Antigen-presenting cell-derived complement modulates graft-versus-host disease.

The Journal of Clinical Investigation
Wing-Hong KwanPeter S Heeger

Abstract

Acute graft-versus-host disease (GvHD) is a serious complication of allogeneic hematopoietic cell transplantation (allo-HCT) that results from donor allogeneic T cell attack on host tissues. Based on previous work implicating immune cell-derived C3a and C5a as regulators of T cell immunity, we examined the effects of locally produced C3a and C5a on murine T cell-mediated GvHD. We found that total body irradiation, a conditioning regimen required to permit engraftment of allo-HCT, caused upregulation and activation of alternative pathway complement components by recipient APCs. Allo-HCT with decay accelerating factor-null (Daf1(-/-)) host BM and Daf1(-/-) donor lymphocytes led to exacerbated GvHD outcome and resulted in splenic and organ-infiltrating T cell expansion. T cells deficient in C3a receptor (C3aR) and/or C5a receptor (C5aR) responded weakly in allogeneic hosts and exhibited limited ability to induce GvHD. Using a clinically relevant treatment strategy, we showed that pharmacological C5aR blockade reduced GvHD morbidity. Our data mechanistically link APC-derived complement to T cell-mediated GvHD and support complement inhibition as a therapeutic strategy for GvHD in humans.

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Citations

Dec 7, 2013·Best Practice & Research. Clinical Haematology·Anthony D Sung, Nelson J Chao
Feb 6, 2013·The Journal of Experimental Medicine·Wing-hong KwanPeter S Heeger
Jan 4, 2013·Stem Cells Translational Medicine·Anthony D Sung, Nelson J Chao
Oct 29, 2013·Seminars in Nephrology·Paolo CravediPeter S Heeger
Sep 6, 2015·Clinical Immunology : the Official Journal of the Clinical Immunology Society·Edimara S ReisJohn D Lambris
Jun 28, 2013·Journal of Cellular and Molecular Medicine·Liren QianJianliang Shen
Sep 17, 2013·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·P CravediP S Heeger
Feb 24, 2015·Molecular Immunology·Joost P M MelisPaul W H I Parren
Sep 12, 2012·Immunobiology·Andreas Barratt-DueTom Eirik Mollnes
Sep 21, 2013·Blood·Daniel Ricklin, Douglas B Cines
Dec 27, 2017·European Journal of Immunology·Shahzad N SyedReinhold E Schmidt
May 26, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Joong-Hyuk SheenPeter S Heeger
Sep 12, 2014·Journal of Leukocyte Biology·Elizabeth V Clarke, Andrea J Tenner
Mar 6, 2018·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·Qi ChengCarl Atkinson
Mar 18, 2017·Journal of the American Society of Nephrology : JASN·Carolina PurroyPaolo Cravedi
Sep 26, 2019·Microbiology and Immunology·Chenglong MaChunjian Qi
Jul 7, 2020·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·Jinyang Zeng-BrouwersLiliana Schaefer
Jul 9, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Yoshihiro FukuokaLawrence B Schwartz
Oct 10, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Daniel G CalameRick A Wetsel
Jun 17, 2018·Mucosal Immunology·Jennifer K MulliganCarl Atkinson
Sep 18, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Ruobing WangNorma P Gerard
May 22, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·William van der TouwPeter S Heeger
Jun 15, 2017·Frontiers in Medicine·Marek Cernoch, Ondrej Viklicky
Jul 2, 2015·Current Opinion in Organ Transplantation·Joong Hyuk Sheen, Peter S Heeger
Jan 11, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Hung NguyenXue-Zhong Yu
Nov 20, 2020·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·Changhai LiCarl Atkinson

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Methods Mentioned

BETA
flow cytometry
FACS
ELISA
PCR

Software Mentioned

ImageJ
FlowJo

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