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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0900339v1 183/3/1625    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Gilson, C. R. Articles by Larsen, C. P. PubMed PubMed Citation Articles by Gilson, C. R. Articles by Larsen, C. P.

Anti-CD40 Monoclonal Antibody Synergizes with CTLA4-Ig in Promoting Long-Term Graft Survival in Murine Models of Transplantation

Christopher R. Gilson^*, Zvonimir Milas^*, Shivaprakash Gangappa^*, Diane Hollenbaugh, Thomas C. Pearson^*, Mandy L. Ford^* and Christian P. Larsen^1,*

^* Department of Surgery and Emory Transplant Center, Emory University, Atlanta, GA 30322; and Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543

Blockade of the CD40/CD154 signaling pathway using anti-CD154 Abs has shown promise in attenuating the alloimmune response and promoting long-term graft survival in murine model systems, although side effects observed in humans have hampered its progression through clinical trials. Appropriately designed anti-CD40 Abs may provide a suitable alternative. We investigated two isoforms of a novel monoclonal rat anti-mouse CD40 Ab (7E1) for characteristics and effects mirroring those of anti-CD154: 7E1-G1 (an IgG1 isotype); and 7E1-G2b (an IgG2b isotype). In vitro proliferation assays to measure the agonist properties of the two anti-CD40 Abs revealed similar responses when plate bound. However, when present as a soluble stimulus, 7E1-G1 but not 7E1-G2b led to proliferation. 7E1-G2b was as effective as anti-CD154 when administered in vivo in concert with CTLA4-Ig in promoting both allogeneic bone marrow chimerism and skin graft survival, whereas 7E1-G1 was not. The protection observed with 7E1-G2b was not due to depletion of CD40-bearing APCs. These data suggest that an appropriately designed anti-CD40 Ab can promote graft survival as well as anti-CD154, making 7E1-G2b an attractive substitute in mouse models of costimulation blockade-based tolerance regimens.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Christian P. Larsen, Woodruff Memorial Building Suite 5105, Emory University, 101 Woodruff Circle, Atlanta, GA 30322. E-mail address: clarsen{at}emory.edu

² Abbreviations used in this paper: 7-AAD, 7-aminoactinomycin D; sCD154, soluble CD154 fusion protein; mOVA, murine OVA; MST, median survival time.