Ethylenecarbodiimide-Fixed Donor Splenocyte Infusions Differentially Target Direct and Indirect Pathways of Allorecognition for Induction of Transplant Tolerance
| Autor: | J. L. Houlihan, Zheng Zhang, Shusen Wang, Stephen D. Miller, James Tasch, Nadine M. Lerret, Kathryn L. Pothoven, Taba Kheradmand, Jane Bryant, Xunrong Luo |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Isoantigens medicine.medical_treatment Immunology Antigen-Presenting Cells Mice Transgenic Spleen Biology Article Mice medicine Splenocyte Animals Immunology and Allergy Gene Knock-In Techniques IL-2 receptor Infusions Intravenous Allorecognition Lymph node Mice Knockout Mice Inbred BALB C Phagocytes Spleen transplantation Graft Survival FOXP3 Adoptive Transfer Mice Inbred C57BL Transplantation Carbodiimides Cross-Linking Reagents medicine.anatomical_structure Transplantation Tolerance Signal Transduction |
| Zdroj: | The Journal of Immunology. 189:804-812 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1103705 |
| Popis: | Strategic exposure to donor Ags prior to transplantation can be an effective way for inducting donor-specific tolerance in allogeneic recipients. We have recently shown that pretransplant infusion of donor splenocytes treated with the chemical cross-linker ethylenecarbodiimide (ECDI-SPs) induces indefinite islet allograft survival in a full MHC-mismatched model without the need for any immunosuppression. Mechanisms of allograft protection by this strategy remain elusive. In this study, we show that the infused donor ECDI-SPs differentially target T cells with indirect versus direct allospecificities. To target indirect allospecific T cells, ECDI-SPs induce upregulation of negative, but not positive, costimulatory molecules on recipient splenic CD11c+ dendritic cells phagocytosing the injected ECDI-SPs. Indirect allospecific T cells activated by such CD11c+ dendritic cells undergo robust initial proliferation followed by rapid clonal depletion. The remaining T cells are sequestered in the spleen without homing to the graft site or the graft draining lymph node. In contrast, direct allospecific T cells interacting with intact donor ECDI-SPs not yet phagocytosed undergo limited proliferation and are subsequently anergized. Furthermore, CD4+CD25+Foxp3+ T cells are induced in lymphoid organs and at the graft site by ECDI-SPs. We conclude that donor ECDI-SP infusions target host allogeneic responses via a multitude of mechanisms, including clonal depletion, anergy, and immunoregulation, which act in a synergistic fashion to induce robust transplant tolerance. This simple form of negative vaccination has significant potential for clinical translation in human transplantation. |
| Databáze: | OpenAIRE |
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