KETOTIFEN THERAPY IN CHRONIC GRAFT-VERSUS-HOST DISEASE (CGVHD) - EFFECT ON MAST-CELLS AND FIBROBLASTS

Current treatment options for cGVHD are limited. Mast cells (MC) and f ibroblasts have been shown to play a role in the murine model of cGVHD . Ketotifen is an anti-H-1 antihistamine with MC-stabilizing propertie s. We therefore treated eight patients with cGVHD with ketotifen (6 mu g/day for 3 months). Three additional age- and sex-matched cGVHD pati ents served as controls. MC count and activation state in cGVHD skin b iopsies and the in vibro effect of peripheral blood mononuclear cell ( PBMC) supernatants on (i) histamine release by MC; (ii) 3T3-fibroblast proliferation; and (iii) prostaglandin E(2) (PGE(2)) production, were evaluated. Ketotifen therapy resulted in clinical improvement in 4/8 patients, stabilization of the disease in 2/8, while in 2/8 patients t he cGVHD progressed and they died of bacterial sepsis. Side effects we re minimal. In the skin biopsies the number of MC was found to be 0.58 +/- 0.17 (n = 8) (field x 400) and the MC looked degranulated (toluid ine blue staining). Following ketotifen therapy MC number was increase d to 1.2 +/- 0.28 (n = 8) (P < 0.05). PBMC supernatants of cGVHD patie nts stimulated histamine release from cultured rat MC (n = 8) (2.7 +/- 0.5 mu g/ml; normal values are 2.1 +/- 0.4 mu g/ml, n = 5). Ketotifen therapy reduced the histamine release level to the normal range (2.0 +/- 0.5 mu g/ml, P < 0.05) (n = 8). Ketotifen therapy had no significa nt effect on: (i) 3T3 fibroblast proliferation which was suppressed by cGVHD PBMC supernatants; (ii) the elevated PGE(2) production which we observed when fibroblasts were incubated with the PBMC supernatants. These results indicate that ketotifen may play a therapeutic role in c GVHD.