Kinetics of Leukocyte and Myeloid Cell Traffic in the Murine Corneal Allograft Response1

Kuffová, Lucia; Lumsden, Lynne; Vesela, Viera; Taylor, Julie; Filipec, Martin; Holáň, Vladimı́r; Dick, Andrew D.; Forrester, John V.

doi:10.1097/00007890-200110150-00019

Cited by 33 publications

(24 citation statements)

References 19 publications

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“…Previous studies have shown this to be a strong immune response that is difficult to suppress (5,(32)(33)(34). It is different mechanistically from allograft rejection in that CD8 ϩ T cells are not involved, and more macrophage-mediated destruction occurs at early time points (35,36). Xenografts are phylogenetically more distant than allografts, and therefore there is the potential for greater involvement of the innate immune system.…”

Section: Discussionmentioning

confidence: 99%

T Cell-Activated Macrophages Are Capable of Both Recognition and Rejection of Pancreatic Islet Xenografts

Hawthorne

Lehnert

et al. 2003

The Journal of Immunology

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Macrophages have been proposed as the major effector cell in T cell-mediated xenograft rejection. To determine their role in this response, NOD-SCID mice were transplanted with fetal pig pancreas (FPP) before reconstitution with CD4+ T cells from BALB/c mice. Twelve days after CD4+ T cell reconstitution, purified macrophages (depleted of T cells) were isolated from CD4+ T cell-reconstituted FPP recipient mice and adoptively transferred to their nonreconstituted counterparts. After adoptive macrophage transfer, FPP recipient mice transferred with macrophages from CD4+ T cell-reconstituted mice demonstrated xenograft destruction along with massive macrophage infiltration at day 4 and complete graft destruction at day 8 postmacrophage transfer. By contrast, FPP recipients that received macrophages from nonreconstituted mice showed intact FPP xenografts with few infiltrating macrophages at both days 4 and 8 after macrophage transfer. The graft-infiltrating macrophages showed increased expression of their activation markers. Depletion of endogenous macrophages or any remaining CD4+ T cells did not delay graft rejection in the macrophage-transferred FPP recipients, whereas depletion of transferred macrophages with clodronate liposomes prevented graft rejection. Our results show that macrophages primed by FPP and activated by CD4+ T cells were attracted from the peripheral circulation and were capable of specific targeting and destruction of FPP xenografts. This suggests that in xenograft rejection, there are macrophage-specific recognition and targeting signals that are independent of those received by T cells.

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Section: Discussionmentioning

confidence: 99%

T Cell-Activated Macrophages Are Capable of Both Recognition and Rejection of Pancreatic Islet Xenografts

Hawthorne

Lehnert

et al. 2003

The Journal of Immunology

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“…The implants were examined under the operating microscope on alternate days and graded according the clinical signs of increased opacity as described previously or extrusion/melt of the implant was clinically obvious. 23 The time to rejection of implants (corneal opacity score) compared with allograft corneas was recorded.…”

Section: Implantation Of Collagen-mpc Hydrogels Into Herpetic Murine mentioning

confidence: 99%

“…Hence, high doses are given systemically to treat HSK. Prophylactic use of ACV reduces disease recurrence in the cornea although not efficiently (e.g., 23.1% of patients on a 12-month treatment regime of 800 mg ACV or 500 mg of its prodrug, valacyclovir, daily still had recurrent disease). 7 Therefore, even at high doses, the drugs are not highly effective and side effects of long-term use include nausea, kidney impairment, and headache, 7 and even ACV-resistance in patients on chronic antiviral prophylaxis.…”

Section: Introductionmentioning

confidence: 99%

Cathelicidin LL-37 and HSV-1 Corneal Infection: Peptide Versus Gene Therapy

Lee

Buznyk

Kuffová

et al. 2014

Trans. Vis. Sci. Tech.

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Purpose: To evaluate the potential utility of collagen-based corneal implants with anti-Herpes Simplex Virus (HSV)-1 activity achieved through sustained release of LL-37, from incorporated nanoparticles, as compared with cell-based delivery from model human corneal epithelial cells (HCECs) transfected to produce endogenous LL-37. Methods:We tested the ability of collagen-phosphorylcholine implants to tolerate the adverse microenvironment of herpetic murine corneas. Then, we investigated the efficacy of LL-37 peptides delivered through nanoparticles incorporated within the corneal implants to block HSV-1 viral activity. In addition, LL-37 complementary DNA (cDNA) was transferred into HCECs to confer viral resistance, and their response to HSV-1 infection was examined.Results: Our implants remained in herpetic murine corneas 7 days longer than allografts. LL-37 released from the implants blocked HSV-1 infection of HCECs by interfering with viral binding. However, in pre-infected HCECs, LL-37 delayed but could not prevent viral spreading nor clear viruses from the infected cells. HCECs transfected with the LL-37 expressed and secreted the peptide. Secreted LL-37 inhibited viral binding in vitro but was insufficient to protect cells completely from HSV-1 infection. Nevertheless, secreted LL-37 reduced both the incidence of plaque formation and plaque size.Conclusion: LL-37 released from composite nanoparticle-hydrogel corneal implants and HCEC-produced peptide, both showed anti-HSV-1 activity by blocking binding. However, while both slowed down virus spread, neither was able on its own to completely inhibit the viruses.Translational Relevance: LL-37 releasing hydrogels may have potential utility as corneal substitutes for grafting in HSV-1 infected corneas, possibly in combination with LL-37 producing therapeutic cells.

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“…At the earliest time points following the onset of corneal rejection in the rat, graftinfiltrating macrophages exceed T cells and NK cells, 9 and in mice, macrophages were reported among the earliest graftinfiltrating cells, before and after the onset of corneal rejection. 10 Second, local depletion of macrophages by subconjunctival administration with clodronate liposomes of corneal allotransplant recipients significantly prolonged corneal graft survival in treated rats using two different strain combinations. 11,12 Local depletion of macrophages was found to down-regulate infiltration of all alloreactive cell types, downregulate local and systemic cytotoxic lymphocyte responses, and prevent the generation of antibodies.…”

mentioning

confidence: 98%

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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Kinetics of Leukocyte and Myeloid Cell Traffic in the Murine Corneal Allograft Response1

Cited by 33 publications

References 19 publications

T Cell-Activated Macrophages Are Capable of Both Recognition and Rejection of Pancreatic Islet Xenografts

T Cell-Activated Macrophages Are Capable of Both Recognition and Rejection of Pancreatic Islet Xenografts

Cathelicidin LL-37 and HSV-1 Corneal Infection: Peptide Versus Gene Therapy

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

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