Skip to main content
Journal cover image

A novel approach to xenotransplantation combining surface engineering and genetic modification of isolated adult porcine islets.

Publication ,  Journal Article
Contreras, JL; Xie, D; Mays, J; Smyth, CA; Eckstein, C; Rahemtulla, FG; Young, CJ; Anthony Thompson, J; Bilbao, G; Curiel, DT; Eckhoff, DE
Published in: Surgery
September 2004

BACKGROUND: Effective cytoprotection to xenoislets would circumvent the major tissue limitation for pancreatic islet transplantation (PIT). Cell-surface engineering with poly[ethylene glycol] (PEG) derivatives can successfully prevent antibody binding to the surface antigens. Gene transfer of the antiapoptotic Bcl-2 gene has been shown to decrease cytotoxicity mediated by xenoreactive natural antibodies and complement. In this study, we assessed survival and function of surface-engineered porcine islets genetically modified to overexpress Bcl-2. METHODS: Incorporation of PEG derivatives into the islet surface and adenovirus-mediated gene transfer of Bcl-2 (AdBcl-2) was accomplished within 24 hours post-isolation. Cytotoxicity induced by human xenoreactive natural antibodies was evaluated by islet intracellular lactate dehydrogenase release and microscopic analysis using membrane-integrity staining. Islet functionality was assessed by static incubation and after intraportal infusion (5000 IEQ) into diabetic NOD-SCID mice reconstituted with human lymphocytes (5 x 10 8 /intraperitoneally/15 days before PIT). RESULTS: No significant change in islet viability, morphology, and functionality was demonstrated after the incorporation of PEG-mono-succimidyl-succinate (MSPEG), or PEG-di-succimidyl-succinate "end"-capped with albumin (DSPEG) with or without gene transfer of Bcl-2. Islets treated with MSPEG presented a significant reduction in lactate dehydrogenase release compared with controls (41.2 +/- 3 vs 72.1 +/- 7, respectively, P <.05). Further protection was accomplished by DSPEG or AdBcl-2. The maximal cytoprotection was achieved by DSPEG +AdBcl-2 (15.5 +/- 4.9%, P <.001). Nonfasting glucose >200 mg/dL was found in 100% of the animals given control islets (n = 6) within 48 hours post-transplant. In contrast, euglycemia was achieved in 100% of the animals given islets modified with DSPEG + AdBcl-2 during the observation time. CONCLUSIONS: Surface-engineering with functionalized PEG derivatives in combination with genetic modification with Bcl-2 significantly reduced islet loss after PIT. Application of this novel technology may improve results in xenoislet transplantation.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Surgery

DOI

ISSN

0039-6060

Publication Date

September 2004

Volume

136

Issue

3

Start / End Page

537 / 547

Location

United States

Related Subject Headings

  • Transplantation, Heterologous
  • Swine
  • Surgery
  • Surface-Active Agents
  • Polyethylene Glycols
  • Models, Animal
  • Islets of Langerhans Transplantation
  • Islets of Langerhans
  • Genes, bcl-2
  • Gene Transfer Techniques
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Contreras, J. L., Xie, D., Mays, J., Smyth, C. A., Eckstein, C., Rahemtulla, F. G., … Eckhoff, D. E. (2004). A novel approach to xenotransplantation combining surface engineering and genetic modification of isolated adult porcine islets. Surgery, 136(3), 537–547. https://doi.org/10.1016/j.surg.2004.05.031
Contreras, Juan L., Dong Xie, Jimmy Mays, Cheryl A. Smyth, Christopher Eckstein, Firoz G. Rahemtulla, Carlton J. Young, et al. “A novel approach to xenotransplantation combining surface engineering and genetic modification of isolated adult porcine islets.Surgery 136, no. 3 (September 2004): 537–47. https://doi.org/10.1016/j.surg.2004.05.031.
Contreras JL, Xie D, Mays J, Smyth CA, Eckstein C, Rahemtulla FG, et al. A novel approach to xenotransplantation combining surface engineering and genetic modification of isolated adult porcine islets. Surgery. 2004 Sep;136(3):537–47.
Contreras, Juan L., et al. “A novel approach to xenotransplantation combining surface engineering and genetic modification of isolated adult porcine islets.Surgery, vol. 136, no. 3, Sept. 2004, pp. 537–47. Pubmed, doi:10.1016/j.surg.2004.05.031.
Contreras JL, Xie D, Mays J, Smyth CA, Eckstein C, Rahemtulla FG, Young CJ, Anthony Thompson J, Bilbao G, Curiel DT, Eckhoff DE. A novel approach to xenotransplantation combining surface engineering and genetic modification of isolated adult porcine islets. Surgery. 2004 Sep;136(3):537–547.
Journal cover image

Published In

Surgery

DOI

ISSN

0039-6060

Publication Date

September 2004

Volume

136

Issue

3

Start / End Page

537 / 547

Location

United States

Related Subject Headings

  • Transplantation, Heterologous
  • Swine
  • Surgery
  • Surface-Active Agents
  • Polyethylene Glycols
  • Models, Animal
  • Islets of Langerhans Transplantation
  • Islets of Langerhans
  • Genes, bcl-2
  • Gene Transfer Techniques