The contribution of Fc effector mechanisms in the efficacy of anti-CD154 immunotherapy depends on the nature of the immune challenge
| Autor: | Christopher D. Benjamin, Ellen Garber, Norma S. Kenyon, Yen Ming Hsu, Renee I. Shapiro, Linda C. Burkly, David M. Harlan, Janine Ferrant, Frederick R. Taylor, Susan L. Kalled, Anne H. Cutler, Hess Donna M, Allan D. Kirk |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Glycosylation
medicine.medical_treatment Immunology CD40 Ligand Islets of Langerhans Transplantation chemical and pharmacologic phenomena medicine.disease_cause Antibodies Monoclonal Humanized Autoimmunity Mice Immune system Co-stimulation immune system diseases medicine Immunology and Allergy Animals Humans Lupus Erythematosus Systemic Transplantation Homologous CD40 Antigens Lupus erythematosus biology Effector Receptors IgG Immunization Passive Antibodies Monoclonal hemic and immune systems General Medicine Immunotherapy medicine.disease Kidney Transplantation Immunoglobulin Fc Fragments Transplantation Disease Models Animal Macaca fascicularis biology.protein Antibody Thrombocythemia Essential |
| Zdroj: | International immunology. 16(11) |
| ISSN: | 0953-8178 |
| Popis: | Blockade of the CD154-CD40 co-stimulatory pathway with anti-CD154 mAbs has shown impressive efficacy in models of autoimmunity and allotransplantation. Clinical benefit was also demonstrated in systemic lupus erythematosus (SLE) and idiopathic thrombocytopenia patients with the humanized anti-CD154 mAb, 5C8 (hu5C8). However, thromboembolic complications that occurred during the course of the hu5C8 clinical trials have proven to be a major setback to the field and safe alternative therapeutics targeting the CD154-CD40 pathway are of great interest. Recently, effector mechanisms have been shown to play a part in anti-CD154 mAb-induced transplant acceptance in murine models, while this issue remains unresolved for humoral-mediated models. Herein, aglycosyl anti-CD154 mAbs with reduced binding to FcgammaR and complement were used as a novel means to test the role of effector mechanisms in non-human primate and murine models not amenable to gene knockout technology. While aglycosyl hu5C8 mAb was relatively ineffective in rhesus renal and islet allotransplantation, it inhibited primary and secondary humoral responses to a protein immunogen in cynomolgus monkeys. Moreover, an aglycosyl, chimeric MR1 mAb (muMR1) prolonged survival and inhibited pathogenic auto-antibody production in a murine model of SLE. Thus, the mechanisms required for efficacy of anti-CD154 mAbs depend on the nature of the immune challenge. |
| Databáze: | OpenAIRE |
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