Absence of STAT1 in donor-derived plasmacytoid dendritic cells results in increased STAT3 and attenuates murine GVHD

Abstract

Key Points • STAT12/2 BM prevents GVHD induced by delayed donor lymphocyte infusion via the expansion of CD92 Siglec H hi pDCs, which are low producers of IFNa and IL-12.• pDCs recovered from STAT1 2/2 BM chimeras show increased expression of S100A8, S100A9, and STAT3.Selective targeting of non-T cells, including antigen-presenting cells (APCs), is a potential strategy to prevent graft-versus-host-disease (GVHD) but to maintain graft-versus-tumor (GVT) effects. Because type I and II interferons signal through signal transducer and activator of transcription-1 (STAT1), and contribute to activation of APCs after allogeneic bone marrow transplant (alloBMT), we examined whether the absence of STAT1 in donor APCs could prevent GVHD while preserving immune competence. 2/2 pDCs that were isolated after alloBMT showed increased gene expression of S100A8 and S100A9, and transplantation of S100A9 2/2 BM reduced GVHD-free survival. Finally, elevated STAT3 was found in STAT1 2/2 pDCs isolated after alloBMT. We conclude that interfering with interferon signaling in APCs such as pDCs provides a novel approach to regulate the GVHD/GVT axis. (Blood. 2014;124(12):1976-1986

Murine allogeneic CD19 CAR T cells harbor potent antileukemic activity but have the potential to mediate lethal GVHD

“…[20][21][22] Our data demonstrates that, at early time points and despite ongoing GVHD-induced immunesuppression, CAR T cells are still functional in generating a specific response toward their antigen, as evidenced by both in vitro assays of CAR T cells harvested post-adoptive transfer and in vivo clearance of leukemia. Despite this early preservation of allogeneic CAR T-cell functionality, the persistence of CAR T cells is significantly lower in the presence of acute GVHD than in syngeneic recipients.…”

“…on May 7, 2018. by guest www.bloodjournal.org From have diminished capacity to respond to vaccines and mediate antitumor responses even with mild subclinical GVHD, [20][21][22] and that adoptively transferred T cells with dual specificity for tumor and alloantigen through a single receptor demonstrate reduced but variable effectiveness dependent on the distribution of the allogeneic antigen. 23 Thus, we evaluated the efficacy of allogeneic CD19-targeted CAR T cells for the prevention of pre-B-cell ALL relapse in an immunocompetent murine model of HLA-matched, minor mismatched allo-BMT.…”

Bringing out the DCs’ softer side in GVHD

“…1 The safety advantage of reduced major bleeding was also consistent across the subgroups, except possibly in cancer patients, in whom the pooled estimate of a 23% RR reduction did not achieve statistical significance (supplemental data). 1 What are the implications for clinical practice? The DOACs should now replace vitamin K antagonists in most patients with VTE.…”

Low Counts of Plasmacytoid Dendritic Cells after Engraftment Are Associated with High Early Mortality after Allogeneic Stem Cell Transplantation

“…Only 1 study before our series analyzed moDC after allogeneic HSCT, having observed higher NRM, and higher relapse rates in patients with lower moDC counts [16]. Previous studies have analyzed the association of DCs with the complex pathophysiology of GVHD with controversial results: some studies in mice have shown that pDC or mDCs may initiate aGVHD whereas others have shown that pDC may protect against aGVHD [33][34][35]. In the clinical setting, all series, including ours, showed that a low DC counts in the PB after transplantation are consistently associated with a higher incidence of aGVHD both in adults and in children [13,15,16,24,36].…”