Severing Corneal Nerves in One Eye Induces Sympathetic Loss of Immune Privilege and Promotes Rejection of Future Corneal Allografts Placed in Either Eye

Paunicka, Kathryn; Mellon, Jessamee; Robertson, Danielle M.; Petroll, Matthew; Brown, Joseph R.; Niederkorn, Jérry Y.

doi:10.1111/ajt.13240

Cited by 73 publications

(77 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We concluded they were HSV-1 induced, as we never see sympathetic nerves in non-infected corneas [9, 10]. In other mouse models, it has been demonstrated that nerve damage alone is sufficient to increase inflammation in the cornea and rescind corneal immune privilege [42]. It remains to be determined whether these modest changes in corneal innervation and sensitivity following HSV-1 KOS infection of C57BL/6 mice result in, or contribute to, the subclinical inflammation that persists in the corneas remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Subclinical Herpes Simplex Virus Type 1 Infections Provide Site-Specific Resistance to an Unrelated Pathogen

Rowe

Yun

Treat

et al. 2017

The Journal of Immunology

View full text Add to dashboard Cite

Herpes Simplex Virus-1 (HSV-1) infections of the cornea range in severity from minor transient discomfort to the blinding disease Herpes Stromal Keratitis (HSK), yet most patients experience a single episode of epithelial keratitis followed by reestablishment of a clear cornea. We asked if a single transient episode of HSV-1 epithelial keratitis causes long-term changes in the corneal microenvironment that influence immune responses to subsequent corneal infection or trauma. We showed that C57BL/6 mouse corneas infected with HSV-1 KOS, which induces transient herpes epithelial keratitis without HSK sequelae, possessed a significant leukocytic infiltrate comprised primarily of CD4+ T cells and macrophages along with elevated chemokines and cytokines that persisted without loss of corneal clarity (subclinical inflammation). Chemokine and cytokine expression was CD4+T cell-dependent, in that their production was significantly reduced by systemic CD4+T cell depletion starting before infection, although short-term (3 day) local CD4+ T cell depletion after infection did not influence chemokine levels in cornea. Corneas with subclinical inflammation developed significantly greater trauma-induced inflammation when they were recipients of syngeneic corneal transplants, but also exhibited significantly increased resistance to infections by unrelated pathogens such as pseudorabies virus (PRV). The resistance to PRV was CD4+ T cell-dependent, since it was eliminated by local CD4+T cell-depletion from the cornea. We conclude that transient HSV-1 corneal infections cause long-term alterations of the corneal microenvironment that provide CD4-dependent innate resistance to subsequent infections by antigenically unrelated pathogens.

show abstract

Section: Discussionmentioning

confidence: 99%

Subclinical Herpes Simplex Virus Type 1 Infections Provide Site-Specific Resistance to an Unrelated Pathogen

Rowe

Yun

Treat

et al. 2017

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Moreover, we also report preservation of corneal nerve sensitivity in challenged mice. This novel insight is relevant as neurogenic maintenance of immune privilege has also been suggested (67,68). Further substantiating the interplay of vaccine-mediated correlates of protection and prevention of ocular disease will also provide a basis for the development of vaccines or therapies for use against other ocular pathogens.…”

Section: Discussionmentioning

confidence: 87%

A Highly Efficacious Herpes Simplex Virus 1 Vaccine Blocks Viral Pathogenesis and Prevents Corneal Immunopathology via Humoral Immunity

Royer

Gurung

Jinkins

et al. 2016

J Virol

View full text Add to dashboard Cite

Correlates of immunologic protection requisite for an efficacious herpes simplex virus 1 (HSV-1) vaccine remain unclear with respect to viral pathogenesis and clinical disease. In the present study, mice were vaccinated with a novel avirulent, live attenuated virus (0⌬NLS) or an adjuvanted glycoprotein D subunit (gD-2) similar to that used in several human clinical trials. Mice vaccinated with 0⌬NLS showed superior protection against early viral replication, neuroinvasion, latency, and mortality compared to that of gD-2-vaccinated or naive mice following ocular challenge with a neurovirulent clinical isolate of HSV-1. Moreover, 0⌬NLS-vaccinated mice exhibited protection against ocular immunopathology and maintained corneal mechanosensory function. Vaccinated mice also showed suppressed T cell activation in the draining lymph nodes following challenge. Vaccine efficacy correlated with serum neutralizing antibody titers. Humoral immunity was identified as the correlate of protection against corneal neovascularization, HSV-1 shedding, and latency through passive immunization. Overall, 0⌬NLS affords remarkable protection against HSV-1-associated ocular sequelae by impeding viral replication, dissemination, and establishment of latency. IMPORTANCEHSV-1 manifests in a variety of clinical presentations ranging from a rather benign "cold sore" to more severe forms of infection, including necrotizing stromal keratitis and herpes simplex encephalitis. The present study was undertaken to evaluate a novel vaccine to ocular HSV-1 infection not only for resistance to viral replication and spread but also for maintenance of the visual axis. The results underscore the necessity to reconsider strategies that utilize attenuated live virus as opposed to subunit vaccines against ocular HSV-1 infection. Herpes simplex virus 1 (HSV-1) is a highly successful human pathogen that results in approximately 40,000 new cases of severe visual impairment each year (1). In such cases, the immune response to the pathogen inadvertently mediates corneal pathology. Moreover, the morbidity associated with ocular infection results from episodic viral recrudescence (2, 3). This etiology is dependent upon reactivation of HSV-1 from latently infected neurons within the trigeminal ganglion (TG), which innervates the cornea and orofacial mucosae. Although gamma interferon (IFN-␥) and other cytokines secreted by T cells and other cornearesident cells facilitate viral clearance in the cornea, these soluble factors also recruit neutrophils and activate macrophages replete with proteases that instigate extracellular matrix remodeling and scar formation, thereby compromising visual acuity (4-10). Furthermore, protracted inflammatory responses sustained beyond clearance of the virus contribute to corneal neovascularization (1, 11). Consequently, developing HSV vaccines that elicit robust protection against infection without enhancing the risk for corneal immunopathology is an important clinical matter as no sanctioned HSV vaccine clinical trials to dat...

show abstract

“…10 We recently found that a similar condition occurs in a mouse model of penetrating keratoplasty in which 50% of the first-time corneal allografts enjoyed long-term survival even in the absence of major histocompatibility complex (MHC) matching and without immunosuppressive drugs. 11 However, >90% of subsequent corneal allografts underwent rejection even if the second corneal transplant was from a donor mouse strain entirely unrelated to the donor of the first corneal allograft. 11 The heightened incidence and tempo of rejection for second corneal allografts was associated with a loss of T reg function.…”

mentioning

confidence: 99%

Effect of Corneal Nerve Ablation on Immune Tolerance Induced by Corneal Allografts, Oral Immunization, or Anterior Chamber Injection of Antigens

Mao

Neelam

Mellon

et al. 2017

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

PurposeSevering corneal nerves during corneal transplantation does not affect first corneal transplants, but abolishes immune privilege of subsequent corneal allografts. This abrogation of immune privilege is attributable to the disabling of T regulatory cells (T regs) induced by corneal transplantation. The goal of this study was to determine if severing corneal nerves induces the development of contrasuppressor (CS) cells, which disable T regs that impair other forms of immune tolerance.MethodsEffect of corneal nerve ablation on immune tolerance was assessed in four forms of immune tolerance: anterior chamber–associated immune deviation (ACAID); oral tolerance; corneal transplantation, and intravenously (IV) induced immune tolerance. T regulatory cell activity was assessed by adoptive transfer and by local adoptive transfer (LAT) of suppression assays.ResultsCorneal nerve ablation prevented ACAID and oral tolerance, but did not affect IV-induced immune tolerance. Contrasuppressor cells blocked the action of T regs that were generated by anterior chamber injection, oral tolerance, or orthotopic corneal transplantation. The neuropeptide substance P (SP) was crucial for contrasuppressor activity as CS cells could not be induced in SP−/− mice and the SP receptor inhibitor, Spantide II, prevented the expression of CS cell activity in vivo. Contrasuppressor cells expressed CD11c surface marker that identifies dendritic cells (DC).ConclusionsThe loss of immune privilege produced by corneal nerve ablation following corneal transplantation extends beyond the eye and also affects immune tolerance induced through mucosal surfaces and appears to be mediated by a novel cell population of CD11c+ CS cells that disables T regs.

show abstract

Severing Corneal Nerves in One Eye Induces Sympathetic Loss of Immune Privilege and Promotes Rejection of Future Corneal Allografts Placed in Either Eye

Cited by 73 publications

References 39 publications

Subclinical Herpes Simplex Virus Type 1 Infections Provide Site-Specific Resistance to an Unrelated Pathogen

Subclinical Herpes Simplex Virus Type 1 Infections Provide Site-Specific Resistance to an Unrelated Pathogen

A Highly Efficacious Herpes Simplex Virus 1 Vaccine Blocks Viral Pathogenesis and Prevents Corneal Immunopathology via Humoral Immunity

Effect of Corneal Nerve Ablation on Immune Tolerance Induced by Corneal Allografts, Oral Immunization, or Anterior Chamber Injection of Antigens

Contact Info

Product

Resources

About