A new humanized mouse line for in vivo research into human immune responses

Examining the immune responses triggered as a result of infection by a pathogen or during inflammatory diseases is a vital research area that will pave the way for the development of effective therapeutic treatments. Several teams from the Institut Pasteur/Inserm/the CNRS, in collaboration with a laboratory at the University of Basel in Switzerland and a team from the IUH in Paris, have made a significant breakthrough in this field by creating a new humanized mouse model that is capable of developing functioning lymph nodes.

Lymph nodes play a vital part in the orchestration of the immune response; they are strategically located in the lymphoid tissue to ensure optimal interaction between B and T lymphocytes and to trigger the most effective cellular and humoral response possible.

Up to now, the research team in the Innate Immunity Unit, led by James Di Santo, has made use of a previously described preclinical model consisting of immunodeficient mice transplanted with human hematopoietic stem cells (HIS mice). Based on this mouse model, they observed that human innate and adaptive immune cells developed normally. But the model had no lymph nodes, as the immunodeficient mice used for the transplant were lacking the signals that would trigger lymph node development. So although B and T lymphocytes developed in HIS mice, these cells did not interact in the lymph node structures and therefore produced suboptimal immune responses.

Previous research by scientists at the University of Basel, however, demonstrated that thymic stromal-derived lymphopoietin (TSLP) cytokines induced the development of lymph nodes during fetal growth. Exploring this avenue, Yan Li, from the Innate Immunity Unit, showed that the expression of TSLP in HIS mice enabled the development of all lymph nodes, allowing scientists to analyze the specific role they play in human immune responses.

Drawing on this research, scientists in the Innate Immunity Unit noted that, among the most surprising results recorded for their new humanized mouse model, HIS mice that had developed lymph nodes generated cellular and humoral responses after immunization, meaning that they could serve as a preclinical model for vaccine research. Moreover, since lymph nodes are a reservoir for HIV, the model will be invaluable in elucidating the latent phase of HIV in lymph node reservoirs and in testing curative therapies for HIV.

This research, coordinated by James Di Santo, benefited from a multidisciplinary, collaborative approach involving several Institut Pasteur teams specializing in the antibody response (Hugo Mouquet), dynamic imaging (Philippe Bousso), histopathology (Grégory Jouvion), zootechnics (Franck Bourgade) and HIV (Olivier Schwartz).

The new HIS mouse line represents a major breakthrough in in vivo research on human immune responses, adding a new tool to the already extensive arsenal of humanized mouse models. Use of this line should prove extremely useful for both fundamental and translational research, and could pave the way for the development of more effective treatments for several inflammatory infections and diseases that affect millions of patients worldwide.

• To find out more and make use of these models, please contact James Di Santo, james.di-santo@pasteur.fr.