A human ectopic-lymphoid-follicle-on-a-chip for testing vaccines and adjuvants

Abstract

Abstract New vaccine candidates evaluated in animals can lead to unpredicted toxicities or poor efficacy in human clinical trials due to species-specific differences in immune responses. To address this problem, we developed the human ectopic lymphoid follicle (LF) chip containing primary human immune cells, including autologous blood B and T lymphocytes and antigen presenting cells, cultured in a three-dimensional extracellular matrix (ECM) gel within an organ-on-a-chip microfluidic device. Superfusion via a parallel channel separated by a microporous membrane is required for LF formation and prevents lymphocyte autoactivation. These germinal center-like LFs contain B cells expressing activation-induced cytidine deaminase and exhibit plasma cell differentiation upon activation. Increased basal lymphocyte proliferation is observed in the human LF chip as compared to conventional 2D cultures lacking ECM or perfusion. The human LF chips demonstrated improved antibody responses to split virion influenza vaccination compared to conventional planar 2D cultures, which were enhanced by the addition of a squalene-in-water emulsion (SWE) adjuvant, and this was accompanied by increases in LF size and number. To extend this work, we modelled intramuscular vaccination by co-culturing monocytes with muscle cells in the presence of different vaccines and adjuvants. We found that presence of muscle cells can promote cytokine production, antigen uptake and monocyte activation. Seeding these monocytes into the LF chips with autologous T and B cells could promote cytokine production and LF formation, which extends the LF chips usage for testing intramuscular vaccination. Supported by grants from the Defense Advanced Research Projects Agency under Cooperative Agreement Number W911NF-12-2-0036, the National Institutes of Health grant UG3HL141797, Bill and Melinda Gates Foundation and the Wyss Institute for Biologically Inspired Engineering.