Immunomodulatory effect of pentoxifylline during human allograft rejection: involvement of tumor necrosis factor-alpha and adhesion molecules.
BACKGROUND
Pentoxifylline (PTX), a methylxanthine phosphodiesterase inhibitor, 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 cyclosporine and prednisone, we have shown that PTX weakened the consequences of rejection on graft survival. To assess the mechanism underlying the beneficial effect recorded during this trial, we analyzed the impact of PTX on tumor necrosis factor (TNF-alpha) production and expression of cell adhesion molecules.


METHODS
Plasma levels of TNF-alpha and its soluble receptors (sTNF-RI, sTNF-RII) and of soluble vascular cell adhesion molecule 1 (sVCAM-1) were monitored over the 6 months postgraft period when PTX or placebo were administered. Expression of VCAM-1 and intercellular cell adhesion molecule 1 was scored by immunohistochemical staining of biopsy specimens from patients who underwent rejection crisis. Lymphocyte subset composition was analyzed longitudinally during cytomegalovirus (CMV) infections.


RESULTS
Plasma TNF-alpha levels were significantly reduced in the PTX-treated group over the 6 months of administration, and specifically during isolated 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 group. During CMV infections, CD8 lymphocytosis and expansion of CD57+ (CD28-) CD8+ T cells were similar in the two groups.


CONCLUSIONS
The data collected during this double-blind study point to an immunomodulatory role of PTX, the beneficial effect on graft survival resulting from a restraining effect of the drug on the inflammatory conditions involved in acute graft rejection.
Noel
C
C
Service de Néphrologie-Hémodialyse-Transplantation, Hôpital Calmette, CHU Lille, France.
Copin
M C
MC
Hazzan
M
M
Labalette
M
M
Susen
S
S
Lelievre
G
G
Dessaint
J P
JP
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D015703:Antigens, CD / Q000097:blood; D015214:Antigens, Differentiation, Myelomonocytic / Q000097:blood; D001706:Biopsy; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D002102:Cadaver; D003586:Cytomegalovirus Infections / Q000097:blood / Q000235:genetics; D004311:Double-Blind Method; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism; D010431:Pentoxifylline / Q000494:pharmacology*; D010641:Phenotype; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D012995:Solubility; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood; D000097382:CD68 Molecule
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018799:Intercellular Adhesion Molecule-1; D010431:Pentoxifylline; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C067980:CD68 antigen, human; D000097382:CD68 Molecule