Plasmacytoid Dendritic Cell Count on Day 28 in HLA-Matched Related Allogeneic Peripheral Blood Stem Cell Transplant Predicts the Incidence of Acute and Chronic GVHD

Although chronic graft-versus-host disease (cGVHD) is a major long-term complication of allogeneic hematopoietic stem cell transplantation, little is known of its pathogenesis. We have systematically examined oral mucosa among cGVHD patients and determined that the clinical severity of oral cGVHD was correlated with apoptotic epithelial cells, often found adjacent to infiltrating effector-memory T cells expressing markers of cytotoxicity and type I cytokine polarization. Accumulation of T-bet ؉ T-cell effectors was asso-

Section: Discussionmentioning

confidence: 57%

Increased T-bet+ cytotoxic effectors and type I interferon–mediated processes in chronic graft-versus-host disease of the oral mucosa

Imanguli

Swaim

League

et al. 2009

“…An increased ratio of pDCs/cDCs is associated with the successful withdrawal of immunosuppressants after liver transplants. 20 In allogeneic hematopoietic stem cell transplantation (HSCT), low pDC count in the peripheral blood is a risk for graft-versus-host disease (GVHD), 21 while larger numbers of pDCs in donor bone marrow (BM) are associated with increased relapse. 22 Collectively, accumulating data suggest that pDCs are mostly tolerogenic in vivo.…”

Section: Introductionmentioning

confidence: 99%

Plasmacytoid dendritic cells prime alloreactive T cells to mediate graft-versus-host disease as antigen-presenting cells

Koyama

Hashimoto

Aoyama

et al. 2009

Dendritic cells (DCs) can be classified into 2 distinct subsets: conventional DCs (cDCs) and plasmacytoid DCs (pDCs). cDCs can prime antigen-specific T-cell immunity, whereas in vivo function of pDCs as antigen-presenting cells remains controversial. We evaluated the contribution of pDCs to allogeneic T-cell responses in vivo in mouse models of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation by an add-back study of MHCexpressing pDCs into major histocompatibility complex-deficient mice that were resistant to GVHD. Alloantigen expression on pDCs alone was sufficient to prime alloreactive T cells and cause GVHD. An inflammatory environment created by host irradiation has the decisive role in maturing pDCs for T-cell priming but this process does not require Toll-like receptor signaling. Thus, functional outcomes of pDC-T-cell interactions depend on the immunologic context of encounter. To our knowledge, these results are the first to directly demonstrate an in vivo pathogenic role of pDCs as antigenpresenting cells in an antigen-specific T cell-mediated disease in the absence of other DC subsets and to provide important insight into developing strategies for tolerance induction in transplantation. IntroductionThe interaction of naive T cells and dendritic cells (DCs) is essential for initiating primary immune responses. DCs can be divided into 2 distinct subsets: conventional DCs (cDCs) and plasmacytoid DCs (pDCs) according to their immunophenotype and functional properties. 1-3 pDCs represent a CD11c int B220 ϩ DC subset that differs from the CD11c high B220 Ϫ major histocompatibility complex (MHC) class II high cDCs, commonly viewed as the classic stimulators of naive T cells. One distinctive feature of pDCs is their capacity to rapidly produce high levels of type I interferon (IFN) in response to viral and bacterial stimuli, highlighting the importance of pDCs in innate immune responses. 2-8 pDCs express low levels of surface MHC and classical costimulatory molecules; therefore, they are poor T-cell stimulators. [5][6][7][8][9][10][11] In contrast, pDCs matured with CD40 ligands or Toll-like receptor (TLR) ligands are potent antigen-presenting cells (APCs), capable of stimulating naive T-cell proliferation and differentiation to helper, killer, memory, and regulatory T cells in vitro. 7,12,13 In vivo, injection of pDCs activated by synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine motifs (CpG), but not immature pDCs, is capable of eliciting antigen-specific CD8 ϩ T-cell responses. 10,14 On the other hand, OVA-pulsed pDCs protected mice against OVA-induced asthma development. 15 pDCs in the tumordraining lymph nodes express indole 2, 3-dioxygenase, and suppress antitumor T-cell responses. 16 In patients with ovarian cancer, large numbers of pDCs, which induced interleukin 10 (IL10)-producing regulatory T cells, were found in ascites. 17 pDCs mediate tolerance and prolong survival of cardiac allografts. 11,18,19 Several recent clinical observations...

“…41 However, depletion of host-derived pDCs is not sufficient to prevent GVHD. 42 Interestingly in humans, decreased levels of pDCs in the circulation have been associated with an increased incidence of acute and chronic GVHD 43,44 ; children without GVHD have high absolute numbers of pDCs, 45 and absence of GVHD has been associated with improved pDC recovery and improved overall survival. 46 Collectively, these studies suggest that pDCs, depending on whether they are donor or host-derived, may be able to modulate GVHD, but they can also be activated in the posttransplant setting to support alloreactivity.…”

Section: Discussionmentioning

confidence: 99%

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

Capitini

Nasholm

Chien

et al. 2014

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