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Immune rejection remains the major obstacle to long-term survival of allogeneic lung transplants. The expression of major histocompatibility complex molecules and minor histocompatibility antigens triggers allogeneic immune responses that can lead to allograft rejection. Transplant outcomes therefore depend on long-term immunosuppression, which is associated with severe side effects. To address this problem, we investigated the effect of genetically engineered transplants with permanently down-regulated swine leukocyte antigen (SLA) expression to prevent rejection in a porcine allogeneic lung transplantation (LTx) model. Minipig donor lungs with unmodified SLA expression (control group, n = 7) or with modified SLA expression (treatment group, n = 7) were used to evaluate the effects of SLA knockdown on allograft survival and on the nature and strength of immune responses after terminating an initial 4-week period of immunosuppression after LTx. Genetic engineering to down-regulate SLA expression was achieved during ex vivo lung perfusion by lentiviral transduction of short hairpin RNAs targeting mRNAs encoding β2-microglobulin and class II transactivator. Whereas all grafts in the control group were rejected within 3 months, five of seven animals in the treatment group maintained graft survival without immunosuppression during the 2-year monitoring period. Compared with controls, SLA-silenced lung recipients had lower donor-specific antibodies and proinflammatory cytokine concentrations in the serum. Together, these data demonstrate a survival benefit of SLA–down-regulated lung transplants in the absence of immunosuppression. Editor's summary: Solid organ transplants have saved the lives of many with late-stage organ failure. However, the need to match major histocompatibility complex (MHC) molecules reduces the number of donor-recipient pairs and results in long waits for donor organs. A strategy to avoid the need for MHC matching is to knock down MHC expression in the transplanted organ altogether. Here, Figueiredo et al. transplanted lungs that underwent gene engineering to knock down MHC expression in recipient pigs. This approach, which relied on lentiviral vectors carrying shRNAs against B2M and CIITA, effectively hid the donor lungs from the immune system, enabling long-term graft survival. Together, these results suggest that MHC knockdown may be a feasible strategy to improve graft survival after solid organ transplantation. —Courtney Malo [ABSTRACT FROM AUTHOR]