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. 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.
Ensminger
S M
SM
Nuffield Departments of. Surgery and Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
Spriewald
B M
BM
Sorensen
H V
HV
Witzke
O
O
Flashman
E G
EG
Bushell
A
A
Morris
P J
PJ
Rose
M L
ML
Rahemtulla
A
A
Wood
K J
KJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001013:Aorta, Thoracic / Q000637:transplantation*; D001161:Arteriosclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D019013:CD40 Antigens / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D023201:CD40 Ligand / Q000235:genetics* / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D054413:Chemokine CCL11; D019742:Chemokines, CC; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004804:Eosinophils / Q000473:pathology; D006183:H-2 Antigens / Q000276:immunology; D064532:Histocompatibility Antigen H-2D; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000235:genetics; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007518:Isoantibodies / Q000096:biosynthesis; D008212:Lymphocyte Depletion; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; C515457:Ccl11 protein, mouse; C515351:Ccr3 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D016207:Cytokines; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D007518:Isoantibodies; D016177:Macrophage-1 Antigen; D012333:RNA, Messenger; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D023201:CD40 Ligand; D015847:Interleukin-4; D007371:Interferon-gamma