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*
Clinical Immunology Section and
Medical Virology Section of Laboratory of Clinical Investigation,
Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, and
§
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
¶
Immunex Corporation, Seattle, WA 98101
CD40/CD40 ligand interactions have a central role in the induction
of both humoral and cellular immunity. In this study, we examined
whether a plasmid expressing CD40 ligand/trimer (CD40LT) could enhance
immune responses in vivo. BALB/c mice were injected with plasmid
expressing ß-galactosidase DNA with or without CD40LT DNA or IL-12
DNA, and immune responses were assessed. Mice vaccinated with ß-gal
DNA plus CD40LT DNA or IL-12 DNA had a striking increase in Ag-specific
production of IFN-
, cytolytic T cell activity, and IgG2a Ab. The
mechanism by which CD40LT DNA enhanced these responses was further
assessed by treating vaccinated mice with anti-IL-12 mAb or CTLA-4
Ig (CTLA4Ig). Production of IFN- and CTL activity was abrogated by
these treatments, suggesting that CD40LT DNA was mediating its effects
on IFN- and CTL activity through induction of IL-12 and enhancement
of B7 expression, respectively. Physiologic relevance for the ability
of CD40LT DNA to enhance immune responses by the aforementioned
pathways was shown in two in vivo models. First, with regard to CTL
activity, mice vaccinated with CD40LT DNA did not develop metastatic
tumor following challenge with lethal dose of tumor. Moreover, in a
mouse model requiring IL-12-dependent production of IFN-, mice
vaccinated with soluble Leishmania Ag and CD40LT DNA
were able to control infection with Leishmania major.
These data suggest that CD40LT DNA could be a useful vaccine adjuvant
for diseases requiring cellular and/or humoral
immunity.
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D. L. Martin, C. L. King, E. Pearlman, E. Strine, and F. P. Heinzel IFN-{gamma} Is Necessary But Not Sufficient for Anti-CD40 Antibody-Mediated Inhibition of the Th2 Response to Schistosoma mansoni Eggs J. Immunol., January 15, 2000; 164(2): 779 - 785. [Abstract] [Full Text] [PDF]
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W. W. Leitner, H. Ying, D. A. Driver, T. W. Dubensky, and N. P. Restifo Enhancement of Tumor-specific Immune Response with Plasmid DNA Replicon Vectors Cancer Res., January 1, 2000; 60(1): 51 - 55. [Abstract] [Full Text]
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K. Honey, S. P. Cobbold, and H. Waldmann CD40 Ligand Blockade Induces CD4+ T Cell Tolerance and Linked Suppression J. Immunol., November 1, 1999; 163(9): 4805 - 4810. [Abstract] [Full Text] [PDF]
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M. Perez-Melgosa, D. Hollenbaugh, and C. B. Wilson Cutting Edge: CD40 Ligand Is a Limiting Factor in the Humoral Response to T Cell-Dependent Antigens J. Immunol., August 1, 1999; 163(3): 1123 - 1127. [Abstract] [Full Text] [PDF]
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