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Pentoxifylline (PTX) has recently been shown to modulate TNF-a production and to reduce the incidence and severity of all major complications after BMT, including mucositis, veno-occlusive disease, renal insufficiency, hypertension, and graft-versus-host disease. To analyze in detail the effect of PTX on immune complications after BMT, we investigated the immunomodulatory effect of PTX on immune responses in vitro.The continuous presence of PTX significantly reduced the proliferative response of PBMC to PHA stimulation and to alloantigens in a dose-dependent manner. Starting at concentrations of 100 μg/ml, PTX was able to inhibit and, at 1000 μg/ml, completely block mitogen-induced proliferation. Maximal inhibition of more than 90% (91 ± 4%) was also observed at PTX concentrations of 1000 μg/ml, in the mixed lymphocyte culture (MLR) and by addition on day 0. However, lower but still significant suppression (13 ± 7%) was achieved at concentrations of 10 μg/ml, PTX. The inhibitory capacity of PTX was increased by mAbs against TNF-a (34 ± 5% additional suppression at 100 us/ml PTX) and not reversed by the addition of rTNF-α. The effect of PTX on the generation of CTLs in vitro was studied in the cell-mediated lymphotoxicity assay. PTX (100 μg/ml) significantly inhibited (P = 0.0178) the in vitro generation of CTLs when PTX was added to the culture on day 0. PTX also showed profound modulatory properties in the NK assay, with a reduction of 23 ± 3% in specific lysis at 10 μg/ml PTX and maximal reductions of 88 ± 3% at 1000 μg/ml PTX.Immunomodulatory properties of PTX were not only associated with blockage of TNF-α, as shown by decreased mRNA expression and TNF-a values in the culture supernatants, but also with an impaired production of other cytokines and secondary messages such as IFN-γ and neopterin. PTX treatment, however, did not affect IFN-a or IL-1β production, and IL-6 release was even increased.PTX, therefore, has profound immunomodulatory properties in vitro, which are associated with selective inhibition of cytokine release and can be enhanced by the addition of mAbs against TNF-α, but not reversed by the addition of rTNF-α.