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Disruption of CD154:CD40 Blocks Generation of Allograft Immunity Without Affecting APC Activation

David M. Shepherd and Nancy I. Kerkvliet
J Immunol September 1, 1999, 163 (5) 2470-2477;
David M. Shepherd
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Nancy I. Kerkvliet
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Abstract

CD154 (CD40 ligand, gp39) interaction with its receptor CD40 has been shown to be critically important for the generation of cell-mediated as well as humoral immunity. It has been proposed that ligation of CD40 on APCs, presumably by activated Th cells, leads to increased APC function as defined by up-regulation of costimulatory molecules and enhancement of IL-12 production. In this report, we directly examined the contribution of the CD154:CD40 pathway in a murine model of allograft rejection. Generation of both the CTL and alloantibody responses following injection with allogeneic P815 tumor cells was severely compromised in CD154 knockout mice and wild-type C57BL/6 mice treated with the anti-CD154 mAb, MR1. Splenic production of IL-2, IFN-γ, and TNF was significantly suppressed from CD154-deficient mice, indicating a lack of T cell priming. However, splenic cells from CD154 knockout mice induced comparable levels of CD86 expression and IL-12 production when compared with their wild-type littermates. The treatment of CD154−/− mice with the agonistic anti-CD40 mAb, FGK45, generated activated APCs yet failed to restore either the CTL or alloantibody responses to P815. Likewise, immunization with B7-transfected P815 tumor cells failed to generate expansion of the CTL effector population in CD154−/− mice. These results suggest that the generation of allograft immunity is dependent on the interaction of CD154 with CD40 but not primarily for the activation of APCs.

  • Received January 11, 1999.
  • Accepted June 11, 1999.
  • Copyright © 1999 by The American Association of Immunologists
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The Journal of Immunology: 163 (5)
The Journal of Immunology
Vol. 163, Issue 5
1 Sep 1999
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Disruption of CD154:CD40 Blocks Generation of Allograft Immunity Without Affecting APC Activation
David M. Shepherd, Nancy I. Kerkvliet
The Journal of Immunology September 1, 1999, 163 (5) 2470-2477;

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Disruption of CD154:CD40 Blocks Generation of Allograft Immunity Without Affecting APC Activation
David M. Shepherd, Nancy I. Kerkvliet
The Journal of Immunology September 1, 1999, 163 (5) 2470-2477;
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Print ISSN 0022-1767        Online ISSN 1550-6606