Reference - Detail
| RRC ID | 88188 |
|---|---|
| Author | Takahashi S, Inoue T, Ensbey KS, Legg SRW, Sekiguchi T, Nelson E, Nemychenkov NS, Joshi T, Minnie SA, Yeh AC, Zhang P, Headley M, Paik J, Amory JK, Hill GR, Koyama M. |
| Title | Targeting donor XCR1+ and CD11b+ dendritic cells prevents Th1- and Th17-dependent GVHD within the gastrointestinal tract. |
| Journal | Blood |
| Abstract |
Acute graft-versus-host disease (GVHD) of the gastrointestinal tract is a primary cause of early transplant mortality after bone marrow transplantation (BMT), driven by local antigen presentation and T-cell expansion. We sought to clarify the role of various subsets of donor dendritic cells (DC) in this process to define therapeutic strategies to prevent gut GVHD. Donor plasmacytoid DC (pDC) were prominent in the ileum of BMT recipients without GVHD but were largely absent in gut during GVHD. In contrast, donor XCR1+ conventional DC (cDC) were dramatically increased in the mesenteric lymph nodes of BMT recipients with GVHD. We utilized Xcr1-DTR mice and Clec4c-DTR mice to enable highly efficient XCR1+ cDC vs pDC depletion. Donor XCR1+ cDC but not pDC deletion attenuated lethal GVHD, depleting most cDC presenting alloantigen, which inhibited α4β7 and the expansion of alloantigen-specific donor Th1 cells in the gut. Aldehyde dehydrogenase 1A (ALDH1A) expression by cDC is known to modulate GVHD and we thus examined the effect of a pan-ALDH1 inhibitor, WIN18446, on this axis. WIN18446 administration improved survival and these effects were ALDH1A1-specific but mediated by inhibition of CD11b+ rather than XCR1+ cDC, inhibiting alloantigen-specific Th17 cell differentiation in the gut. These findings highlight the limited role of pDC in the induction of gut GVHD and identify differential and dominant roles for XCR1+ and CD11b+ donor cDC in controlling Th1- and Th17-mediated gut aGVHD. The targeting of donor cDC subsets represents an effective strategy to prevent lethal gut GVHD. |
| Volume | 147(18) |
| Pages | 2143-2155 |
| Published | 2026-4-30 |
| DOI | 10.1182/blood.2025029431 |
| PII | 566482 |
| PMID | 41662631 |
| PMC | PMC13155963 |
| MeSH | Aldehyde Dehydrogenase 1 Family Animals Bone Marrow Transplantation / adverse effects CD11b Antigen* / immunology CD11b Antigen* / metabolism Dendritic Cells* / immunology Dendritic Cells* / metabolism Dendritic Cells* / transplantation Gastrointestinal Tract* / immunology Gastrointestinal Tract* / pathology Graft vs Host Disease* / immunology Graft vs Host Disease* / pathology Graft vs Host Disease* / prevention & control Mice Mice, Inbred C57BL Receptors, Chemokine Retinal Dehydrogenase / antagonists & inhibitors Th1 Cells* / immunology Th1 Cells* / pathology Th17 Cells* / immunology Th17 Cells* / pathology |
| IF | 17.794 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 2 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Mice | RBRC09485 RBRC09486 |