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Critical Role for IL-4 in the Development of Transplant Arteriosclerosis in the Absence of CD40-CD154 Costimulation¹

Stephan M. Ensminger^2,*, Bernd M. Spriewald^2,*, Henrik V. Sorensen, Oliver Witzke^*, Emily G. Flashman^*, Andrew Bushell^*, Peter J. Morris^*, Marlene L. Rose, Amin Rahemtulla and Kathryn J. Wood^3,*

Nuffield Departments of ^* Surgery and Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; and National Heart and Lung Institute, Imperial College, School of Medicine, Harefield Hospital, Middlesex, United Kingdom.

Blockade of the CD40-CD154 pathway can inhibit CD4⁺ T cell activation but is unable to prevent immune responses mediated by CD8⁺ T cells. However, even in the absence of CD8⁺ T cells, inhibition of the CD40-CD154 pathway is insufficient to prevent the development of transplant arteriosclerosis. This study investigated the mechanisms of transplant arteriosclerosis in the absence of the CD40 pathway. C57BL/6 CD40^-/- (H2^b) recipients were transplanted with MHC-mismatched BALB/c (H2^d) aortas. Transplant arteriosclerosis was evident in both CD40^-/- and CD40^+/- mice (intimal proliferation was 59 ± 5% for CD40^-/- mice vs 58 ± 4% for CD40^+/- mice) in the presence or absence of CD8⁺ T cells (intimal proliferation was 46 ± 7% for CD40^-/- anti-CD8-treated mice vs 50 ± 10% for CD40^+/- anti-CD8-treated mice), confirming that CD8⁺ T cells are not essential effector cells for the development of this disease. In CD40^-/- recipients depleted of CD8⁺ T cells, the number of eosinophils infiltrating the graft was markedly increased (109 ± 24 eosinophils/grid for CD40^-/- anti-CD8-treated mice vs 28 ± 7 for CD40^+/- anti-CD8-treated mice). The increased presence of eosinophils correlated with augmented intragraft production of IL-4. To test the hypothesis that IL-4 was responsible for the intimal proliferation, CD8 T cell-depleted CD40^-/- recipients were treated with anti-IL-4 mAb. This resulted in significantly reduced eosinophil infiltration into the graft (12 ± 5 eosinophils/grid for CD40^-/- anti-CD8⁺, anti-IL-4-treated mice vs 109 ± 24 for CD40^-/- anti-CD8-treated mice), intragraft eotaxin, CCR3 mRNA production, and the level of intimal proliferation (18 ± 5% for CD40^-/- anti-CD8⁺-, anti-IL-4-treated mice vs 46 ± 7% for CD40^-/- anti-CD8-treated mice). In conclusion, elevated intragraft IL-4 production results in an eosinophil infiltrate and is an important mechanism for CD8⁺ T cell-independent transplant arteriosclerosis in the absence of CD40-CD154 costimulation.

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