To prevent graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplant (HSCT) recipients, vasoactive intestinal polypeptide (VIP), an anti-inflammatory neuropeptide with pleiotropic cardiovascular effects, induces differentiation of hematopoietic stem cells into regulatory dendritic cells. Researchers had previously demonstrated that bone marrow (BM) donor grafts, including donor plasmacytoid dendritic cells (pDCs), inhibit the development of GVHD.
The current work used both in vivo and in vitro model systems to demonstrate that both murine and human pDCs express VIP and that VIP-expressing pDCs restrict T-cell activation and growth. In murine bone marrow transplantation (BMT), they demonstrated that donor pDCs and T cells have comparable homing tendencies to the primary sites for alloactivation of donor T cells: the spleen and gut. In major histocompatibility complex mismatched allogeneic BMT, cotransplanting VIP-knockout (KO) pDCs with hematopoietic stem cells and T cells resulted in decreased survival, higher GVHD scores, and more colon crypt cell death than transplanting wild-type pDCs.
Compared to wild-type pDCs, BMT recipients of VIP-KO pDCs had more T helper 1 pola33rized T cells and higher plasma levels of granulocyte-macrophage colony-stimulating and tumor necrosis factor. In comparison to T cells from recipients of wild-type pDCs, T cells from VIP-KO pDC recipients showed greater levels of CyclophilinA/Ppia transcripts at day 15 and increased levels of bhlhe40 transcripts over the first two weeks after transplant.
All of the findings supported a unique mechanism by which donor immune cells control T-cell activation and GVHD in allogeneic BMT: paracrine VIP production by donor pDCs reduces pathogenic T-cell inflammation.
Reference: ashpublications.org/blood/article/140/12/1431/485002/Donor-plasmacytoid-dendritic-cells-limit-graft
