Dendritic Cell Therapies in Transplantation Revisited: Deletion of Recipient DCs Deters the Effect of Therapeutic DCs

• Published in: American journal of transplantation Vol. 12; no. 6; pp. 1398 - 1408
• Main Authors: Wang, Z., Divito, S. J., Shufesky, W. J., Sumpter, T., Wang, H., Tkacheva, O. A., Wang, W., Liu, C., Larregina, A. T., Morelli, A. E.
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01.06.2012; Wiley
• Subjects: Adoptive Transfer; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Applied cell therapy and gene therapy; Biological and medical sciences; dendritic cell therapies; Dendritic Cells; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Fundamental immunology; immunosuppression; Immunosuppressive Agents - administration & dosage; Medical sciences; Mice; Mice, Inbred Strains; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Tissue, organ and graft immunology; tolerance; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplantation; Human; Dendritic cell; dendritic cell therapies; Cell therapy; Dendritic cells; Homograft; Tolerance; Accessory cell; Recipient; Transplantation; Homotransplantation; Immunosuppression; Treatment; Motivation; Antigen presenting cell; Surgery; Deletion; Graft
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2012.04060.x

A critical goal in transplantation is the achievement of donor‐specific tolerance, minimizing the use of immunosuppressants. Dendritic cells (DCs) are antigen (Ag) presenting cells (APCs) with capability to promote immunity or tolerance. The immune‐regulatory properties of DCs have been exploited for generation of tolerogenic/immunosuppressive (IS) DCs that, when transfer systemically, prolong allograft survival in murine models. Surprisingly, the in vivo mechanisms of therapies based on (donor‐ or recipient‐derived) ISDCs in transplantation remain unknown, given that previous studies investigated their effects in vitro, or ex vivo after transplantation. Since once injected, ISDCs are short‐lived and transfer Ag to recipient APCs, we assessed the role of recipient DCs by depleting them at the time of ISDC‐therapy in a mouse model of cardiac transplantation. The results indicate that, contrary to the accepted paradigm, systemically administered ISDCs reduce the alloresponse and prolong allograft survival, not by themselves, but through conventional DCs (cDCs) of the recipient. These findings raise doubts on the advantages of the currently used ISDC‐therapies, since the immune‐regulatory properties of the injected ISDC do not seem to be functionally relevant in vivo, and the quiescent/pro‐tolerogenic status of cDCs may be compromised in patients with end‐stage diseases that require transplantation. This study provides in vivo evidence that therapeutic tolerogenic dendritic cells administered systemically decrease the antidonor response and prolong cardiac allograft survival in mice, not by themselves, but through conventional dendritic cells of the recipient. See editorial by Alegre and Molinero on page 1363.