1. March1-dependent modulation of donor MHC II on CD103+ dendritic cells mitigates alloimmunity
- Author
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Satoshi Ishido, Stuart K. Calderwood, Cristina Bonorino, Benjamin J. Lang, João Ismael Budelon Gonçalves, Priscila Vianna, Naoka Murakami, Rafael Fernandes Zanin, Laura M. Bellan, Jeoung-Sook Shin, Thiago J. Borges, Krist Helen Antunes, Mayuko Uehara, Felipe D. Machado, María José Pérez-Sáez, Gabriel Birrane, Ana Paula de Souza, Rafael Lopes, Reza Abdi, Ayesha Murshid, Leonardo V. Riella, and Jamil Azzi
- Subjects
0301 basic medicine ,General Physics and Astronomy ,Inbred C57BL ,Mice ,0302 clinical medicine ,Allograft survival ,2.1 Biological and endogenous factors ,Aetiology ,lcsh:Science ,Inbred BALB C ,Mice, Inbred BALB C ,Multidisciplinary ,biology ,Chemistry ,food and beverages ,hemic and immune systems ,CD ,Interleukin-10 ,3. Good health ,Cell biology ,Basic-Leucine Zipper Transcription Factors ,Interaction with host ,Lymph ,Integrin alpha Chains ,STAT3 Transcription Factor ,Ubiquitin-Protein Ligases ,Science ,chemical and pharmacologic phenomena ,Major histocompatibility complex ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Antigens, CD ,Animals ,Antigens ,Transplantation ,Inflammatory and immune system ,Alloimmunity ,fungi ,Histocompatibility Antigens Class II ,Organ Transplantation ,Dendritic Cells ,General Chemistry ,In vitro ,Mice, Inbred C57BL ,Repressor Proteins ,030104 developmental biology ,biology.protein ,lcsh:Q ,Murine skin ,030215 immunology - Abstract
In transplantation, donor dendritic cells (do-DCs) initiate the alloimmune response either by direct interaction with host T cells or by transferring intact donor MHC to host DCs. However, how do-DCs can be targeted for improving allograft survival is still unclear. Here we show CD103+ DCs are the major do-DC subset involved in the acute rejection of murine skin transplants. In the absence of CD103+ do-DCs, less donor MHC-II is carried to host lymph nodes, fewer allogenic T cells are primed and allograft survival is prolonged. Incubation of skin grafts with the anti-inflammatory mycobacterial protein DnaK reduces donor MHC-II on CD103+DCs and prolongs graft survival. This effect is mediated through IL-10-induced March1, which ubiquitinates and decreases MHC-II levels. Importantly, in vitro pre-treatment of human DCs with DnaK reduces their ability to prime alloreactive T cells. Our findings demonstrate a novel therapeutic approach to dampen alloimmunity by targeting donor MHC-II on CD103+DCs., Donor-derived dendritic cells (do-DC) in the graft can contribute to the induction of alloimmunity and tissue rejection, but how do-DC can be targeted for improving graft survival is unclear. Here the authors show that reducing MHC-II expression on do-DCs by DnaK pre-treatment can decrease the priming of alloimmunity and prolong graft survival in mouse models.
- Published
- 2018