Specific Prolongation of Skin Graft Survival Following Retroviral Transduction of Bone Marrow With an Allogeneic Major Histocompatibility Complex Gene

Sykes, Megan; Sachs, David H.; Nienhuis, Arthur W.; Pearson, Denise A.; Moulton, A D; Bodine, David M.

doi:10.1097/00007890-199301000-00037

Cited by 102 publications

(37 citation statements)

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“…These include donor MHC gene transfer to recipient thymus 29 or BM. 30,31 Thus, retroviral constructs have been employed for ex vivo transfer of MHC class I genes into recipient hematopoietic cells to confer specific hyporesponsiveness to allogeneic skin grafts. Alternatively, transfection of donor organs with…”

Section: Discussionmentioning

confidence: 99%

Adenoviral delivery of CTLA4Ig into myeloid dendritic cells promotes their in vitro tolerogenicity and survival in allogeneic recipients

et al. 1999

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Dendritic cells (DC) are highly specialized antigennon-transduced DC. Whereas transduction of marker presenting cells (APC) that initiate and modulate immune genes (LacZ or enhanced green fluorescence protein responses. They are essential for naive T cell activation, (EGFP) ) did not alter their potent allostimulatory activity, but may also play roles both in central and peripheral toler-DC transduced with CTLA4Ig exhibited striking reductions ance. Blockade of costimulatory pathways that provide the in cell surface staining for CD86, but not MHC class II, and crucial second signal for lymphocyte activation is one stratwere poor stimulators of T cell proliferation and cytotoxic egy to augment the potential tolerogenicity of DC. Here, in T lymphocyte (CTL) responses. In addition, they induced vitro propagated DC were transduced using an adenoviral alloantigen-specific T cell hyporesponsiveness. They were (Ad) vector to express the gene encoding cytotoxic T detected, following local injection, in significantly increased lymphocyte antigen 4-immunoglobulin (CTLA4Ig), which numbers in the lymphoid tissue of unmodified allogeneic blocks interaction of CD80 and CD86 on DC with CD28 on recipients. This is the first report of the functional properties T cells. Supernatants of AdCTLA4Ig-transduced DC strikof DC genetically engineered to express CTLA4Ig. ingly inhibited mixed leukocyte reactions (MLR) induced by

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Section: Discussionmentioning

confidence: 99%

Adenoviral delivery of CTLA4Ig into myeloid dendritic cells promotes their in vitro tolerogenicity and survival in allogeneic recipients

et al. 1999

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“…Recently, gene transfer techniques have been investigated to avoid graft rejection, 23,26,[30][31][32][33] using delivery of immunomodulating molecules 23,26,[30][31][32] or alloantigens 33 within the graft. The rationale behind local immunosuppression is based on the following two hypotheses: first, that rejection can be effectively suppressed by controlling only those immunologic events that occur at the graft site, and second, that by administering immunosuppressants directly into the allograft, one can simultaneously prevent rejection and diminish or eliminate both drugspecific and general adverse consequences of systemic immunosuppression.…”

Section: Discussionmentioning

confidence: 99%

“…To date, gene transfer into grafts has been achieved by modifying the graft either ex vivo just before grafting, [19][20][21][22]30 or in vivo upon grafting. 23,26,32,33 Our successful outcome following in vivo IL-10 gene transfer before grafting provides the basis for effective IL-10 gene therapies to suppress the immune response following allotransplantation.…”

Section: Figure 2 Histologic Findings In Hepatic Grafts After Hematoxmentioning

confidence: 99%

Allograft transduction of IL-10 prolongs survival following orthotopic liver transplantation

et al. 1999

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Interleukin-10 (IL-10) is an ideal candidate cytokine for AdCMVhIL-10 induced a prolongation of median survival suppressing the alloimmune response in transplantation.to more than 87 days, with two of five transduced grafts To determine whether genetic modulation of the hepatic showing more than 100 days of ongoing survival, when graft with IL-10 could prolong survival following orthotopic compared with 11 days for grafts transduced with a control liver transplantation, we constructed a replication-deficient adenovirus vector carrying the E. coli ␤-galactosidase adenovirus vector expressing human IL-10 (AdCMVhILgene (P = 0.0021) and 11 days for untreated grafts 10). Intraportal injection of this vector into a donor rat 24-(P = 0.0021). Pathological findings occurring in the 48 h before grafting resulted in efficient release of IL-10AdCMVhIL-10-transduced hepatic grafts revealed no eviinto the circulation of a recipient rat after transplantation.dence of progressive rejection reaction resulting in graft Moreover, levels of hIL-10 from the suprahepatic venafailure. These results demonstrate that hepatic grafts cava were significantly (1.48-fold) higher than those from modulated by IL-10 gene transfer make local and effective the infrahepatic vena cava (P = 0.013), indicating local ILimmunosuppression feasible in the transplantation setting. 10 production within the transduced hepatic graft.

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“…81,82 These cells have been shown to offer significant advantages over the use of differentiated cell types and may be capable of inducing specific tolerance to transgenic proteins. [83][84][85] In experiments carried out by the Dunbar laboratory, a retroviral neoexpression vector was delivered, ex vivo, to both lymphocytes and hematopoietic stem cells (HSCs) and subsequently reinjected into Rhesus monkeys. 86 The modified lymphocytes were quickly rejected by the host, whereas transfer of the genetically modified HSCs resulted in long-term engraftment and tolerance to the neopeptide.…”

Section: A "Dangerous" Therapymentioning

confidence: 99%

Dangerous liaisons: the role of “danger” signals in the immune response to gene therapy

Brown

Lillicrap

2002

Blood

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Specific Prolongation of Skin Graft Survival Following Retroviral Transduction of Bone Marrow With an Allogeneic Major Histocompatibility Complex Gene

Cited by 102 publications

References 0 publications

Adenoviral delivery of CTLA4Ig into myeloid dendritic cells promotes their in vitro tolerogenicity and survival in allogeneic recipients

Adenoviral delivery of CTLA4Ig into myeloid dendritic cells promotes their in vitro tolerogenicity and survival in allogeneic recipients

Allograft transduction of IL-10 prolongs survival following orthotopic liver transplantation

Dangerous liaisons: the role of “danger” signals in the immune response to gene therapy

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