Effect of upregulated TLR2 expression from G-CSF-mobilized donor grafts on acute graft-versus-host disease

Lee, Won-Sik; Kim, Joo-Yong; Won, Hae-Jeong; Lee, Soung-Min; Suh, Young-Sill; Joo, Young-Don; Lee, Ji-Young; Jang, Wonhee; Kang, Sung Goo; Kang, Mi-Sun; Park, Sae-Gwang; Choi, Il‐Whan; Choi, Inhak; Seo, Su‐Kil

doi:10.1016/j.intimp.2015.10.007

Cited by 7 publications

(6 citation statements)

References 30 publications

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“…Collaboration can also occur between G–CSF and other hematopoietic growth factors to impact lymphoid and erythroid cell development and functions. Recent studies suggest both a synergistic and antagonistic relationship between TLR2 ligands and G–CSF in the regulation of hematopoiesis 10 , 39 , 40 . While FSL–1 administered post TBI is associated with increased G–CSF secretion and accelerated hematopoiesis, delayed enhancement of G–CSF found within serum of non–treated, irradiated mice is likely a compensatory mechanism to restore severe lymphatic tissue damage.…”

Section: Discussionmentioning

confidence: 99%

“…This mechanism has been observed in the intestine where TLR2 stimulation drives monocyte differentiation in a G–CSF–dependent manner 39 . In a model of graft versus host disease, it was demonstrated that G–CSF mobilization of myeloid cells is diminished in Tlr2 −/− mice and in mice treated with TLR2 inhibitors 40 . Our radiation exposure data suggest that TLR2/6 stimulation by FSL–1 drives G–CSF, which then mediates hematopoietic cell mobilization.…”

Section: Discussionmentioning

confidence: 99%

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The Toll–Like Receptor 2/6 Agonist, FSL–1 Lipopeptide, Therapeutically Mitigates Acute Radiation Syndrome

Kurkjian

Guo

Montgomery

et al. 2017

Sci Rep

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Risks of radiation exposure from nuclear incidents and cancer radiotherapy are undeniable realities. These dangers urgently compel the development of agents for ameliorating radiation–induced injuries. Biologic pathways mediated by myeloid differentiation primary response gene 88 (MyD88), the common adaptor for toll–like receptor (TLR) and Interleukin–1 receptor signaling, are critical for radioprotection. Treating with agonists prior to radiation enhances survival by activating TLR signaling, whereas radiomitigating TLR–activating therapeutics given after exposure are less defined. We examine the radiomitigation capability of TLR agonists and identify one that is superior for its efficacy and reduced toxic consequences compared to other tested agonists. We demonstrate that the synthetic TLR2/6 ligand Fibroblast–stimulating lipopeptide (FSL–1) substantially prolongs survival in both male and female mice when administered 24 hours after radiation and shows MyD88–dependent function. FSL–1 treatment results in accelerated hematopoiesis in bone marrow, spleen and periphery, and augments systemic levels of hematopoiesis–stimulating factors. The ability of FSL–1 to stimulate hematopoiesis is critical, as hematopoietic dysfunction results from a range of ionizing radiation doses. The efficacy of a single FSL–1 dose for alleviating radiation injury while protecting against adverse effects reveals a viable radiation countermeasures agent.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Toll–Like Receptor 2/6 Agonist, FSL–1 Lipopeptide, Therapeutically Mitigates Acute Radiation Syndrome

Kurkjian

Guo

Montgomery

et al. 2017

Sci Rep

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“…TLR2 recognizes cell-wall components such as peptidoglycan (PGN) from gram-positive bacteria as well as zymosan from yeast. Intriguingly, granulocyte-colony stimulating factor (G-CSF) mobilized donor grafts showed the increase level of TLR2 expression on myeloid cell populations (19), but upregulated TLR2 expression did not correlate with enhanced allogeneic responses (20). The studies utilizing TLR2 −/− animals as either donor or host demonstrated that TLR2 has little effect on acute GVHD (12, 20).…”

Section: Toll-like Receptorsmentioning

confidence: 99%

Danger Signals and Graft-versus-host Disease: Current Understanding and Future Perspectives

et al. 2016

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Graft-versus-host response after allogeneic hematopoietic stem cell transplantation (allo-HCT) represents one of the most intense inflammatory responses observed in humans. Host conditioning facilitates engraftment of donor cells, but the tissue injury caused from it primes the critical first steps in the development of acute graft-versus-host disease (GVHD). Tissue injuries release pro-inflammatory cytokines (such as TNF-α, IL-1β, and IL-6) through widespread stimulation of pattern recognition receptors (PRRs) by the release of danger stimuli, such as damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). DAMPs and PAMPs function as potent stimulators for host and donor-derived antigen presenting cells (APCs) that in turn activate and amplify the responses of alloreactive donor T cells. Emerging data also point towards a role for suppression of DAMP induced inflammation by the APCs and donor T cells in mitigating GVHD severity. In this review, we summarize the current understanding on the role of danger stimuli, such as the DAMPs and PAMPs, in GVHD.

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“…Administration of 3M-011 after allogenic transplant increased GVHD mortality, but pre-treatment with 3M-011 reduced the damage to target organs by inducing IDO expression in the colon (394142). Alterations to TLR2 expression on recipient lymphoid and myeloid cells from splenocytes had little effect on acute GVHD (43) (Table I). Thus, each of the TLRs is involved in acute GVHD to a different extent (43444546).…”

Section: Gut Microbiome and Innate Immunity In Acute Intestinal Gvhdmentioning

confidence: 99%

“…Alterations to TLR2 expression on recipient lymphoid and myeloid cells from splenocytes had little effect on acute GVHD (43) (Table I). Thus, each of the TLRs is involved in acute GVHD to a different extent (43444546). Reports on the functional associations of TLRs and their adaptor molecules with GVHD are summarized in Table I and Table II.…”

Section: Gut Microbiome and Innate Immunity In Acute Intestinal Gvhdmentioning

confidence: 99%

TLR/MyD88-mediated Innate Immunity in Intestinal Graft-versus-Host Disease

2017

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Graft-versus-host disease (GHVD) is a severe complication after allogeneic hematopoietic stem cell transplantation. The degree of inflammation in the gastrointestinal tract, a major GVHD target organ, correlates with the disease severity. Intestinal inflammation is initiated by epithelial damage caused by pre-conditioning irradiation. In combination with damages caused by donor-derived T cells, such damage disrupts the epithelial barrier and exposes innate immune cells to pathogenic and commensal intestinal bacteria, which release ligands for Toll-like receptors (TLRs). Dysbiosis of intestinal microbiota and signaling through the TLR/myeloid differentiation primary response gene 88 (MyD88) pathways contribute to the development of intestinal GVHD. Understanding the changes in the microbial flora and the roles of TLR signaling in intestinal GVHD will facilitate the development of preventative and therapeutic strategies.

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Effect of upregulated TLR2 expression from G-CSF-mobilized donor grafts on acute graft-versus-host disease

Cited by 7 publications

References 30 publications

The Toll–Like Receptor 2/6 Agonist, FSL–1 Lipopeptide, Therapeutically Mitigates Acute Radiation Syndrome

The Toll–Like Receptor 2/6 Agonist, FSL–1 Lipopeptide, Therapeutically Mitigates Acute Radiation Syndrome

Danger Signals and Graft-versus-host Disease: Current Understanding and Future Perspectives

TLR/MyD88-mediated Innate Immunity in Intestinal Graft-versus-Host Disease

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