CD40 provides immune privilege to the bone marrow hematopoietic niche
CD40 provides immune privilege to the bone marrow hematopoietic niche
Abstract Allogeneic bone marrow transplantation remains the only therapeutic option for a wide range of hematological malignancies despite the risk of possible adverse, immune-related events, such as infection and acute graft-versus-host disease (aGVHD). aGVHD is characterized by T-cell activation, defective B-cell development and osteoblastic niche destruction in bone marrow (BM) among other issues. Transplant conditioning regimens cause excessive inflammatory cytokines production and impaired regulatory T-cell control of aberrant T-cell activation. Here, we show that mesenchymal cells (MSCs) upregulated CD40 upon irradiation at the expense of mesenchymal markers, and that CD40 endows MSC of regulatory function on Treg homeostasis and fitness. Transplantation of wild type hematopoietic cells into a CD40-null recipient reduces Treg numbers allowing persistent T-cell activation and pro-inflammatory cytokines production causing, impaired B-lymphopoiesis. These evidences find correlation in aGVHD patients showing the loss of CD40+ BM-MSCs along with reduction in cells of the B-lineage. Modeling aGVHD in mice we show that the elimination of CD40+ BM-MSCs relies on their higher expression of MHC-I molecules. Indeed, aGVHD mice compared to MHC-matched controls showed the loss of MHC-I + radio-resistant host BM-MSCs. Our data point to CD40+ MHC-I+BM-MSCs as a key regulator of BM tolerogenic niches. Key pointsCD40 regulates BM immunological tolerance following total body irradiation (TBI) and transplantation (BMT).Loss of CD40+MHC-IhighBM-MSCs is associated to BM manifestation of aGVHD in human and murine model.
Portararo Paola、Botti Laura、Bolli Niccol¨°、Joehrens Korinna、Curti Antonio、Colombo Mario P.、Sangaletti Sabina、Na Il-Kang、Chiodoni Claudia、Gulino Alessandro、Anagnostopoulos Ioannis、Cappetti Barbara、Ciciarello Marilena、Tripodo Claudio、Bassani Barbara
Department of Research, Fondazione IRCCS Istituto Nazionale TumoriDepartment of Research, Fondazione IRCCS Istituto Nazionale TumoriDepartment of Oncology and Hemato-Oncology, University of Milan||Department of Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei TumoriInstitute of Pathology, Charit¨|-Universit?tsmedizin BerlinDepartment of Experimental, Diagnostic and Specialty Medicine ¨C DIMES, Institute of Hematology ?°Ser¨¤gnoli?±Department of Research, Fondazione IRCCS Istituto Nazionale TumoriDepartment of Research, Fondazione IRCCS Istituto Nazionale TumoriDepartment of Hematology, Oncology and Tumor Immunology, Charit¨| - Universit?tsmedizin Berlin, corporate member of Freie Universit?t Berlin, Humboldt-Universit?t zu Berlin, and Berlin Institute of Health||Experimental and Clinical Research Center Berlin-Brandenburg Center for Regenerative Therapies||Berlin Institute of HealthDepartment of Research, Fondazione IRCCS Istituto Nazionale TumoriUniversity of PalermoInstitute of Pathology, Charit¨|-Universit?tsmedizin BerlinDepartment of Research, Fondazione IRCCS Istituto Nazionale TumoriDepartment of Experimental, Diagnostic and Specialty Medicine ¨C DIMES, Institute of Hematology ?°Ser¨¤gnoli?±University of PalermoDepartment of Research, Fondazione IRCCS Istituto Nazionale Tumori
基础医学医学研究方法
Portararo Paola,Botti Laura,Bolli Niccol¨°,Joehrens Korinna,Curti Antonio,Colombo Mario P.,Sangaletti Sabina,Na Il-Kang,Chiodoni Claudia,Gulino Alessandro,Anagnostopoulos Ioannis,Cappetti Barbara,Ciciarello Marilena,Tripodo Claudio,Bassani Barbara.CD40 provides immune privilege to the bone marrow hematopoietic niche[EB/OL].(2025-03-28)[2025-05-29].https://www.biorxiv.org/content/10.1101/2020.08.10.243691.点此复制
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