Anti-CD28 Antibody-Initiated Cytokine Storm in Canines
| Autor: | Steven Lawrence Rosinski, Rainer Storb, Mesfin M. Gewe, Julie Randolph-Habecker, Diane Stone, V. Kraig Abrams, Roland K. Strong, Della Friend, Scott S. Graves, George E. Sale |
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| Rok vydání: | 2015 |
| Předmět: |
Transplantation
Graft rejection biology business.industry Original Basic Science CD28 medicine.disease T-Cell Receptor Activation 3. Good health Blockade surgical procedures operative Immune system Immunology ComputingMethodologies_DOCUMENTANDTEXTPROCESSING medicine biology.protein Antibody Cytokine storm business |
| Zdroj: | Transplantation Direct |
| ISSN: | 2373-8731 |
| DOI: | 10.1097/txd.0000000000000516 |
| Popis: | Supplemental digital content is available in the text. Background CD28 signal blockade after T cell receptor activation is under intense investigation as a tolerance-inducing therapy for transplantation. Our goal is to produce a CD28-specific reagent as a therapy for the prevention of graft rejection and graft-versus-host disease in the canine model of allogeneic hematopoietic cell transplantation. Methods We infused a monoclonal mouse anticanine CD28 antibody (1C6 mAb) into 4 dogs and a fragment of antigen-binding (1C6 Fab) into 2 dogs. Pharmacokinetics, pathology, cytokine release, and the crystal structure of 1C6 Fv were evaluated. Results Within an hour of an intravenous injection of the 1C6 mAb, the dogs became leukopenic and developed a steroid-refractory cytokine storm. Two of the dogs developed high fevers, one experienced diffuse alveolar hemorrhage and another developed gastrointestinal hemorrhage. The cytokine storm was characterized by elevated plasma levels of monocyte chemotactic protein-1, interferon gamma inducible protein-10, interleukin (IL)-10, IL-6, and tumor necrosis factor-α. In addition, 1 dog showed elevated levels of IL-2, IL-8, and IL-18. In contrast, infusion of 1C6 Fab was well tolerated without any side effects. Dry-coating 1C6 mAb onto tissue culture plates induced CD3-independent proliferation and tumor necrosis factor-α production. Crystal structure analysis revealed that 1C6 binds to canine CD28 in a manner different than previously reported for conventional agonistic or superagonistic antibodies. Conclusions These results indicate that dogs and humans develop a similar cytokine storm after infusion of anti-CD28 mAb, providing an appropriate large animal for further study. The 1C6 Fab warrants evaluation as a tolerance-inducing reagent in the canine model of allogeneic hematopoietic cell transplantation. |
| Databáze: | OpenAIRE |
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