MONOCYTE ACTIVATION BY AN ORAL IMMUNOMODULATOR (BESTATIN) IN LYMPHOMAPATIENTS FOLLOWING AUTOLOGOUS BONE-MARROW TRANSPLANTATION

Bestatin (ubenimex), an inhibitor of aminopeptidase, is an oral immuno modulator that binds to CD13 (aminopeptidase N) on macrophages/monocyt es. To examine its immunomodulatory effect after high-dose therapy and autologous bone marrow transplantation (BMT), a dose-finding phase Ib trial was conducted with 30 Hodgkin's disease and non-Hodgkin's lymph oma patients who received no drug (control), 10 and 30 mg (low dose), or 90 and 180 mg (high dose) of bestatin daily for 60 days following a utologous BMT. Bestatin administration was initiated when the absolute neutrophil count was greater than 250/mm3 on 2 consecutive days. The serum neopterin levels, an indicator of monocyte/macrophage activation , increased in the high-dose group compared to the control group (not significantly) and the low-dose group (significantly). Similarly, the colony-stimulating activity in the sera was significantly increased in the high-dose group compared to the control and low-dose groups. We a lso examined the expression of cell-surface markers on monocytes in th ese patients by fluorescent cytometry analysis. There was no significa nt difference either in the frequency or absolute number of monocytes (CD14(+)) among the three groups at any time. However, a significant i ncrease in the frequency of CD16(FcgRIII)-positive monocytes (a marker of activation) was observed in the high-dose group compared to contro ls from day 14 to day 60 after the start of bestatin administration. F urther, the frequency of HLA-DR(+) monocytes (another marker of activa tion) was significantly increased in the high-dose group. These result s indicate that bestatin at higher doses (90 and 180 mg daily), but no t lower doses, activates macrophages/monocytes, as demonstrated by phe notypic marker (HLA-DR and CD16) up-regulation, and this provides augm entation of neopterin and colony-stimulating activity in the serum of patients following autologous BMT.