| RRC ID |
55781
|
| 著者 |
Balam S, Schiechl-Brachner G, Buchtler S, Halbritter D, Schmidbauer K, Talke Y, Neumayer S, Salewski JN, Winter F, Karasuyama H, Yamanishi Y, Renner K, Geissler EK, Mack M.
|
| タイトル |
IL-3 Triggers Chronic Rejection of Cardiac Allografts by Activation of Infiltrating Basophils.
|
| ジャーナル |
J Immunol
|
| Abstract |
Chronic rejection is a major problem in transplantation medicine, largely resistant to therapy, and poorly understood. We have shown previously that basophil-derived IL-4 contributes to fibrosis and vasculopathy in a model of heart transplantation with depletion of CD4+ T cells. However, it is unknown how basophils are activated in the allografts and whether they play a role when cyclosporin A (CsA) immunosuppression is applied. BALB/c donor hearts were heterotopically transplanted into fully MHC-mismatched C57BL/6 recipients and acute rejection was prevented by depletion of CD4+ T cells or treatment with CsA. We found that IL-3 is significantly upregulated in chronically rejecting allografts and is the major activator of basophils in allografts. Using IL-3-deficient mice and depletion of basophils, we show that IL-3 contributes to allograft fibrosis and organ failure in a basophil-dependent manner. Also, in the model of chronic rejection involving CsA, IL-3 and basophils substantially contribute to organ remodeling, despite the almost complete suppression of IL-4 by CsA. In this study, basophil-derived IL-6 that is resistant to suppression by CsA, was largely responsible for allograft fibrosis and limited transplant survival. Our data show that IL-3 induces allograft fibrosis and chronic rejection of heart transplants, and exerts its profibrotic effects by activation of infiltrating basophils. Blockade of IL-3 or basophil-derived cytokines may provide new strategies to prevent or delay the development of chronic allograft rejection.
|
| 巻・号 |
202(12)
|
| ページ |
3514-3523
|
| 公開日 |
2019-6-15
|
| DOI |
10.4049/jimmunol.1801269
|
| PII |
jimmunol.1801269
|
| PMID |
31068389
|
| MeSH |
Animals
Basophils / immunology*
Cell Movement
Cells, Cultured
Chronic Disease
Disease Models, Animal
Graft Rejection / immunology*
Heart Transplantation*
Humans
Interleukin-3 / genetics
Interleukin-3 / metabolism*
Interleukin-6 / genetics
Interleukin-6 / metabolism
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Transplantation, Homologous
Up-Regulation
|
| IF |
4.718
|
| 引用数 |
2
|
| リソース情報 |
| 実験動物マウス |
RBRC02298 |
