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 × 10⁶ cells, iv) 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-γ), 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.