Antagonistic and Agonistic Anti-canine CD28 Monoclonal Antibodies: Tools for Allogeneic Transplantation
| Autor: | Carol Loretz, Richard A. Nash, Laura J. Peterson, Scott S. Graves, Diane Stone, George E. Georges, Marina Lesnikova, Billanna Hwang, Rainer Storb |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Graft Rejection
Time Factors medicine.drug_class Recombinant Fusion Proteins T-Lymphocytes CD3 Lymphocyte Enzyme-Linked Immunosorbent Assay chemical and pharmacologic phenomena Lymphocyte proliferation Biology Pharmacology Lymphocyte Activation Monoclonal antibody T-Lymphocytes Regulatory Article Mice Dogs CD28 Antigens Antigen Antigens CD medicine Animals Transplantation Homologous Cytotoxic T cell CTLA-4 Antigen Cell Proliferation Transplantation Hybridomas Dose-Response Relationship Drug Antibodies Monoclonal CD28 hemic and immune systems Organ Transplantation Molecular biology medicine.anatomical_structure biology.protein Binding Sites Antibody Lymphocyte Culture Test Mixed T-Lymphocytes Cytotoxic |
| Zdroj: | Transplantation. 91:833-840 |
| ISSN: | 0041-1337 |
| DOI: | 10.1097/tp.0b013e31820f07ff |
| Popis: | It has been presumed that antibody-mediated selective costimulatory molecule blockade of CD28 is superior to cytotoxic T lymphocyte antigen 4 (CTLA4)-Ig. This is based on the premise that specifically blocking CD28 allows inhibitory signals through CTLA-4 to proceed, which furthermore suppresses T-cell function.The extracelluar domain of canine (ca)CD28 was cloned from dog peripheral blood mononuclear cells. Mice were immunized with a caCD28/murine IgG2a fusion protein. Hybridomas were produced by fusing splenocytes with mouse NSO cells and screened for caCD28 binding by ELISA. Agonistic and antagonistic activities of the monoclonal antibodies (mAb) were tested in mixed leukocyte reactions. Canine regulatory T cells were expanded using plate-bound anti-CD3 and an anti-CD28 agonist mAb.One agonistic and seven antagonistic mAbs to canine (ca)CD28 were cloned. Binding studies indicated that an agonistic (5B8) and an antagonistic (1C6) mAb bound equally well to a caCD28/caIgG1 fusion protein and to CD28 expressed on CD4+ and CD8+ peripheral blood T cells. Antagonistic antibody blocked mixed lymphocyte reactions (MLR) in a dose-dependent manner similar to CTLA4-Ig, whereas the agonistic antibody to caCD28 enhanced MLR. The 5B8 was superior to 1C6 when either was combined with anti-caCD3 to stimulate lymphocyte proliferation. Furthermore, the agonistic mAb, 5B8, together with anti-CD3 mAb induced 100-fold proliferation of canine regulatory T cells. Relative to untreated control cells, anti-caCD28 (1C6) and CTLA4-Ig equivalently inhibited cytotoxic T lymphocyte-mediated killing of alloreactive target cells.These studies demonstrated that mouse anti-caCD28 mAbs can be generated with agonistic or antagonistic function. |
| Databáze: | OpenAIRE |
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