Abstract

Ocular infection with herpes simplex virus 1 (HSV-1) results in a chronic immunoinflamammtory reaction in the cornea, which is primarily orchestrated by CD4(+) T cells. Hence, targeting proinflammatory CD4(+) T cells or increasing the representation of cells that regulate their function is a relevant therapeutic strategy. In this report, we demonstrate that effective therapeutic control can be achieved using a combination of approaches under circumstances where monotherapy is ineffective. We use a convenient and highly effective monoclonal antibody (MAb) approach with MAbT25 to expand cells that express the tumor necrosis factor receptor superfamily member 25 (TNFRSF25). In naïve animals, these are predominantly cells that are Foxp3-positive regulatory T cells. MAbT25 treatment before or at the time of initial HSV infection was an effective means of reducing the severity of subsequent stromal keratitis lesions. However, MAbT25 treatment was not effective if given 6 days after infection since it expanded proinflammatory effector T cells, which also express TNFRSF25. Therefore, the MAbT25 procedure was combined with galectin-9 (Gal-9), an approach that compromises the activity of T cells involved in tissue damage. The combination therapy provided highly effective lesion control over that achieved by treatment with one of them. The beneficial outcome of the combination therapy was attributed to the expansion of the regulatory T cell population that additionally expressed activation markers such as CD103 needed to access inflammatory sites. Additionally, there was a marked reduction of CD4(+) gamma interferon-producing effector T cells responsible for orchestrating the tissue damage. The approach that we describe has potential application to control a wide range of inflammatory diseases, in addition to stromal keratitis, an important cause of human blindness.

Links

Publisher Full Text

Authors

J Reddy PB, Schreiber TH, Rajasagi NK, Suryawanshi A, Mulik S, Veiga-Parga T, Niki T, Hirashima M, Podack ER, Rouse BT

Institution

Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, USA.

Source

Journal of virology 86:19 2012 Oct pg 10606-20

MeSH

Animals
Antibodies
Antibodies, Monoclonal
Antigens, CD
Apoptosis
CD4-Positive T-Lymphocytes
Cell Proliferation
Cornea
Cricetinae
Female
Forkhead Transcription Factors
Galectins
Green Fluorescent Proteins
Herpes Simplex
Inflammation
Integrin alpha Chains
Keratitis, Herpetic
Kinetics
Mice
Mice, Inbred C57BL
Receptors, Tumor Necrosis Factor, Member 25
Simplexvirus

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

22811539