Protection against Herpetic Ocular Disease by Immunotherapy with Monoclonal Antibodies to Herpes simplex Virus Glycoproteins

Abstract

In this paper we describe the ability of monoclonal antibodies to prevent herpetic stromal or interstitial keratitis following corneal infection in an outbred mouse model. Monoclonal antibodies recognizing antigenic determinants on glycoproteins B, C, D, and E of herpes simplex virus type 1 were injected intraperitoneally into CF-1 outbred mice 24 or 48 h following inoculation of the cornea with the RE strain of herpes simplex virus type 1. Passive, postexposure immunization with monoclonal antibodies had little effect on the severity of the initial corneal infection or the frequency of latent viral infections in the trigeminal ganglia, except for virus-neutralizing antibodies specific for glycoproteins B and D. A significant correlation was found between the severity of epithelial keratitis and the frequency of latent ganglionic infections. However, immunization with monoclonal antibodies protected the mice against encephalitis and prevented the development of necrotizing stromal keratitis that leads to permanent corneal scarring and blindness. This form of herpetic ocular disease does not respond to antiviral chemotherapy. Since nonneutralizing monoclonal antibodies were just as effective in prevention of encephalitis and stromal keratitis as ones that neutralized the virus in vitro, and antibodies were not administered until 24 or 48 h after corneal inoculation, we suggest that inactivation of infectious virus is not the only protective mechanism in this model.

Passive immunization protects the mouse eye from damage after herpes simplex virus infection by limiting spread of virus in the nervous system

“…We have argued previously that in non-immune animals the extensive centrifugal spread of virus back to the eye is likely to contribute significantly to the later development of severe ocular damage such as irreversible corneal opacity (Dyson et al, 1987). Hence in passively immunized mice the restricted spread of infection in the nervous system seems the most likely explanation for the absence of such damage, that we and other workers (Metcalf et al, 1987(Metcalf et al, , 1988Raizman & Foster, 1988;Foster et aL, 1988;Thompson et al, 1988;Lausch et al, 1989) have observed in such animals.…”

“…Detailed studies have been done to identify which monoclonal antibodies to viral glycoproteins (Metcalf et al, 1987(Metcalf et al, , 1988 and which subclasses oflgG (Raizman & Foster, 1988) are capable of conferring passive protection, but little is known of their site of action in vivo. We now report that passive immunization of mice before inoculation of the cornea with virus has no direct effect on replication of virus in the cornea.…”

Analysis of the role of antibody-dependent cellular cytotoxic antibody activity in murine neonatal herpes simplex virus infection with antibodies to synthetic peptides of glycoprotein D and monoclonal antibodies to glycoprotein B.

“…It has been shown that MAb reactive with infected cells but not virus could promote recovery from HSV infection (35). With some exceptions (36) neutralizing activity of MAbs has been shown to be unrelated to their in vivo protection in animal models (35,(37)(38)(39)(40). When tested, protection correlated with ADCC function (35,37,38).…”

The Herpes Simplex Virus 1 IgG Fc Receptor Blocks Antibody-Mediated Complement Activation and Antibody-Dependent Cellular CytotoxicityIn Vivo

“…Murine IgG antibody to HSV-1 (murine immune IgG) was purified from sera of mice infected by flank scarification with HSV-1 NS and bled 2 to 3 weeks postinfection. Polyclonal rabbit anti-HSV-1 (Dako), UP575 anti-gE, UP1928 anti-gI, and NC-1 anti-VP5 and murine monoclonal antibody (MAb) Fd69 anti-gI have been previously described (3,12,22,31,40,56). Antiactin MAb C4 was obtained from MP Biomedicals, while rat anti-mouse Thy1.2 (PharMingen) was used as a neuronal cell marker.…”