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Effect of Herpes Simplex Virus-1 gD or gD-IL-2 DNA Vaccine on Herpetic Keratitis

Inoue, Tomoyuki M.D.; Inoue, Yoshitsugu M.D.; Hayashi, Kozaburo M.D.; Shimomura, Yoshikazu M.D.; Fujisawa, Yukio Ph.D.; Aono, Aki Ph.D.; Tano, Yasuo M.D.

doi: 10.1097/01.ico.0000263124.91639.4e
Symposium 2

Purpose To evaluate the efficacy of DNA immunization using herpes simplex virus (HSV)-1 gD or gD-IL-2 (chimeric gene of gD and human IL-2) with reference to their immune responses and preventive effect on the development of murine herpetic stromal keratitis, based on our previous work.

Methods Plasmids containing gD (pHSDneo1) or gD-IL-2 (pHDLneo1) were constructed, and gD or gD-IL-2 peptides were purified. BALB/c mice were immunized by hypodermal injection, subconjunctival injection, or topical eye drop twice at 7-day intervals. Attained anti-HSV immune reaction was estimated, including neutralizing antibody, delayed-type hypersensitivity (DTH) measured by the swelling of the ear pinna, and cytotoxic T lymphocyte (CTL) measured by 51Cr release from MHC-matched target cells by splenic and/or local lymph node cells. The corneas of a group of the immunized mice were challenged with CHR3 strain of HSV-1 (10 μL of 3 × 106 PFU/mL) 3 weeks after the last immunization. Clinical signs (stromal and epithelial keratitis) were scored.

Results All gD- or gD-IL-2-immunized mice developed specific neutralizing antibody. Delayed-type hypersensitivity and CTL were obtained in gD DNA- or gD-IL-2 DNA-immunized mice. Chimeric DNA vaccine gD-IL-2 elicited higher DTH and more vigorous CTL activity. The scores of stromal keratitis for all gD- or gD-IL-2-immunized mice were significantly suppressed, although those of epithelial keratitis were not.

Conclusion Immunization with gD or gD-IL-2 was effective against herpetic stromal keratitis. By focusing specifically on high induction of cell-mediated immunity, gD-IL-2 DNA could have possible clinical applications against HSV-1 in the future.

Department of Ophthalmology (T.I., Y.T.), Osaka University Medical School, Osaka; Department of Ophthalmology (Y.I.), Faculty of Medicine, Tottori University, Tottori; Kobe Institute of Health (K.H.), Hyogo; Department of Ophthalmology (Y.S.), Kink University School of Medicine, Osaka; and Biotechnology Research Laboratories (Y.F., A.A.), Research and Development Division, Takeda Chemical Industries, Osaka, Japan.

Address correspondence and reprint requests to Dr. T. Inoue, Department of Ophthalmology, Osaka University Medical School, 2-2 Yamad-aoka, Suita 565-0871, Japan. E-mail:

This work was supported in part by grant-in-aid no. 12470365 for scientific research from the Ministry of Education, Science and Culture, Japan, and by grants from Osaka Eye Bank and Kobe City Health and Welfare Administration.

Submitted March 26, 2002. Accepted April 26, 2002.

© 2002 Lippincott Williams & Wilkins, Inc.