Donor plasmacytoid dendritic cells limit graft-versus-host disease through vasoactive intestinal polypeptide expression

Abstract

Vasoactive intestinal peptide (VIP), an anti-inflammatory neuropeptide with pleiotropic cardio-vascular effects, induces differentiation of hematopoietic stem cells into regulatory dendritic cells that limit graft-versus-host disease (GvHD) in allogeneic hematopoietic stem cell transplant (HSCT) recipients. We have previously shown that donor plasmacytoid dendritic cells (pDCs) in bone marrow (BM) donor grafts limit the pathogenesis of GvHD. In this current study we show that murine and human pDCs express VIP, and that VIP-expressing pDCs limit T cell activation and expansion using both in vivo and in vitro model systems. Using T cells or pDCs from transgenic luciferase+ donors in murine BMT, we show similar homing patterns of donor pDCs and T cells to the major sites for allo-activation of donor T cells: spleen, and gut. Co-transplanting VIP-KO pDCs with hematopoietic stem cells (HSCs) and T cells in MHC mis-matched allogeneic BMT led to lower survival, higher GvHD scores, and more colon crypt cell apoptosis than transplanting wild-type pDCs. BMT recipients of VIP-KO pDCs had more Th1 polarized T cells, and higher plasma levels of GM-CSF and TNF-alpha than recipients of wild-type pDCs. T cells from VIP-KO pDC recipients had increasing levels of bhlhe40 transcripts during the first two weeks post-transplant, and higher levels of CyclophilinA/Ppia transcripts at day 15 compared with T cells from recipients of wild type pDCs. Collectively, these data indicate paracrine VIP synthesis by donor pDCs limits pathogenic T cell inflammation, supporting a novel mechanism by which donor immune cells regulate T cell activation and GvHD in allogeneic BMT.

Current perspective on biological properties of plasmacytoid dendritic cells and dysfunction in gut

“…The gene expression patterns of Flt3L‐induced human and mouse pDCs are strikingly similar 200 . Therefore, donor pDCs limited pathogenic T‐cell inflammation while also balancing GVHD and GVL activities 191 …”

“…200 Therefore, donor pDCs limited pathogenic Tcell inflammation while also balancing GVHD and GVL activities. 191 The essential role of pDCs has been validated in both humans and mice. Although clinical data hints that the transfer of donor-type pDCs may be a cellular therapy for GVHD prevention, 194 there is still a rigid demand for optimizing tolerogenic pDCs production therapy in GVHD, particularly how to manufacture adequate amounts of pDCs.…”

The magic of small-molecule drugs during ex vivo expansion in adoptive cell therapy

“…More recent studies showed that VIP enhances M2 macrophage polarization and promotes macrophages with a less-inflammatory physiologic profile that promotes tissue repair (88-90). We recently noted that VIP produced by activated T cells limits their proliferation in vitro (91), and VIP produced by donor plasmacytoid dendritic cells (pDCs) limits Graft-versus-Host Disease (GVHD) in vivo (92). The emerging immunoregulatory role of VIP on innate and adaptive immune functions makes it a candidate immunotherapy target.…”

Bioinformatics analysis and experimental validation of tumorigenic role of PPIA in gastric cancer

“…Moreover, PPIA participates in the modulation of various biological processes, including apoptosis, inflammation, transcription and intracellular signaling 16 – 19 . Previous studies suggest that the extracellular fractions of PPIA are potent pro-inflammatory mediators and PPIA is associated with a variety of inflammatory diseases 20 . Recent studies indicate that PPIA also plays a pivotal role in the development of human cancers 16 , including colon cancer 21 , hepatocellular carcinoma (HCC) 22 , multiple myeloma 23 , lung adenocarcinoma 24 and GC 25 .…”