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

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-κB (NF-κB), causing production of gene products that have detrimental effects on β-cell survival and function. We hypothesized that small interfering RNA targeting of IKKβ, a crucial kinase in the NF-κB 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 RNA-based spherical nucleic acid nanoparticle conjugates targeting IKKβ IKKβ SNA-NCs). We treated isolated islets with IKKβ SNA-NCs and assessed the functional consequences of IKKβ knockdown in vitro and after intraportal transplantation in mice. RESULTS:Treatment of freshly isolated mouse islets with IKKβ SNA-NCs reduced constitutive IKKβ expression and protected against proinflammatory cytokine-induced NF-κB 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-κB activation ameliorates the detrimental effects of host cytokines and demonstrates that preconditioning freshly isolated islets in culture with IKKβ SNA-NCs may be a promising therapy to enhance islet graft function and survival after transplantation.

journal_name

Transplantation

journal_title

Transplantation

authors

Rink JS,McMahon KM,Zhang X,Chen X,Mirkin CA,Thaxton CS,Kaufman DB

doi

10.1097/TP.0b013e3182a4190e

subject

Has Abstract

pub_date

2013-11-27 00:00:00

pages

877-84

issue

eissn

0041-1337

issn

1534-6080

pii

00007890-201311270-00007

journal_volume

pub_type

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