Endogenous dendritic cells mediate the effects of intravenously injected therapeutic immunosuppressive dendritic cells in transplantation

• Published in: Blood Vol. 116; no. 15; pp. 2694 - 2705
• Main Authors: Divito, Sherrie J., Wang, Zhiliang, Shufesky, William J., Liu, Quan, Tkacheva, Olga A., Montecalvo, Angela, Erdos, Geza, Larregina, Adriana T., Morelli, Adrian E.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 14.10.2010; Americain Society of Hematology; American Society of Hematology
• Series: Immunobiology
• Subjects: Animals; Antigen Presentation; Base Sequence; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; Cell Differentiation; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - transplantation; DNA Primers - genetics; Hematologic and hematopoietic diseases; Immunobiology; Immunosuppression; Injections, Intravenous; Isoantigens; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Tissue Donors; Transplantation, Homologous; Dendritic cell; Immunosuppression; Endogenous; Treatment; Intravenous administration; Hematology; Antigen presenting cell; Surgery; Graft; Transplantation; Immunosuppressive agent
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-10-251058

The prevailing idea regarding the mechanism(s) by which therapeutic immunosuppressive dendritic cells (DCs) restrain alloimmunity is based on the concept that they interact directly with antidonor T cells, inducing anergy, deletion, and/or regulation. However, this idea has not been tested in vivo. Using prototypic in vitro–generated maturation-resistant (MR) DCs, we demonstrate that once MR-DCs carrying donor antigen (Ag) are administered intravenously, they decrease the direct and indirect pathway T-cell responses and prolong heart allograft survival but fail to directly regulate T cells in vivo. Rather, injected MR-DCs are short-lived and reprocessed by recipient DCs for presentation to indirect pathway CD4+ T cells, resulting in abortive activation and deletion without detrimental effect on the number of indirect CD4+ FoxP3+ T cells, thus increasing the regulatory to effector T cell relative percentage. The effect on the antidonor response was independent of the method used to generate therapeutic DCs or their viability; and in accordance with the idea that recipient Ag-presenting cells mediate the effects of therapeutic DCs in transplantation, prolongation of allograft survival was achieved using donor apoptotic MR-DCs or those lacking surface major histocompatibility complex molecules. We therefore conclude that therapeutic DCs function as Ag-transporting cells rather than Ag-presenting cells to prolong allograft survival.