Knockdown of intraislet IKKA by spherical nucleic acid conjugates prevents cytokine-induced injury and enhances graft survival

Jonathan S. Rink, Kaylin M. McMahon, Xiaomin Zhang, Xiaojuan Chen, Chad A. Mirkin, C. Shad Thaxton, Dixon B. Kaufman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Background. The efficiency of islet graft survival after intraportal implantation is compromised by host innate immune responses and the production of proinflammatory cytokines that cause acute cellular injury. This reaction activates intraislet nuclear factor-JB (NF-JB), causing production of gene products that have detrimental effects on β-cell survival and function. We hypothesized that small interfering RNA targeting of IKKA, a crucial kinase in the NF-JB activation pathway, in islets before transplantation would ameliorate the detrimental effects of cytokines and improve islet survival after transplantation. Methods. To test this hypothesis, we prepared small interfering RNAYbased spherical nucleic acid nanoparticle conjugates targeting IKKA IKKA SNA-NCs). We treated isolated islets with IKKA SNA-NCs and assessed the functional consequences of IKKA knockdown in vitro and after intraportal transplantation in mice. Results. Treatment of freshly isolated mouse islets with IKKA SNA-NCs reduced constitutive IKKA expression and protected against proinflammatory cytokine-induced NF-JB activation, resulting in improved cell viability and decreased expression of gene products associated with β-cell dysfunction. Intraportal transplantation of a marginal mass (50 islets) of syngeneic islets treated with nanoparticle conjugates targeting IKKβ resulted in reversion to normoglycemia in 50% of streptozotocin-induced diabetic recipients (n=12) compared with 0% of controls (n=12). Histologic analyses showed reduced CD11b+ cellular infiltration and decreased islet apoptosis. Conclusions. These results are consistent with the hypothesis that inhibition of intraislet NF-JB activation ameliorates the detrimental effects of host cytokines and demonstrates that preconditioning freshly isolated islets in culture with IKKβ SNANCs may be a promising therapy to enhance islet graft function and survival after transplantation.

Original languageEnglish (US)
Pages (from-to)877-884
Number of pages8
JournalTransplantation
Volume96
Issue number10
DOIs
StatePublished - 2013

Keywords

  • Cytokines
  • Islet transplantation
  • Nanotechnology
  • β cell

ASJC Scopus subject areas

  • Transplantation

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