IL-10 and TGF-$beta; gene transfer to rodent islets: Effect on xenogeneic islet graft survival in naive and B-cell deficient mice

Deng, Shaoping; Yang, Zhaopeng; Kucher, T.; Weber, Markus; Chu, Guiyang; Shaked, A.; Markman, James; Naji, Ali; Ketchum, R.J.; Brayman, Kenneth L.

doi:10.1016/0963-6897(96)82309-8

Cited by 8 publications

(11 citation statements)

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“…Mice that received i.m. injection of up to 10 11 particles of recombinant virus per mouse appeared healthy and gained body weight at a rate similar to saline-treated mice. There was no evidence of local inflammation in the injection areas checked at 10 days after injection (data not shown).…”

Section: Efficient Transgene Expression After a Single Systemic Adminmentioning

confidence: 75%

Suppression of Autoimmune Diabetes by Viral IL-10 Gene Transfer

Yang¹,

Chen²,

Wu³

et al. 2002

The Journal of Immunology

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Th1 cell activation and cytokine production shift the balance between Th1 and Th2, favoring the up-regulation of proinflammatory activity that leads to destruction of insulin-producing pancreatic β cells in type 1 diabetes. Th2-type cytokines, such as IL-10, have immune regulatory function. Administration of IL-10, or IL-10 gene transfer, prevents autoimmune diabetes in nonobese diabetic (NOD) mice. However, constant administration of purified rIL-10 is not practical for long-term therapy to prevent diabetes. In this study, we transferred the BCRF-1 gene, an open reading frame in the Epstein-Barr viral genome with remarkable homology to mouse IL-10 (viral IL-10 or vIL-10), by an adeno-associated viral (AAV) vector to NOD mice to attain sustained vIL-10 gene expression. Like endogenous mouse IL-10, vIL-10 has potent immunoregulatory and immunosuppressive functions, but can be specifically distinguished from endogenous mouse IL-10 for monitoring of the transgene expression. A single systemic administration of AAV vIL-10 significantly reduced insulitis and prevented diabetes development in NOD mice. This protective effect correlated with sustained transgene expression and protein production. Moreover, splenocytes from the treated mice blocked diabetes transfer to NOD recipients, suggesting that vIL-10 induces an active suppression of autoimmunity. This study provides evidence to support the possibility of using vIL-10 gene therapy to prevent type 1 diabetes.

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Section: Efficient Transgene Expression After a Single Systemic Adminmentioning

confidence: 75%

Suppression of Autoimmune Diabetes by Viral IL-10 Gene Transfer

Yang¹,

Chen²,

Wu³

et al. 2002

The Journal of Immunology

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“…[19][20][21] Additionally, a series of immunoregulatory genes has been inserted into adenoviral vectors and expressed from murine islets transplanted into allogeneic and xenogeneic hosts. 11,[21][22][23][24] Although long-term expression and protection of islets from rejection has been achieved under particular experimental conditions, 23 the non-integrating nature and inherent immunogenicity of the recombinant adenovirus necessitate the use of a stably integrating, non-immunogenic gene delivery system. In this report we have demonstrated that intact islets can be infected with a lentiviral vector to a degree similar to that of adenoviral vectors.…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…Recently, the use of immunosuppressive cytokines like IL-10, TGF-␤ [9][10][11] and proteins that can block co-stimulation such as CTLA4Ig [12][13][14][15][16] and monoclonal antibodies against CD40L 17,18 has yielded promising results in a variety of animal models where allogeneic and even xenogeneic graft survival was significantly prolonged following engraftment. The local transfer of genes encoding immunosuppressive agents to islets could be used to prolong engraftment of allogeneic islets following transplantation.…”

Section: Introductionmentioning

confidence: 99%

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Infection of intact human islets by a lentiviral vector

et al. 1999

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“…For example, transfer of genes encoding immunomodulatory and cell protective molecules such as CTLA4-Ig, sCD40-Ig, IL-4, IL-10, hemoxygenase, MnSOD, and Bcl-2 to islets has resulted in prolonged survival and/or function of the transplant. [11][12][13][14][15][16] However, the rate-limiting step for successful clinical application of gene transfer to islets to facilitate transplantation is the efficiency of gene delivery. Adenoviral vectors have been used extensively for infection of both human and rodent islets, resulting in gene transfer to greater than 50% of the b-cells within the intact islet without interfering with b-cell function.…”

Section: Introductionmentioning

confidence: 99%

Efficient gene delivery to human and rodent islets with double-stranded (ds) AAV-based vectors

et al. 2005

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Transplantation of allogeneic pancreatic islets is an effective approach to treat type 1 diabetes. To bypass the need for systemic administration of immunosuppression drugs following transplantation, approaches to genetically modify allogeneic islets to express anti-inflammatory, immunosuppressive, or antiapoptotic proteins prior to transplantation are being developed. Adeno-associated viral (AAV) based vectors have been used for gene transfer to islets, but the efficiency of functional transduction is low. Recently, doublestranded (ds) or double-copy (dc) based AAV vectors have been developed that allow for more rapid and efficient AAVmediated transgene expression following transduction. Here we demonstrate that intact human and murine islets can be transduced with dsAAV2-eGFP efficiently compared to single-stranded AAV2-eGFP. Furthermore, our results demonstrate that murine islets transduced with dsAAV2-eGFP have normal islet glucose responsiveness, viability, and islet insulin content. Transplantation of the dsAAV2-eGFP transduced islet restored normal glycemia in diabetic mice without eliciting an immune response. Significant dsAAV2-mediated eGFP expression was observed in the islet grafts for at least 6 months post-transplant. Finally, we demonstrated that dsAAV serotypes 2, 6, and 8 infect human islets efficiently. Taken together, these results suggest that dsAAV based vectors are highly appropriate for gene transfer to islets to facilitate transplantation.

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IL-10 and TGF-$beta; gene transfer to rodent islets: Effect on xenogeneic islet graft survival in naive and B-cell deficient mice

Cited by 8 publications

References 0 publications

Suppression of Autoimmune Diabetes by Viral IL-10 Gene Transfer

Suppression of Autoimmune Diabetes by Viral IL-10 Gene Transfer

Infection of intact human islets by a lentiviral vector

Efficient gene delivery to human and rodent islets with double-stranded (ds) AAV-based vectors

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