Adenoviral transfection of canine islet xenografts with immunosuppressive cytokine genes abrogates primary nonfunction and prolongs graft survival

Deng, Shaoping; Ketchum, R.J.; Kucher, T.; Weber, Markus; Shaked, Abraham; Naji, Ali; Brayman, Kenneth L.

doi:10.1016/s0041-1345(96)00477-0

Cited by 15 publications

(4 citation statements)

References 1 publication

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“…This may turn out to be the case for immunoregulatory cytokines whose genes are expressed at very high levels when under the control of a strong promoter like that of cytomegalovirus. 11,21,37 Indeed, even 5% of islet cells secreting a soluble protein such as IL-1Ra following lentiviral infection, may adequately suppress an autoimmune or allogeneic immune response.…”

Section: Discussionmentioning

confidence: 99%

Infection of intact human islets by a lentiviral vector

et al. 1999

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Section: Discussionmentioning

confidence: 99%

Infection of intact human islets by a lentiviral vector

et al. 1999

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“…In the case of IDDM, genetic modification of islets preceding transplantation has been shown to prolong graft survival by site-specific delivery of immunosuppressive molecules (Hunger et al, 1997;Korbutt et al, 1995;Deng et al, 1997a;Gainer et al, 1997Gainer et al, , 1998. Although retroviral or adenoviral vectors can transfer genes into primary cells, both systems have limitations for long-term transfer of genes into /3-cells.…”

Section: Overview Summarymentioning

confidence: 99%

Lentivirus-Mediated Transduction of Islet Grafts with Interleukin 4 Results in Sustained Gene Expression and Protection from Insulitis

et al. 1998

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Autoimmune destruction of islets in the pancreas leads to the development of insulin-dependent diabetes mellitus (IDDM). Replacement of insulin-producing tissue by transplantation of islets provides a cure to disease but requires immunosuppression or a means of controlling anti-graft immune responses. To promote islet survival we have utilized a local approach by expressing immunoregulatory molecules in islet grafts. The results presented here show that the human immunodeficiency virus (HIV)-based lentiviral vector is capable of stably transducing whole islets. Foreign reporter gene expression was observed both in vitro and in vivo 30 days after transplantation. Grafts containing insulin-positive beta-islet cells expressing foreign protein indicate that transduction does not interfere with glucose regulation. The absence of inflammatory infiltrates in grafts suggests that transduction does not activate the immune system. When islets transduced with an HIV vector expressing IL-4 were transplanted into diabetes-prone mice, animals were protected from autoimmune insulitis and islet destruction. As demonstrated by proliferative and cytokine analysis, protection was consistent with a switching of islet-antigen-specific T cell responses toward a Th2 phenotype. These results suggest that HIV-based lentivirus vectors can efficiently transduce islet cells with genes encoding potentially therapeutic molecules, for possibly managing diabetes.

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“…Cellular antigens can be modified to reduce recognition by the immune system (89). Immunomodulatory cytokines, such as interleukin (IL)-4, IL-10, IL-12, or TGF-0 (transforming growth factor-p), can be released locally to alter cellular responses (90). Co-stimulation pathways for T-cell activation can be blocked with CTLA4 or other proteins (91).…”

Section: Scientific Impediments Current State Of the Art For Islet Trmentioning

confidence: 99%

Scientific and Political Impediments to Successful Islet Transplantation

Bonner-Weir²

1997

Diabetes

130

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Islet transplantation is a treatment for diabetes that has the potential to normalize glucose levels and prevent the development of complications. In spite of the simplicity of the concept and the urgent need to provide such a treatment to patients, there has been a frustrating lack of progress. This perspective delves into the scientific and political impediments to success. The scientific barriers are the need to find a satisfactory source of insulin-producing tissue and the requirement to prevent this tissue from being destroyed by immune rejection and autoimmunity. The problems and potential of allografts, xenografts, and the development of cell lines are discussed. Multiple approaches to the prevention of immune destruction are considered, including immunobarrier devices, immunosuppression, development of tolerance, and genetic manipulation. The political barriers discussed include the problems of high expectations, the controversy surrounding targeted research, the balance between basic and applied research, the roles of industry and academia, the concerns about xenotransplantation, and the difficulties in developing a planned approach to the problem.

show abstract

Adenoviral transfection of canine islet xenografts with immunosuppressive cytokine genes abrogates primary nonfunction and prolongs graft survival

Cited by 15 publications

References 1 publication

Infection of intact human islets by a lentiviral vector

Infection of intact human islets by a lentiviral vector

Lentivirus-Mediated Transduction of Islet Grafts with Interleukin 4 Results in Sustained Gene Expression and Protection from Insulitis

Scientific and Political Impediments to Successful Islet Transplantation

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