Prevention of Murine Acute Graft-versus-Host Disease by Recipient-Derived Paired Immunoglobulin-Like Receptor B Lentivirus-Transfected Dendritic Cells

Zhao, Juan; Luo, Yi‐Bo; Wang, Xiaochong; Zhou, Hao; Li, Qiubai; You, Yingjian; Zou, Ping

doi:10.1159/000315553

Cited by 7 publications

(9 citation statements)

References 27 publications

(19 reference statements)

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“… 64 When PirB is ectopically expressed in DCs, there is a significant decrease in morbidity and mortality within an allograft graft-vs.-host disease model with the DCs exerting a suppressive function on alloreactive T cells. 137 In apparent contradiction, the knockout of PirB was found to impair the maturation of DCs with a hypothesized alteration of cell signaling involving granulocyte-macrophage colony stimulating factor. 138 …”

Section: Relevance To Cancermentioning

confidence: 99%

Inhibitory leukocyte immunoglobulin-like receptors: Immune checkpoint proteins and tumor sustaining factors

et al. 2016

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Inhibitory leukocyte immunoglobulin-like receptors (LILRBs 1-5) transduce signals via intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that recruit protein tyrosine phosphatase non-receptor type 6 (PTPN6 or SHP-1), protein tyrosine phosphatase non-receptor type 11 (PTPN11 or SHP-2), or Src homology 2 domain-containing inositol phosphatase (SHIP), leading to negative regulation of immune cell activation. Certain of these receptors also play regulatory roles in neuronal activity and osteoclast development. The activation of LILRBs on immune cells by their ligands may contribute to immune evasion by tumors. Recent studies found that several members of LILRB family are expressed by tumor cells, notably hematopoietic cancer cells, and may directly regulate cancer development and relapse as well as the activity of cancer stem cells. LILRBs thus have dual concordant roles in tumor biology – as immune checkpoint molecules and as tumor-sustaining factors. Importantly, the study of knockout mice indicated that LILRBs do not affect hematopoiesis and normal development. Therefore LILRBs may represent ideal targets for tumor treatment. This review aims to summarize current knowledge on expression patterns, ligands, signaling, and functions of LILRB family members in the context of cancer development.

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Section: Relevance To Cancermentioning

confidence: 99%

Inhibitory leukocyte immunoglobulin-like receptors: Immune checkpoint proteins and tumor sustaining factors

et al. 2016

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“…Treatment with PIR B transfected DC has been shown to prevent lethal GVHD, and PIR B deficiency in BMT recipient mice results in exacerbated GVHD [55,56]. Young and older DCreg express PIR B in vitro (Figure 2A), and PIR B expression at d +3 was significantly higher on young (but not older) DCreg compared to the phenotype observed at the end of culture (Figure 6C).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Regulatory Dendritic Cells That Mitigate Acute Graft-versus-Host Disease in Older Mice Following Allogeneic Bone Marrow Transplantation

et al. 2013

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Despite improvements in human leukocyte antigen matching and pharmacologic prophylaxis, acute graft-versus-host disease (GVHD) is often a fatal complication following hematopoietic stem cell transplant (HSCT). Older HSCT recipients experience significantly increased morbidity and mortality compared to young recipients. Prophylaxis with syngeneic regulatory dendritic cells (DCreg) in young bone marrow transplanted (BMT) mice has been shown to decrease GVHD-associated mortality. To evaluate this approach in older BMT recipients, young (3–4 months) and older (14–18 months) DCreg were generated using GM-CSF, IL-10, and TGFβ. Analysis of young versus older DCreg following culture revealed no differences in phenotype. The efficacy of DCreg treatment in older BMT mice was evaluated in a BALB/c→C57Bl/6 model of GVHD; on day 2 post-BMT (d +2), mice received syngeneic, age-matched DCreg. Although older DCreg-treated BMT mice showed decreased morbidity and mortality compared to untreated BMT mice (all of which died), there was a small but significant decrease in the survival of older DCreg-treated BMT mice (75% survival) compared to young DCreg-treated BMT mice (90% survival). To investigate differences between dendritic cells (DC) in young and older DCreg-treated BMT mice that may play a role in DCreg function in vivo, DC phenotypes were assessed following DCreg adoptive transfer. Transferred DCreg identified in older DCreg-treated BMT mice at d +3 showed significantly lower expression of PD-L1 and PIR B compared to DCreg from young DCreg-treated BMT mice. In addition, donor DC identified in d +21 DCreg-treated BMT mice displayed increased inhibitory molecule and decreased co-stimulatory molecule expression compared to d +3, suggesting induction of a regulatory phenotype on the donor DC. In conclusion, these data indicate DCreg treatment is effective in the modulation of GVHD in older BMT recipients and provide evidence for inhibitory pathways that DCreg and donor DC may utilize to induce and maintain tolerance to GVHD.

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“…Finally, donor DC upregulated PD-L1 (and PIR B is a type I transmembrane protein expressed on APC that binds to CL I and delivers inhibitory signals through the phosphorylation of ITIMs [196,197]. Treatment with PIR B transfected DC has been shown to prevent lethal GVHD, and PIR B deficiency in BMT recipient mice results in exacerbated GVHD [220,229]. Young and older DCreg express PIR B in vitro ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…DCreg have been shown effective in the prevention of lethal systemic inflammatory responses, allergic airway disease, solid organ allograft rejection, and lethal GVHD [89,91,[101][102][103], as well as the treatment of allergic airway and autoimmune diseases [97]. Numerous molecules and phenotypic characteristics have been associated with various DC with tolerogenic capacity, including IDO [207,208,216,217], CD103 [205,206,218,219], PIR B [220], CCR9 [98], CD200R3 [198], and inhibitory B7 family members [55,56,103,193,200,221]. Prior to in vivo transfer, cultured young and older DCreg express very low levels of co-stimulatory molecules and high levels of inhibitory molecules ( Fig.…”

Section: Discussionmentioning

confidence: 99%

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Generation and characteriztion of regulatory dendritic cells for the amelioration of acute graft versus host disease

Scroggins¹

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____________________________________ Nicholas Zavazavaii To my supportive mother, loving husband, and beautiful children vi shared stories about her life and family. She was also like another grandmother to my four children and was fantastic at entertaining them when the occasion arose. A special thanks is extended to Lorraine Tygrett. She started out as my lab Mom when I was an undergraduate and continued to nurture my growth throughout the years. Lorraine became a confidant and close friend. Thanks also go to the many fellow students who have facilitated and often insisted on "helping" me have fun. Emily Hemann and Nicole Chapman have brought fun Sabrina out to play on occasion and I appreciate your persistence and friendship. I also want to thank Alex Boyden for his friendship and constructive feedback. A special thanks also goes to Carla-Maria Alexander and Niki Goldman. You were my closest friends and there for me through the most difficult times in my life. I have missed the two of you dearly. vii ABSTRACT Despite Human Leukocyte Antigen (HLA) matching and use of immunosuppressive drugs, graft-versus-host disease (GVHD) following hematopoietic stem cell transplant (HSCT) is prevalent and often fatal.Additionally, older HSCT recipients experience increased morbidity and mortality. Prophylactic treatment with age-matched syngeneic (recipient strain-derived) cultured regulatory DC (DCreg) has been shown to decrease GVHD-associated mortality in young bone marrow transplanted (BMT) mice.The purpose of this study was to investigate: 1) the potential to generate DCreg from older mice and their subsequent ability to ameliorate GVHD in older BMT mice, 2) the mechanism(s) by which DCreg mitigate GVHD in vivo, 3) the ability of DCreg-treated BMT mice to respond to infectious pathogens, and 4) whether DCreg can be generated under clinically relevant conditions from healthy donor and HSCT recipient PBMCs.To evaluate the efficacy of DCreg treatment in older mice, complete MHC-mismatched BMT mice were treated with DCreg (hereafter referred to as DCreg-treated BMT mice). Although DCreg treatment ameliorated GVHD in older BMT mice, these mice had increased morbidity and decreased survival compared to their young counterparts.Following transfer into BMT mice, older DCreg failed to increase inhibitory molecule (PD-L1 and PIR B) expression while significantly ix (PBMC) cryopreservation, 2) in bovine serum-free media, and 3) from older individuals and HSCT recipients. DCreg were generated from healthy donor and HSCT patient PBMCs isolated from young (<30 years old) and older (> 50 years old) individuals by culturing cells in X-vivo serum-free.

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Prevention of Murine Acute Graft-versus-Host Disease by Recipient-Derived Paired Immunoglobulin-Like Receptor B Lentivirus-Transfected Dendritic Cells

Cited by 7 publications

References 27 publications

Inhibitory leukocyte immunoglobulin-like receptors: Immune checkpoint proteins and tumor sustaining factors

Inhibitory leukocyte immunoglobulin-like receptors: Immune checkpoint proteins and tumor sustaining factors

Characterization of Regulatory Dendritic Cells That Mitigate Acute Graft-versus-Host Disease in Older Mice Following Allogeneic Bone Marrow Transplantation

Generation and characteriztion of regulatory dendritic cells for the amelioration of acute graft versus host disease

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