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Clinical and Vaccine Immunology, November 2006, p. 1223-1230, Vol. 13, No. 11
1071-412X/06/$08.00+0     doi:10.1128/CVI.00198-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Macaque Multimeric Soluble CD40 Ligand and GITR Ligand Constructs Are Immunostimulatory Molecules In Vitro

Geoffrey W. Stone,^1,2,3, Suzanne Barzee,^1, Victoria Snarsky,¹ Celsa A. Spina,^2,3 Jeffrey D. Lifson,⁴ Vinod Kumar Bhaskara Pillai,⁵ Rama Rao Amara,⁵ François Villinger,⁶ and Richard S. Kornbluth^1,3*

Department of Medicine,¹ Department of Pathology, University of California, San Diego, 9500 Gilman Drive #0679, La Jolla, California,² VA San Diego Healthcare System, 3350 La Jolla Village Dr., La Jolla, California,³ AIDS Vaccine Program, Inc., SAIC Frederick, National Cancer Institute at Frederick, Frederick, Maryland,⁴ Department of Microbiology and Immunology, Emory Vaccine Center and Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia,⁵ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia⁶

Received 31 May 2006/ Returned for modification 14 July 2006/ Accepted 28 August 2006

CD40 ligand (CD40L) and GITR ligand (glucocorticoid-induced tumor necrosis factor receptor-related protein ligand [GITRL]) are tumor necrosis factor superfamily molecules that can be used as vaccine adjuvants. In a previous human immunodeficiency virus (HIV) DNA vaccine study in mice, we found that plasmids expressing multimeric soluble forms of trimeric CD40L (i.e., many trimers) were stronger activators of CD8⁺ T-cell responses than were single-trimer soluble forms or the natural membrane-bound molecule. This report describes similar multimeric soluble molecules that were constructed for studies in macaques. Both two-trimer and four-trimer forms of macaque CD40L were active in B-cell proliferation assays using macaque and human cells. With human cells, four-trimer macaque GITRL costimulated CD4⁺ T-cell proliferation and abrogated the immunosuppressive effects of CD4⁺ CD25⁺ regulatory T cells on a mixed leukocyte reaction. These molecular adjuvants provide new tools for vaccine development in the simian immunodeficiency virus system and other macaque models.

Published ahead of print on 20 September 2006.

G.W.S. and S.B. contributed equally to this paper.

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