IMPACT OF LARGE MAMMALS MODELS IN IMMUNOLOGY

Abstract

Immune responses that control tolerance to self, tolerance to conceptus during pregnancy, and defense against cancer and pathogens are governed by dendritic cells (DC), that are key immune cell types that integrate environment signals and direct T and B cell immune responses. Different DC subtypes exist in mice that each trigger a specific type of immune response, such as cytotoxicity, antibody production, and regulatory processes. Interestingly in mice, it is possible to target specific DC subtypes with antigenised antibodies and obtain a desired type of immune response. However this conceptual breakthrough in vaccinology and immune regulation manipulation may only be valid for laboratory mice, as unfortunately often encountered in the process of bench to bed side translation. Furthermore, whether DC subsets knowledge and manipulation can be translated to human and to animal of socio-economical importance is still not known. We adressed this question in pigs and ruminants. The interest of these species over mice are that (1) they are the direct target species for vaccines, (2) they present genetic diversities and live in an open environment, (3) they present physiological similarities with human such as skin for pigs with skin being a main site for vaccination, (4) skin migrated DC and DC subsets can be collected from lymph after surgical catheterisation of lymph ducts in these species, and not in mice. We studied the molecular characterisation profiles of DC subsets from skin in ruminant and swine and evaluated how they compare to mouse and human DC subsets, based on comparative transcriptomic analyses. We assessed whether ruminant and swine DC subsets share functional similarities and differences with the corresponding murine subsets, and whether these properties translate into novel vaccine developements. Overall our work unravel conserved molecular and functional features that allow characterization of dendritic cell subtypes across mammals and possibly across vertebrates. In the past few decades, a tremendous amount of effort has been invested in developing gene and cell therapies for inherited genetic diseases such as Huntington's disease (HD). However, progress in their clinical application has been very limited. One of the major barriers is the lack of appropriate animal models that allow precise prediction patterns in human patients. Most of the animal models used for gene and cell therapy study are primarily focused on safety and toxicity evaluation, while therapeutic efficacy cannot be fully addressed because they do not carry the same human diseases. Although mouse models of human diseases are available and have been widely used for the development of new therapies, mice are not good predictors for humans because of the fundamental differences (genome composition, body size, life span and metabolic mechanism) between humans and rodents. Although monkeys are one of the best models for studying pharmacokinetics and overall impact of treatment, they are primarily used for safety and toxicity evaluation. Even HD monkey models, created by chemical induction or focal gene transfer in the brain, develop similar cellular pathology, therapeutic efficacy and systemic evaluation cannot be determined, which is one of the major barriers in drug and therapeutic development. The development of transgenic HD monkeys has opened the door for a new paradigm of animal modeling for the advancement of novel gene and cell therapy. HD monkeys not only carry the genetic defect that leads to human HD, they also develop clinical features comparable to humans that no other animal model does. While testing in HD monkeys has yet to be achieved until a cohort of well characterized HD monkeys was established, iPS cell lines derived from HD monkeys with a board spectrum of HD pathology and clinical features are a unique in vitro model for studying HD pathogenesis and the development of novel therapeutic approaches. New knowledge and treatments generated from iPS cells can next be translated and applied in HD monkeys from whom the stem cells were derived, thus the goal of personalized medicine can also be evaluated.

This work was funded by a grant from NCRR/NIH (R24RR018827).