Abstract
Encapsulation of pancreatic islets in alginate-microcapsules is used to reduce or avoid the application of life-long immunosuppression in preventing rejection. Long-term graft function, however, is limited due to varying degrees of host tissue responses against the capsules. Major graft-longevity limiting responses include inflammatory responses provoked by biomaterials and islet-derived danger-associated molecular patterns (DAMPs). This paper reports on a novel strategy for engineering alginate microcapsules presenting immunomodulatory polymer pectin with varying degrees of methyl-esterification (DM) to reduce these host tissue responses. DM18-pectin/alginate microcapsules show a significant decrease of DAMP-induced Toll-Like Receptor-2 mediated immune activation in vitro, and reduce peri-capsular fibrosis in vivo in mice compared to higher DM-pectin/alginate microcapsules and conventional alginate microcapsules. By testing efficacy of DM18-pectin/alginate microcapsules in vivo, we demonstrate that low-DM pectin support long-term survival of xenotransplanted rat islets in diabetic mice. This study provides a novel strategy to attenuate host responses by creating immunomodulatory capsule surfaces that attenuate activation of specific pro-inflammatory immune receptors locally at the transplantation site.
Highlights
Type 1 Diabetes (T1D) is an autoimmune disease caused by destruction of insulin-producing pancreatic β-cells
Pectins can vary in degrees of methyl-esterification (DM) levels, which might influence Toll-Like Receptors (TLRs) binding and inhibiting capacity in vivo when administered as dietary supplement [43,55]
As we previously found that islet-derived danger-associated molecular patterns (DAMPs) are involved in activation of immune cells in the vicinity of encapsulated islets [26,35], we hypothesized that interference with key-inflammatory receptors such as TLR2/1 would attenuate immune responses
Summary
Type 1 Diabetes (T1D) is an autoimmune disease caused by destruction of insulin-producing pancreatic β-cells. The disease requires a minute-to-minute regulation of glucose levels which cannot be ach ieved with insulin injections [1,2]. This tight regulation can be accom plished by transplanting insulin-producing cells from cadaveric donors, but this requires life-long administration of immunosuppressive drugs [3]. Cell microencapsulation allows for transplantation in the absence of chronic immunosuppression [4,5]. Efficacy has been shown with microencapsulated cells in curing T1D, insulin indepen dence was limited to several months in most studies [8,9]
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