Immunomodulatory effect of pentoxifylline during human allograft rejection- Involvement of tumor necrosis factor-alpha and adhesion molecules

Background Pentoxifylline (PTX), a methylxanthine phosphodiesterase inhibit or, is poorly active as an immunosuppressant but prevents the synthesis of proinflammatory cytokines, In a randomized double-blind study comparing PTX versus placebo in 140 patients receiving cadaveric kidney grafts under cyc losporine and prednisone, we have shown that PTX weakened the consequences of rejection on graft survival. To assess the mechanism underlying the bene ficial effect recorded during this trial, we analyzed the impact of PTX on tumor necrosis factor (TNF-alpha) production and expression of cell adhesio n molecules. Methods. Plasma levels of TNF-alpha and its soluble receptors (sTNF-RI, sTN F-RII) and of soluble vascular cell adhesion molecule 1 (sVCAM-1) were moni tored over the 6 months postgraft period when PTX or placebo were administe red. Expression of VCAM-1 and intercellular cell adhesion molecule 1 was sc ored by immunohistochemical staining of biopsy specimens from patients who underwent rejection crisis. Lymphocyte subset composition was analyzed long itudinally during cytomegalovirus (CMV) infections. Results, Plasma TNF-alpha levels were significantly reduced in the PTX-trea ted group over the 6 months of administration, and specifically during isol ated rejection episodes and during CMV infections. Plasma levels of sTNFR-I , sTNFR-II, and sVCAM-1 did not differ between the two groups of patients, but a decrease in renal tubular VCAM-1 expression was observed in the PTX g roup. During CMV infections, CD8 lymphocytosis and expansion of CD57(+) (CD 28(-)) CD8(+) T cells were similar in the two groups. Conclusion. The data collected during this double-blind study point to an i mmunomodulatory role of PTX, the beneficial effect on graft survival result ing from a restraining effect of the drug on the inflammatory conditions in volved in acute graft rejection.