DEVELOPMENT OF CHEMOKINE-RELEASING MICROPARTICLES FOR THE MANIPULATION OF IMMUNE CELL RESPONSES

Abstract

A confounding obstacle faced by the medical field is the ability of many disease agents to suppress the body’s immune system which allows them to avoid elimination by the host. In this study, we have proposed a novel nanotechnology-based platform for achieving sustained delivery of immune-modulating chemokines (CKs) as a means for manipulating host immune responses. Functionalized hydrogel microparticles (MPs) were coupled with a variety of affinity baits and measured for their abilities to bind and release CKs. Favorable chemokine-loaded MP (CK-MP) pairs demonstrated affinities in the range of low micromolar to high nanomolar and maintained sustained CK release for more than 20 h in vivo. Upon injection in an established mouse model of subcutaneous hind footpad (FP) injection, a significant portion of the MPs accumulated in the regional draining lymph nodes (LNs). MP diffusion through the lymphatics and delivery by phagocytic cells to the LNs was advantageous as Bacillus anthracis, our model inducer of immunosuppression, injected in this manner demonstrates the same distribution and localization in the host. Pre-treatment of spore-challenged animals with MPs loaded with neutrophil-attracting CKs (CK-MPs) provided significant protection against the infectious bacterium, even in the absence of any additional antibiotic intervention, although therapeutic (post-treatment) injection of the CK-MPs was not protective by itself. Both the bait-coupled MPs and their released CKs played important roles contributing to improved survival. The MPs induced endogenous expression of several pro-inflammatory cytokines and CKs to promote further stimulation of immune activity favorable for the host. Further mechanistic evidence for the protection conferred in vivo was that epidermal resident antigen-presenting cells (Langerhans cells) were activated and migrated to the local LN in response to CK-MP treatment. We propose further investigation into the potential clinical use of CK-MPs for achieving predictable, sustained modulation of immune activity.