Inhibition of TNF-alpha reduces transplant arteriosclerosis in a murine aortic transplant model.
Experimental and clinical data provide evidence that TNF-alpha contributes to acute and chronic allograft rejection. In this study, we explored the effect of TNF-alpha blockade using the chimeric monoclonal antibody infliximab on the development of transplant arterisoclerosis in a fully mismatched aortic allograft model. Post-transplant treatment of CBA (H2(k)) recipients with 250 mug infliximab (cumulative dose 1.25 mg) reduced luminal occlusion of C57Bl/6 (H2(b)) aortic grafts on day 30 from 77 +/- 5% in untreated controls to 52 +/- 6%. Increasing the dose of anti-TNF-alpha antibody had no further beneficial effect. Treatment with human control immunoglobulin had no effect on intima proliferation. Under TNF-alpha blockade, ICAM-1 and PDGF mRNA expression within the grafts was strongly reduced, whereas iNOS expression was enhanced. The data show that TNF-alpha blockade using infliximab can reduce the development of transplant arteriosclerosis in fully mismatched murine aortic grafts.
Wollin
Martina
M
Department for Internal Medicine 3 and Institute for Clinical Immunology, University Erlangen-Nürnberg, Erlangen, Germany.
Abele
Silke
S
Bruns
Heiko
H
Weyand
Michael
M
Kalden
Joachim R
JR
Ensminger
Stephan M
SM
Spriewald
Bernd M
BM
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001011:Aorta / Q000473:pathology / Q000637:transplantation*; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000069285:Infliximab; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007962:Leukocytes / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D011183:Postoperative Complications / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects / Q000276:immunology / Q000473:pathology
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D016207:Cytokines; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D000069285:Infliximab; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse