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 histocom...
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| Format: | Journal article |
| Language: | English |
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2008
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| _version_ | 1826264528347725824 |
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| author | Spriewald, B Ensminger, S Bushell, A Wood, K |
| author_facet | Spriewald, B Ensminger, S Bushell, A Wood, K |
| author_sort | Spriewald, B |
| collection | OXFORD |
| description | 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 (H2k+Kb) donor aortas were transplanted into CBA (H2k) 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. |
| first_indexed | 2024-03-06T20:09:16Z |
| format | Journal article |
| id | oxford-uuid:2a02d72b-9f3f-4d02-8ab8-ed791e9ea2e7 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:09:16Z |
| publishDate | 2008 |
| record_format | dspace |
| spelling | oxford-uuid:2a02d72b-9f3f-4d02-8ab8-ed791e9ea2e72022-03-26T12:22:25ZNeutralizing interleukin-4 prevents transplant arteriosclerosis mediated by indirect pathway T cells under CD40-CD154 costimulation blockade.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2a02d72b-9f3f-4d02-8ab8-ed791e9ea2e7EnglishSymplectic Elements at Oxford2008Spriewald, BEnsminger, SBushell, AWood, K 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 (H2k+Kb) donor aortas were transplanted into CBA (H2k) 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. |
| spellingShingle | Spriewald, B Ensminger, S Bushell, A Wood, K Neutralizing interleukin-4 prevents transplant arteriosclerosis mediated by indirect pathway T cells under CD40-CD154 costimulation blockade. |
| title | Neutralizing interleukin-4 prevents transplant arteriosclerosis mediated by indirect pathway T cells under CD40-CD154 costimulation blockade. |
| title_full | Neutralizing interleukin-4 prevents transplant arteriosclerosis mediated by indirect pathway T cells under CD40-CD154 costimulation blockade. |
| title_fullStr | Neutralizing interleukin-4 prevents transplant arteriosclerosis mediated by indirect pathway T cells under CD40-CD154 costimulation blockade. |
| title_full_unstemmed | Neutralizing interleukin-4 prevents transplant arteriosclerosis mediated by indirect pathway T cells under CD40-CD154 costimulation blockade. |
| title_short | Neutralizing interleukin-4 prevents transplant arteriosclerosis mediated by indirect pathway T cells under CD40-CD154 costimulation blockade. |
| title_sort | neutralizing interleukin 4 prevents transplant arteriosclerosis mediated by indirect pathway t cells under cd40 cd154 costimulation blockade |
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