Neutralizing Interleukin-4 Prevents Transplant Arteriosclerosis Mediated by Indirect Pathway T Cells Under CD40-CD154 Costimulation Blockade

Introduction. Blockade of the CD40-CD154 costimulatory pathway can prolong allograft survival, but does not prevent the development of transplant arteriosclerosis in several models. In this study, we investigated the mechanisms of CD40-CD154-independent transplant arteriosclerosis in major histocompatibility complex (MHC)-class I-mismatched aortic allografts. Methods. MHC class I-mismatched CBK (H2(k) + K-b) donor aortas were transplanted into CBA (H2(k)) recipients who can only recognize the graft through CD8(+) T cells and CD4(+) T cells responding to the class I MHC mismatch through the indirect pathway of allorecognition. Recipients were treated with anti-CD154 antibody (MR1) alone or in combination with anti-CD8 (YTS169) or anti-interleukin (IL)-4 (11B11) antibodies. Grafts were analyzed by histology on days 30 and 60 and for intragraft mRNA expression on day 14 after transplantation. Results. Repeated treatment with anti-CD154 alone or in combination with anti-CD8 antibody did not prevent intimal proliferation compared with untreated controls (65%+/- 6%, 62%+/- 9%, and 71%+/- 7% luminal occlusion, respectively, 60 days after transplantation). In both treatment groups, the expression of IL-4, IL-5, and eotaxin was increased compared with control grafts, and an eosinophilic infiltration was observed. Neutralizing IL-4 in combination with CD40-CD154 blockade and CD8(+) T-cell depletion abrogated transplant arteriosclerosis (9%+/- 4% luminal occlusion 60 days after transplantation). Conclusion. Prolonged treatment with anti-CD154 was not able to prevent the development of transplant arteriosclerosis in MHC class I-mismatched aortic allografts, in the presence or absence of CD8(+) T cells. This CD40-CD154 pathway resistant transplant arteriosclerosis was mediated by IL-4, because neutralizing IL-4 in addition to CD40-CD154 costimulation blockade and CD8(+) T-cell depletion prevented its development.