Anti-CD40 Monoclonal Antibody Synergizes with CTLA4-Ig in Promoting Long-Term Graft Survival in Murine Models of Transplantation
| Autor: | Thomas C. Pearson, Christian P. Larsen, Christopher R. Gilson, Zvonimir Milas, Diane Hollenbaugh, Shivaprakash Gangappa, Mandy L. Ford |
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| Rok vydání: | 2009 |
| Předmět: |
medicine.drug_class
Immunology Immunoglobulins Biology Monoclonal antibody Article Immune tolerance Mice Antigens CD In vivo Immune Tolerance medicine Animals Transplantation Homologous Immunology and Allergy CTLA-4 Antigen CD40 Antigens CD154 Bone Marrow Transplantation Cell Proliferation Graft Survival Antibodies Monoclonal Drug Synergism hemic and immune systems Skin Transplantation Isotype Blockade Transplantation Models Animal Monoclonal |
| Zdroj: | The Journal of Immunology. 183:1625-1635 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.0900339 |
| Popis: | Blockade of the CD40/CD154 signaling pathway using anti-CD154 antibodies has shown promise in attenuating the alloimmune response and promoting long-term graft survival in murine model systems. Unfortunately, thromboembolic side effects observed in humans have hampered its progression through clinical trials. Appropriately designed anti-CD40 antibodies may provide a suitable alternative. We investigated two isoforms of a novel monoclonal rat anti-mouse CD40 antibody (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 antibodies revealed similar responses when plate-bound. However, when present as a soluble stimulus, 7E1-G1 but not 7E1-G2b led to proliferation. Importantly, 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, while 7E1-G1 was not. The protection observed with 7E1-G2b was not due to depletion of CD40 bearing antigen presenting cells. These data suggest that an appropriately designed anti-CD40 antibody can promote graft survival as well as anti-CD154, making 7E1-G2b an attractive substitute in mouse models of costimulation blockade-based tolerance regimens. |
| Databáze: | OpenAIRE |
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