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1.
J Immunol ; 202(12): 3514-3523, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31068389

RESUMO

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.


Assuntos
Basófilos/imunologia , Rejeição de Enxerto/imunologia , Transplante de Coração , Interleucina-3/metabolismo , Animais , Movimento Celular , Células Cultivadas , Doença Crônica , Modelos Animais de Doenças , Humanos , Interleucina-3/genética , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transplante Homólogo , Regulação para Cima
2.
J Am Soc Nephrol ; 29(7): 1859-1873, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29777019

RESUMO

Background Interstitial fibrosis is associated with chronic renal failure. In addition to fibroblasts, bone marrow-derived cells and tubular epithelial cells have the capacity to produce collagen. However, the amount of collagen produced by each of these cell types and the relevance of fibrosis to renal function are unclear.Methods We generated conditional cell type-specific collagen I knockout mice and used (reversible) unilateral ureteral obstruction and adenine-induced nephropathy to study renal fibrosis and function.Results In these mouse models, hematopoietic, bone marrow-derived cells contributed to 38%-50% of the overall deposition of collagen I in the kidney. The influence of fibrosis on renal function was dependent on the type of damage. In unilateral ureteral obstruction, collagen production by resident fibroblasts was essential to preserve renal function, whereas in the chronic model of adenine-induced nephropathy, collagen production was detrimental to renal function.Conclusions Our data show that hematopoietic cells are a major source of collagen and that antifibrotic therapies need to be carefully considered depending on the type of disease and the underlying cause of fibrosis.


Assuntos
Injúria Renal Aguda/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Rim/patologia , Insuficiência Renal Crônica/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Injúria Renal Aguda/fisiopatologia , Adenina , Animais , Células da Medula Óssea/metabolismo , Linhagem da Célula , Células Epiteliais/metabolismo , Feminino , Fibroblastos/metabolismo , Fibrose , Taxa de Filtração Glomerular , Hematopoese , Rim/fisiopatologia , Túbulos Renais/citologia , Camundongos , Camundongos Knockout , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/fisiopatologia , Obstrução Ureteral/complicações
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