Infusion of Mesenchymal Stem Cells and Rapamycin Synergize to Attenuate Alloimmune Responses and Promote Cardiac Allograft Tolerance

• Published in: American journal of transplantation Vol. 9; no. 8; pp. 1760 - 1772
• Main Authors: Ge, W., Jiang, J., Baroja, M. L., Arp, J., Zassoko, R., Liu, W., Bartholomew, A., Garcia, B., Wang, H.
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01.08.2009; Wiley
• Subjects: Animal models; Animals; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; Cell Movement - physiology; Cells, Cultured; dendritic cells; Dendritic Cells - pathology; Dose-Response Relationship, Drug; Forkhead Transcription Factors - metabolism; Graft Rejection - immunology; Graft Rejection - prevention & control; Heart Transplantation - immunology; Heart Transplantation - pathology; Immunosuppressive Agents - therapeutic use; Interleukin-2 Receptor alpha Subunit - metabolism; Male; Medical sciences; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells - pathology; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Transgenic; Models, Animal; Pharmacology. Drug treatments; regulatory T cells; Sirolimus - therapeutic use; stem cells; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; tolerance induction; transplant immunology and tolerance; Transplantation Tolerance - immunology; Antineoplastic agent; Heart; Animal model; Animal models; Sirolimus; Stem cell; Transplantation; tolerance induction; Homotransplantation; Allogeneic system; Macrocycle; Isoimmunization; Immunology; dendritic cells; Antigen presenting cell; Surgery; T-Lymphocyte; Graft; Protein synthesis inhibitor; Regulatory cell; Dendritic cell; stem cells; Immune response; Lactone; Accessory cell; Mesenchymal cell; Macrolide; regulatory T cells; Antibiotic; Treatment; Perfusion; Immune tolerance; transplant immunology and tolerance; Circulatory system; Immunosuppressive agent; Antibacterial agent
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2009.02721.x

The inherent immunosuppressive properties and low immunogenicity of mesenchymal stems cells (MSCs) suggested their therapeutic potential in transplantation. We investigated whether MSCs could prolong allograft survival. Treatment involving infusion of MSCs into BALB/c recipients 24 hours after receiving a heart allograft from a C57BL/6 donor significantly abated rejection and doubled graft mean survival time compared to untreated recipients. Furthermore, combination therapy of MSCs and low‐dose Rapamycin (Rapa) achieved long‐term heart graft survival (>100 days) with normal histology. The treated recipients readily accepted donor skin grafts but rejected third‐party skin grafts, indicating the establishment of tolerance. Tolerant recipients exhibited neither intragraft nor circulating antidonor antibodies, but demonstrated significantly high frequencies of both tolerogenic dendritic cells (Tol‐DCs) and CD4+CD25+Foxp3+T cells in the spleens. Infusion of GFP+C57BL/6‐MSCs in combination with Rapa revealed that the GFP‐MSCs accumulated in the lymphoid organs and grafts of tolerant recipients. Thus, engraftment of infused MSCs within the recipient's lymphoid organs and allograft appeared to be instrumental in the induction of allograft‐specific tolerance when administered in combination with a subtherapeutic dose of Rapamycin. This study supports the clinical applicability of MSCs in transplantation. Engraftment of infused mesenchymal stem cells combined with rapamycin synergistically induced prolonged heart transplant survival in mice, with high frequencies of tolerogenic dendritic cells and CD4+CD25+Foxp3+ T cells.