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Although antibody\u2010based targeting of the CD40\/CD40 ligand costimulatory pathway can prevent aGvHD, side effects hampered their clinical application, prompting a need for other ways to interfere with this important dendritic T\u2010cell costimulatory pathway. Here, we used small interfering RNA (siRNA) complexed with \u03b2\u2010glucan allowing the binding and uptake of the siRNA\/\u03b2\u2010glucan complex (siCD40\/schizophyllan [SPG]; chemical modifications called NJA\u2010312, NJA\u2010302, and NJA\u2010515) into Dectin1+ cells, which recognize this pathogen\u2010associated molecular pattern receptor. aGvHD was induced by the transplantation of splenocytes and bone marrow cells from C57BL\/6J into CBF1 mice. Splenic dendritic cells retained Dectin1 expression after HSCT but showed lower expression after irradiation. The administration of siCD40\/SPG, NJA\u2010312, and NJA\u2010302 ameliorated aGvHD\u2010mediated lethality and tissue damage of spleen and liver, but not skin. Multiple NJA\u2010312high injections prevented aGvHD but resulted in early weight loss in allogeneic HSCT mice. In addition, NJA\u2010312 treatment caused delayed initial donor T and B\u2010cell recovery but resulted in stable chimerism in surviving mice. Mechanistically, NJA\u2010312 reduced organ damage by suppressing CCR2+, F4\/80+, and IL17A\u2010expressing cell accumulation in spleen, liver, and thymus but not the skin of mice with aGvHD. Our work demonstrates that siRNA targeting of CD40 delivered via the PAMP\u2010recognizing lectin Dectin1 changes the immunological niche, suppresses organ\u2010specific murine aGvHD, and induces immune tolerance after organ transplantation. Our work charts future directions for therapeutic interventions to modulate tissue\u2010specific immune reactions using Pathogen\u2010associated molecular pattern (PAMP) molecules like 1,3\u2010\u03b2\u2010glucan for cell delivery of siRNA.<\/jats:p>","DOI":"10.1002\/jha2.439","type":"journal-article","created":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T09:10:45Z","timestamp":1651828245000},"page":"849-861","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["siRNA against CD40 delivered via a fungal recognition receptor ameliorates murine acute graft\u2010versus\u2010host disease"],"prefix":"10.1002","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0348-5934","authenticated-orcid":false,"given":"Beate","family":"Heissig","sequence":"first","affiliation":[{"name":"Department of Research Support Utilizing Bioresource Bank Graduate School of Medicine Juntendo University School of Medicine  Tokyo 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