Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 3, Issue 8, Pages 968-976Publisher
BLACKWELL MUNKSGAARD
DOI: 10.1034/j.1600-6143.2003.00164.x
Keywords
graft arterial disease; heart transplant; interferon-gamma; tumor necrosis factor
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Funding
- NHLBI NIH HHS [R01 HL 43364] Funding Source: Medline
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Graft arterial disease (GAD) remains the leading cause of long-term solid organ allograft failure. Tumor necrosis factor (TNF) promotes multiple aspects of allograft rejection via binding to type 1 (p55) and type 2 (p75) receptors. We used TNF type 1 receptor deficient (TNFR1KO), type 2 receptor deficient (TNFR2KO) and receptor double-deficient (TNFRDKO) mice to assess the relative roles of TNFR in acute rejection and GAD. Heterotopic cardiac transplantation was performed between C57BL/6 (B/6) and Balb/c (B/c) mice (total allomismatches) to assess the effects on graft survival; B/6 and Bm12 mice (class II mismatches) were used to assess the effects on GAD 8 weeks after transplantation. We found that graft survival in the total allomismatch combinations was the same regardless of TNFR status. In class II mismatches, wild-type (WT) combinations showed severe GAD, and GAD was not diminished when WT hearts were transplanted into TNFRDKO hosts. TNFR1KO donors or TNFR2KO donors had GAD comparable to WT donors, however, GAD was significantly diminished in B/6 TNFRDKO donor hearts. We conclude that both p55 and p75 signals on donor vascular wall cells are involved in the development of GAD, and either TNFR is capable of mediating a response that will culminate in GAD.
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