Lentivectors encoding immunosuppressive proteins genetically engineer pancreatic β-cells to correct diabetes in allogeneic mice

Kojaoghlanian, Tsoline; Joseph, Aviva; Follenzi, Antonia; Zheng, Jin; Leiser, Margarita; Fleischer, Norman; Horwitz, Marshall S.; DiLorenzo, Teresa P.; Goldstein, Harris

doi:10.1038/gt.2008.172

Cited by 9 publications

(7 citation statements)

References 44 publications

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“…Our findings, however, do not concur with other studies reporting engraftment of MHC class I − cells in xenogeneic or allogeneic recipients without active suppression of NK cell activity [28]–[32], [56]. In view of the different strategies used in these studies (i.e.…”

Section: Discussioncontrasting

confidence: 99%

Exploitation of Herpesvirus Immune Evasion Strategies to Modify the Immunogenicity of Human Mesenchymal Stem Cell Transplants

et al. 2011

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BackgroundMesenchymal stem cells (MSCs) are multipotent cells residing in the connective tissue of many organs and holding great potential for tissue repair. In culture, human MSCs (hMSCs) are capable of extensive proliferation without showing chromosomal aberrations. Large numbers of hMSCs can thus be acquired from small samples of easily obtainable tissues like fat and bone marrow. MSCs can contribute to regeneration indirectly by secretion of cytokines or directly by differentiation into specialized cell types. The latter mechanism requires their long-term acceptance by the recipient. Although MSCs do not elicit immune responses in vitro, animal studies have revealed that allogeneic and xenogeneic MSCs are rejected.Methodology/Principal FindingsWe aim to overcome MSC immune rejection through permanent down-regulation of major histocompatibility complex (MHC) class I proteins on the surface of these MHC class II-negative cells through the use of viral immune evasion proteins. Transduction of hMSCs with a retroviral vector encoding the human cytomegalovirus US11 protein resulted in strong inhibition of MHC class I surface expression. When transplanted into immunocompetent mice, persistence of the US11-expressing and HLA-ABC-negative hMSCs at levels resembling those found in immunodeficient (i.e., NOD/SCID) mice could be attained provided that recipients' natural killer (NK) cells were depleted prior to cell transplantation.Conclusions/SignificanceOur findings demonstrate the potential utility of herpesviral immunoevasins to prevent rejection of xenogeneic MSCs. The observation that down-regulation of MHC class I surface expression renders hMSCs vulnerable to NK cell recognition and cytolysis implies that multiple viral immune evasion proteins are likely required to make hMSCs non-immunogenic and thereby universally transplantable.

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Section: Discussioncontrasting

confidence: 99%

Exploitation of Herpesvirus Immune Evasion Strategies to Modify the Immunogenicity of Human Mesenchymal Stem Cell Transplants

et al. 2011

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“…Basically, the same strategy was successfully used for the treatment of EAE and in the coecal ligation and puncture (CLP), models for multiple sclerosis and sepsis in humans, respectively [106]. Even viral proteins with immunosuppressive properties can be expressed by lentivectors to induce tolerance [116].…”

Section: �� Enetic �Odi�cation O� ��S ��mentioning

confidence: 99%

Retroviral and Lentiviral Vectors for the Induction of Immunological Tolerance

et al. 2012

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Retroviral and lentiviral vectors have proven to be particularly efficient systems to deliver genes of interest into target cells, either in vivo or in cell cultures. They have been used for some time for gene therapy and the development of gene vaccines. Recently retroviral and lentiviral vectors have been used to generate tolerogenic dendritic cells, key professional antigen presenting cells that regulate immune responses. Thus, three main approaches have been undertaken to induce immunological tolerance; delivery of potent immunosuppressive cytokines and other molecules, modification of intracellular signalling pathways in dendritic cells, and de-targeting transgene expression from dendritic cells using microRNA technology. In this review we briefly describe retroviral and lentiviral vector biology, and their application to induce immunological tolerance.

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“…The adenovirus E3 region contains, among others, the gp19K protein that interferes with MHC I‐restricted antigen presentation 114 , 115 , 116 , 117 and three proteins that inhibit apoptosis (reviewed in (Refs 118 , 119 , 120 )). Expression of the E3‐encoded MHC I‐ and apoptosis‐inhibiting proteins or the entire E3 region by β‐cells protected them from allogeneic rejection after transplantation in mice 121 , 122 . Further experiments are needed to evaluate whether this protection is because of CTL evasion or inhibition of apoptosis.…”

Section: Exploiting Herpesvirus Stealth Technologymentioning

confidence: 99%

Exploiting human herpesvirus immune evasion for therapeutic gain: potential and pitfalls

2011

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Herpesviruses stand out for their capacity to establish lifelong infections of immunocompetent hosts, generally without causing overt symptoms. Herpesviruses are equipped with sophisticated immune evasion strategies, allowing these viruses to persist for life despite the presence of a strong antiviral immune response. Although viral evasion tactics appear to target virtually any stage of the innate and adaptive host immune response, detailed knowledge is now available on the molecular mechanisms underlying herpesvirus obstruction of MHC class I-restricted antigen presentation to T cells. This opens the way for clinical application. Here, we review and discuss recent efforts to exploit human herpesvirus MHC class I evasion strategies for the rational design of novel strategies for vaccine development, cancer treatment, transplant protection and gene therapy.

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Lentivectors encoding immunosuppressive proteins genetically engineer pancreatic β-cells to correct diabetes in allogeneic mice

Cited by 9 publications

References 44 publications

Exploitation of Herpesvirus Immune Evasion Strategies to Modify the Immunogenicity of Human Mesenchymal Stem Cell Transplants

Exploitation of Herpesvirus Immune Evasion Strategies to Modify the Immunogenicity of Human Mesenchymal Stem Cell Transplants

Retroviral and Lentiviral Vectors for the Induction of Immunological Tolerance

Exploiting human herpesvirus immune evasion for therapeutic gain: potential and pitfalls

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