Critical role for IL-4 in the development of transplant arteriosclerosis in the absence of CD40-CD154 costimulation.
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...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2001
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| _version_ | 1797072985714065408 |
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| author | Ensminger, S Spriewald, B Sorensen, H Witzke, O Flashman, E Bushell, A Morris, P Rose, M Rahemtulla, A Wood, K |
| author_facet | Ensminger, S Spriewald, B Sorensen, H Witzke, O Flashman, E Bushell, A Morris, P Rose, M Rahemtulla, A Wood, K |
| author_sort | Ensminger, S |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T23:15:35Z |
| format | Journal article |
| id | oxford-uuid:67040bb8-ddc9-4516-b95d-6a3802aad2e6 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:15:35Z |
| publishDate | 2001 |
| record_format | dspace |
| spelling | oxford-uuid:67040bb8-ddc9-4516-b95d-6a3802aad2e62022-03-26T18:35:30ZCritical role for IL-4 in the development of transplant arteriosclerosis in the absence of CD40-CD154 costimulation.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:67040bb8-ddc9-4516-b95d-6a3802aad2e6EnglishSymplectic Elements at Oxford2001Ensminger, SSpriewald, BSorensen, HWitzke, OFlashman, EBushell, AMorris, PRose, MRahemtulla, AWood, KBlockade 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. |
| spellingShingle | Ensminger, S Spriewald, B Sorensen, H Witzke, O Flashman, E Bushell, A Morris, P Rose, M Rahemtulla, A Wood, K Critical role for IL-4 in the development of transplant arteriosclerosis in the absence of CD40-CD154 costimulation. |
| title | Critical role for IL-4 in the development of transplant arteriosclerosis in the absence of CD40-CD154 costimulation. |
| title_full | Critical role for IL-4 in the development of transplant arteriosclerosis in the absence of CD40-CD154 costimulation. |
| title_fullStr | Critical role for IL-4 in the development of transplant arteriosclerosis in the absence of CD40-CD154 costimulation. |
| title_full_unstemmed | Critical role for IL-4 in the development of transplant arteriosclerosis in the absence of CD40-CD154 costimulation. |
| title_short | Critical role for IL-4 in the development of transplant arteriosclerosis in the absence of CD40-CD154 costimulation. |
| title_sort | critical role for il 4 in the development of transplant arteriosclerosis in the absence of cd40 cd154 costimulation |
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