Modeling Human Immunity In Vitro: Improving Artificial Lymph Node Physiology by Stromal Cells

Abstract

There has recently been an increasing demand for modeling the human immune system in vitro and the use of such models for testing immune responses against pharmaceutical drugs, cosmetics, and chemicals. The human artificial lymph node (HuALN) model has been developed for testing biopharmaceuticals and vaccines assessing immunomodulation, immunogenicity, and immunotoxicity. The system uses peripheral blood mononuclear cells (PBMCs) of leucapheresis material or whole blood donations of healthy volunteers for long-term three-dimensional (3D) culture in a perfused bioreactor system. A part of the current development is the implementation of lymph node (LN) stromal-like cells differentiated/obtained from mesenchymal stromal cells (MSCs) to improve structural organization and functionality. Development, structural organization, and function of lymphoid tissues and organ system are dependent on the interaction between hematopoietic and nonhematopoietic cells. In this study, we show the identification of a suitable differentiation protocol for LN stromal-like cells and their use for cocultivation in the HuALN model to improve the formation of microorganoids in long-term culture. During cocultivation with allogeneic PBMCs and antigen-presenting dendritic cells, MSC-derived stromal cells form a 3D network after seeding into the hydrogel matrix. The MSC network attracts PBMCs and influences the drug-induced immune responses, which are monitored by cytokine analysis in culture supernatants.