1. ECDI-fixed allogeneic splenocytes induce donor-specific tolerance for long-term survival of islet transplants via two distinct mechanisms.
- Author
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Luo X, Pothoven KL, McCarthy D, DeGutes M, Martin A, Getts DR, Xia G, He J, Zhang X, Kaufman DB, and Miller SD
- Subjects
- Animals, Antibodies immunology, Apoptosis Regulatory Proteins immunology, CD4-Positive T-Lymphocytes immunology, Cytokines immunology, Fixatives pharmacology, Histocompatibility Antigens Class I immunology, Histocompatibility Antigens Class II immunology, Humans, Interleukin-2 Receptor alpha Subunit immunology, Islets of Langerhans surgery, Islets of Langerhans Transplantation methods, Male, Mice, Mice, Inbred BALB C, Signal Transduction immunology, Spleen cytology, T-Lymphocytes immunology, Time Factors, Transplantation, Homologous, Ethyldimethylaminopropyl Carbodiimide pharmacology, Islets of Langerhans immunology, Islets of Langerhans Transplantation immunology, Spleen immunology, Transplantation Tolerance drug effects
- Abstract
A major challenge for human allogeneic islet transplantation is the development of effective methods to induce donor-specific tolerance to obviate the need for life-long immunosuppression that is toxic to the insulin-producing beta cells and detrimental to the host. We developed an efficient donor-specific tolerance therapy that utilizes infusions of ethylene carbodiimide (ECDI)-treated donor splenic antigen-presenting cells that results in indefinite survival of allogeneic islet grafts in the absence of immunosuppression. Furthermore, we show that induction of tolerance is critically dependent on synergistic effects between an intact programmed death 1 receptor-programmed death ligand 1 signaling pathway and CD4(+)CD25(+)Foxp3(+) regulatory T cells. This highly efficient antigen-specific therapy with a complete avoidance of immunosuppression has significant therapeutic potential in human islet cell transplantation.
- Published
- 2008
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