032855:nafamostat