Inhibition of Innate Co-Receptor TREM-1 Signaling Reduces CD4+ T Cell Activation and Prolongs Cardiac Allograft Survival
| Autor: | Gabriela Schiechl, Stefan Fichtner-Feigl, Stephan Hirt, Edward K. Geissler, Rebecca Kesselring, S. M. Brunner, Hans J. Schlitt, Maria Laura Martin, Matthias Mack, P. Ruemmele |
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| Rok vydání: | 2013 |
| Předmět: |
CD4-Positive T-Lymphocytes
Graft Rejection CCR2 medicine.medical_treatment Cell Antigen-Presenting Cells Lymphocyte Activation Real-Time Polymerase Chain Reaction Mice medicine Animals Transplantation Homologous Immunology and Allergy Pharmacology (medical) Receptors Immunologic Receptor Heart transplantation Transplantation Membrane Glycoproteins Innate immune system biology business.industry Graft Survival Pattern recognition receptor Flow Cytometry Immunohistochemistry Coculture Techniques Triggering Receptor Expressed on Myeloid Cells-1 Mice Inbred C57BL Disease Models Animal medicine.anatomical_structure Gene Expression Regulation Integrin alpha M Immunology biology.protein Heart Transplantation RNA Female business CD8 Signal Transduction |
| Zdroj: | American Journal of Transplantation. 13:1168-1180 |
| ISSN: | 1600-6135 |
| DOI: | 10.1111/ajt.12186 |
| Popis: | The innate receptor "triggering-receptor-expressed-on-myeloid-cells-1" (TREM-1) enhances downstream signaling of "pattern recognition receptor" (PRR) molecules implicated in inflammatory responses. However the mechanistic role of TREM-1 in chronic heart rejection has yet to be elucidated. We examined the effect of TREM-1(+) antigen-presenting cells (APC) on alloreactive CD4(+) lymphocytes. Bm12 donor hearts were transplanted into wild-type MHC-class-II-mismatched C57BL/6J recipient mice. Progressive allograft rejection of bm12-donor hearts with decreased organ function, severe vasculopathy and allograft fibrosis was evident within 4 weeks. TREM-1(+) CD11b(+) MHC-II(+) F4/80(+) CCR2(+) APC and IFNγ-producing CD4(+) cells were detected during chronic rejection. Peptide inhibition of TREM-1 attenuated graft vasculopathy, reduced graft-infiltrating leukocytes and prolonged allograft survival, while being accompanied by sustained low levels of CD4(+) and CD8(+) cell infiltration. Remarkably, temporary inhibition of TREM-1 during early immune activation was sufficient for long-term allograft survival. Mechanistically, TREM-1 inhibition leads to reduced differentiation and proliferation of IFNγ-producing Th1 cells. In conclusion, TREM-1 influences chronic heart rejection by regulating the infiltration and differentiation of CD4(+) lymphocytes. |
| Databáze: | OpenAIRE |
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