Brief exposure to hyperglycemia activates dendritic cells in vitro and in vivo.

Dendritic cells are key players in regulating immunity. These cells both activate and inhibit the immune response depending on their cellular environment. Their response to hyperglycemia, a condition common amongst diabetics wherein glucose is abnormally elevated, remains to be elucidated. In this study, the phenotype and immune response of dendritic cells exposed to hyperglycemia were characterized in vitro and in vivo using the streptozotocin-induced diabetes model. Dendritic cells were shown to be sensitive to hyperglycemia both during and after differentiation from bone marrow precursor cells. Dendritic cell behavior under hyperglycemic conditions was found to vary by phenotype, among which, tolerogenic dendritic cells were particularly sensitive. Expression of the costimulatory molecule CD86 was found to reliably increase when dendritic cells were exposed to hyperglycemia. Additionally, hydrogel-based delivery of the anti-inflammatory molecule interleukin-10 was shown to partially inhibit these effects in vivo.

IL-10-Functionalized Hydrogels Support Immunosuppressive Dendritic Cell Phenotype and Function.

Biomaterial systems such as hydrogels enable localized delivery and postinjection modulation of cellular therapies in a wide array of contexts. Biomaterials as adjuvants have been an active area of investigation, but the study of functionalized biomaterials supporting immunosuppressive cell therapies for tolerogenic applications is still nascent. Here, we developed a 4-arm poly(ethylene-glycol)-maleimide (PEG-4MAL) hydrogel functionalized with interleukin-10 (IL-10) to improve the local delivery and efficacy of a cell therapy against autoimmune disease. The biophysical and biochemical properties of PEG-4MAL hydrogels were optimized to support dendritic cell (DC) viability and an immature phenotype. IL-10-functionalized PEG-4MAL (PEG-IL10) hydrogels exhibited controlled IL-10 release, extended the duration of DC support, and protected DCs from inflammatory assault. After incorporation in PEG-IL10 hydrogels, these DCs induced CD25+FoxP3+ regulatory T cells (Tregs) during in vitro coculture. These studies serve as a proof-of-concept for improving the efficacy of immunosuppressive cell therapies through biomaterial delivery. The flexible nature of this system enables its widespread application across a breadth of other tolerogenic applications for future investigation.

Localized hydrogel delivery of dendritic cells for attenuation of multiple sclerosis in a murine model.

In multiple sclerosis (MS), abnormally activated immune cells responsive to myelin proteins result in widespread damage throughout the central nervous system (CNS) and ultimately irreversible disability. Immunomodulation by delivering dendritic cells (DCs) utilizes a potent and rapid MS disease progression driver therapeutically. Here, we investigated delivering DCs for disease severity attenuation using an experimental autoimmune encephalomyelitis preclinical MS model. DCs treated with interleukin-10 (IL-10) (DC10s) were transplanted using in situ gelling poly(ethylene glycol)-based hydrogel for target site localization. DC delivery increased hydrogel longevity and altered the injection site recruited, endogenous immune cell profile within 2 days postinjection. Furthermore, hydrogel-mediated DC transplantation efficacy depended on the injection-site. DCs delivered to the neck local to MS-associated CNS-draining cervical lymph nodes attenuated paralysis, compared to untreated controls, while delivery to the flank did not alter paralysis severity. This study demonstrates that local delivery of DC10s modulates immune cell recruitment and attenuates disease progression in a preclinical model of MS.