Lymph nodes have an essential role in the initiation of protective immune responses. In this proposal we will utilise human and mouse adipose derived stem cells (ADSCs) and peripheral blood lymphocytes and dendritic cells to generate artificial lymph node (ALN) structures in vitro. This represents a novel approach to the analysis of human immune function and mouse lymph node development, organisation and function. This technology will have key applications in toxicology and mechanistic studies of new therapeutics and as a tool to determine the role of specific signalling pathways and physical forces in LNs, thus replacing and reducing animals in research. The development and application of human monoclonal antibody (mAb) to treat disease requires determination of toxicology and efficacy and understanding the mechanism of action. The current approach utilises large numbers of mice and non-human primate models and surrogate antibodies that are not the best predictor of human immune system. Through the development of ALNs we will generate a technology to address key questions on mAb safety and efficacy in vitro replacing and reducing mouse and non-human primates in therapeutic development. We have developed a methodology to differentiate ADSCs into T and B cell lymphoid stroma. ProBioGen has developed bioreactor technology that can maintain the survival and function of human lymphocytes over 4 weeks in culture. In this research program we will bring the two technologies together to construct a human ALN that contain all the key cell types and organisation found in vivo in highly structured 3D culture system. With the joint expertise in stromal cell culture, human immunology, 3D culture systems, bioreactors and measurements of immune responses in vitro we believe we can not only develop the technology to assay and visualise human immune responses in vitro but can commercialise the culture system, directly reducing the use of animals in drug development.
Nayar S et al. (2019). Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology. PNAS 116(27):13490-13497. doi: 10.1073/pnas.1905301116