IFN-γ-induced production of monocyte cytotoxic factor

Kildahl-Andersen, Odd; Espevik, Terje; Nissen‐Meyer, Jon

doi:10.1016/0008-8749(85)90326-0

Cited by 21 publications

(6 citation statements)

References 36 publications

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“…Furthermore, monocytes had an additional direct cytotoxic effect on human corneal endothelium ex vivo but only in the context of inflammation. This suggests therefore that the inflammatory cellular microenvironment either drives further proinflammatory cytokine release and subsequent cytotoxicity; in keeping with published evidence showing inflammatory cytokines to promote endothelial cell apoptosis, [38][39][40][41] or that the monocytes themselves become activated and release tissue-destructive lysosomal enzymes or free radicals that are directly cytotoxic. [42][43][44] Further characterization of the fate and phenotype of the MDMs that accumulate during corneal rejection is necessary to test these hypotheses.…”

Section: Discussionsupporting

confidence: 80%

Identification of Therapeutic Targets of Inflammatory Monocyte Recruitment to Modulate the Allogeneic Injury to Donor Cornea

Lapp

Zaher

Haas

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Lapp T, Zaher SS, Haas CT, et al. Identification of therapeutic targets of inflammatory monocyte recruitment to modulate the allogeneic injury to donor cornea. Invest Ophthalmol Vis Sci. 2015;56:7250-7259. DOI:10.1167/iovs.15-16941 PURPOSE. We sought to test the hypothesis that monocytes contribute to the immunopathogenesis of corneal allograft rejection and identify therapeutic targets to inhibit monocyte recruitment. METHODS.Monocytes and proinflammatory mediators within anterior chamber samples during corneal graft rejection were quantified by flow cytometry and multiplex protein assays. Lipopolysaccharide or IFN-c stimulation of monocyte-derived macrophages (MDMs) was used to generate inflammatory conditioned media (CoM). Corneal endothelial viability was tested by nuclear counting, connexin 43, and propidium iodide staining. Chemokine and chemokine receptor expression in monocytes and MDMs was assessed in microarray transcriptomic data. The role of chemokine pathways in monocyte migration across microvascular endothelium was tested in vitro by chemokine depletion or chemokine receptor inhibitors.RESULTS. Inflammatory monocytes were significantly enriched in anterior chamber samples within 1 week of the onset of symptoms of corneal graft rejection. The MDM inflammatory CoM was cytopathic to transformed human corneal endothelia. This effect was also evident in endothelium of excised human cornea and increased in the presence of monocytes. Gene expression microarrays identified monocyte chemokine receptors and cognate chemokines in MDM inflammatory responses, which were also enriched in anterior chamber samples. Depletion of selected chemokines in MDM inflammatory CoM had no effect on monocyte transmigration across an endothelial blood-eye barrier, but selective chemokine receptor inhibition reduced monocyte recruitment significantly.CONCLUSIONS. We propose a role for inflammatory monocytes in endothelial cytotoxicity in corneal graft rejection. Therefore, targeting monocyte recruitment offers a putative novel strategy to reduce donor endothelial cell injury in survival of human corneal allografts.

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Section: Discussionsupporting

confidence: 80%

Identification of Therapeutic Targets of Inflammatory Monocyte Recruitment to Modulate the Allogeneic Injury to Donor Cornea

Lapp

Zaher

Haas

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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“…We were unable to find specific cytotoxic activity in sera from untreated cancer patients. It has previously been shown that CF is not only secreted from human monocytes, but is also linked to the monocyte membrane [6], possibly being an effector molecule in monocyte-mediated cytolysis [4], If this is the main mechanism of TNF/CF in anti-cancer defence in man, negligible amounts may be secreted and the concentration may be below the detection limit of the assay. Consequently, no firm conclusions can be drawn from our observations regarding the role of TNF in cancer patients.…”

Section: Resultsmentioning

confidence: 99%

Detection of Tumour Necrosis Factor‐Like Cytotoxicity in Serum from Patients With Septicaemia but Not from Untreated Cancer Patients

Waage¹,

Espevik²,

Lamvik³

1986

Scand J Immunol

122

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With a bioassay sensitive for recombinant tumour necrosis factor at a concentration of 10(-4) ng/ml, we were able to detect tumour necrosis factor-like cytotoxicity in serum from three patients in the initial phase of septicaemia. The cytotoxic activity corresponded to a concentration of recombinant tumour necrosis factor of 2 X 10(-2)-3 X 10(-3) ng/ml serum. The concentration in cerebrospinal fluid was estimated to be three times higher than in serum. In 23 untreated patients with malignant disease of varying origin and stage, including two patients with severe cachexia, we were not able to detect tumour necrosis factor-like cytotoxicity.

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“…In fact, none of the mice receiving human NK-depleted PBMCs survived, compared with 60% survival in the control group. Monocyte-derived cytokines, such as IL-12, IL-15, and IL-18 enhance NK cell-mediated cytotoxicity and IFN-γ production (25)(26)(27), the latter of which is likely critical for early effective monocyte/macrophage function (31)(32)(33)(34), but may also have both direct and indirect anti-tumor effects (35)(36)(37). Another potential mechanism that might account for improved survival in the GM-CSF and IL-2 treated hu-PBL-SCID mice is the production of lymphokine-activated killer cells (LAKs), which are typically generated by incubating lymphoid cells with IL-2.…”

Section: Discussionmentioning

confidence: 99%

GM-CSF and IL-2 induce specific cellular immunity and provide protection against Epstein-Barr virus lymphoproliferative disorder

Baiocchi

Ward²,

Carrodeguas³

et al. 2001

J. Clin. Invest.

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Epstein-Barr virus-associated lymphoproliferative disease (EBV-LPD) is a potentially life-threatening complication in immune-deficient patients. We have used the severe combined immune deficient (SCID) mouse engrafted with human leukocytes (hu-PBL-SCID) to evaluate the use of human cytokines in the prevention of EBV-LPD in vivo. Daily low-dose IL-2 therapy can prevent EBV-LPD in the hu-PBL-SCID mouse, but protection is lost if murine natural killer (NK) cells are depleted. Here we demonstrate that combined therapy with human GM-CSF and low-dose IL-2 is capable of preventing EBV-LPD in the hu-PBL-SCID mouse in the absence of murine NK cells. Lymphocyte depletion experiments showed that human NK cells, CD8 + T cells, and monocytes were each required for the protective effects of GM-CSF and IL-2 combination therapy. This treatment resulted in a marked expansion of human CD3 + CD8 + lymphocytes in vivo. Using HLA tetramers complexed with EBV immunodominant peptides, a subset of these lymphocytes was found to be EBV-specific. These data establish that combined GM-CSF and low-dose IL-2 therapy can prevent the immune deficiencies that lead to fatal EBV-LPD in the hu-PBL-SCID mouse depleted of murine NK cells, and they point to a critical role for several human cellular subsets in mediating this protective effect.

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IFN-γ-induced production of monocyte cytotoxic factor

Cited by 21 publications

References 36 publications

Identification of Therapeutic Targets of Inflammatory Monocyte Recruitment to Modulate the Allogeneic Injury to Donor Cornea

Identification of Therapeutic Targets of Inflammatory Monocyte Recruitment to Modulate the Allogeneic Injury to Donor Cornea

Detection of Tumour Necrosis Factor‐Like Cytotoxicity in Serum from Patients With Septicaemia but Not from Untreated Cancer Patients

GM-CSF and IL-2 induce specific cellular immunity and provide protection against Epstein-Barr virus lymphoproliferative disorder

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