Viral interleukin-10 gene therapy to induce tolerance to solid organ transplants in mice.
In this study, a novel gene therapy approach to prolong allograft survival was designed. Autologous (syngeneic) hematopoietic stem cell-enriched bone marrow cells (HSC; lin(-)) engineered with the vIL-10 gene (vIL-10-HSC) were injected (4 to 6 x 10(6) cells, i.v.) into lethally (9.5 Gy) or sublethally (4 Gy) irradiated CBA/J mice 6 weeks prior to allogeneic heart (C57BL/6) transplantation (Tx). Cardiac allograft survival was significantly (P <.004) prolonged in lethally (71 +/- 40 days) and sublethally (114 +/- 15 days) irradiated mice that received vIL-10-HSC compared to controls that received no HSC (11 +/- 1 days), unengineered HSC, or vector-DNA-engineered HSC (12 to 16 days). Tolerant graft histopathology demonstrated mild arteritis/venulitis (grade 0.7) and rejection (grade 1.0). Intragraft expression of costimulatory molecules (B7.1, B7.2), cytokines (IL-2, IL-4, mIL-10, IFN-gamma), and iNOS molecules were markedly lower in tolerant grafts that survived for >100 days; recipient T lymphocytes demonstrated hyporeactivity to donor and third-party antigens in mixed lymphocyte cultures. These findings have important implications and potential therapeutic applications in transplantation and autoimmune diseases.
Salgar
S K
SK
Department of Surgery, University of Miami, Miami, FL 33136, USA. Ssalgar@med.miami.edu
Yang
D
D
Ruiz
P
P
Miller
J
J
Tzakis
A G
AG
D000818:Animals; D016026:Bone Marrow Transplantation; D015316:Genetic Therapy / Q000379:methods*; D006085:Graft Survival / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics* / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D033581:Stem Cell Transplantation; D023001:Transplantation Tolerance / Q000276:immunology*; D014182:Transplantation, Autologous; D014184:Transplantation, Homologous / Q000276:immunology*; D014780:Viruses / Q000276:immunology
D016753:Interleukin-10