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DNA Vaccination with CCL2 DNA Modified by the Addition of an Adjuvant Epitope Protects against "Nonimmune" Toxic Renal Injury

Guoping Zheng^*, Yiping Wang^*, Shi-Hua Xiang, Yuet-Ching Tay^*, Huiling Wu^,, Debbie Watson, Jason Coombes^*, Gopala K. Rangan^*, Stephen I. Alexander and David C.H. Harris^*

^* Centre for Transplantation and Renal Research, the University of Sydney at Westmead Millenium Institute; Centre for Kidney Research, the Children’s Hospital at Westmead; Department of Renal Medicine, Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales, Australia; and Department of Cancer Immunology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts

Address correspondence to: Dr. Guoping Zheng, Centre for Transplantation and Renal Research, University of Sydney at Westmead Millenium Institute, Westmead, Sydney, NSW 2145 Australia. Phone: +61-2-9845-8906; Fax: +61-2-9633-9351; guoping_zheng{at}wmi.usyd.edu.au

Received for publication February 13, 2005. Accepted for publication November 25, 2005.

CC-chemokine-encoding DNA vaccine has been reported to be capable of inducing immunologic memory to corresponding pathogenic self CC-chemokines in animal models of autoimmune disease. This study investigated whether introduction of a foreign T helper epitope into monocyte chemoattractant protein 1 (CCL2) DNA vaccine could boost its immunogenicity by inducing strong neutralizing autoantibody against the pathogenic chemokine CCL2 sufficiently to be protective in a classically nonimmune model of disease, Adriamycin nephropathy (AN). Modification of the CCL2 DNA vaccine by replacing a surface loop region of CCL2 sequence with tetanus toxoid T helper epitope P30 elicited a strong self-specific CCL2 autoantibody production, as well as an IFN-–producing T cell cellular response. The increased immunogenicity of modified CCL2 DNA vaccination but not unmodified CCL2 DNA vaccination was protective against functional and structural renal injury in rat AN. The protective effect of the modified CCL2 DNA vaccine was associated with blockade of glomerular and interstitial macrophage recruitment by neutralizing autoantibody against CCL2, which plays a critical role in eliciting renal injury in AN. Therefore, modification with a foreign T helper epitope breaks self-tolerance by inducing a cellular and humoral response against self-protein and provides a strategy to increase the potency of DNA vaccination sufficiently to afford protection in toxin-induced chronic renal disease.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673