The wide utility of rabbits as models of human diseases

Experimental & Molecular Medicine, May 2018

Studies using the European rabbit Oryctolagus cuniculus contributed to elucidating numerous fundamental aspects of antibody structure and diversification mechanisms and continue to be valuable for the development and testing of therapeutic humanized polyclonal and monoclonal antibodies. Additionally, during the last two decades, the use of the European rabbit as an animal model has been increasingly extended to many human diseases. This review documents the continuing wide utility of the rabbit as a reliable disease model for development of therapeutics and vaccines and studies of the cellular and molecular mechanisms underlying many human diseases. Examples include syphilis, tuberculosis, HIV-AIDS, acute hepatic failure and diseases caused by noroviruses, ocular herpes, and papillomaviruses. The use of rabbits for vaccine development studies, which began with Louis Pasteur’s rabies vaccine in 1881, continues today with targets that include the potentially blinding HSV-1 virus infection and HIV-AIDS. Additionally, two highly fatal viral diseases, rabbit hemorrhagic disease and myxomatosis, affect the European rabbit and provide unique models to understand co-evolution between a vertebrate host and viral pathogens.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://www.nature.com/articles/s12276-018-0094-1.pdf

The wide utility of rabbits as models of human diseases

Abstract Studies using the European rabbit Oryctolagus cuniculus contributed to elucidating numerous fundamental aspects of antibody structure and diversification mechanisms and continue to be valuable for the development and testing of therapeutic humanized polyclonal and monoclonal antibodies. Additionally, during the last two decades, the use of the European rabbit as an animal model has been increasingly extended to many human diseases. This review documents the continuing wide utility of the rabbit as a reliable disease model for development of therapeutics and vaccines and studies of the cellular and molecular mechanisms underlying many human diseases. Examples include syphilis, tuberculosis, HIV-AIDS, acute hepatic failure and diseases caused by noroviruses, ocular herpes, and papillomaviruses. The use of rabbits for vaccine development studies, which began with Louis Pasteur’s rabies vaccine in 1881, continues today with targets that include the potentially blinding HSV-1 virus infection and HIV-AIDS. Additionally, two highly fatal viral diseases, rabbit hemorrhagic disease and myxomatosis, affect the European rabbit and provide unique models to understand co-evolution between a vertebrate host and viral pathogens. Introduction Small laboratory animals, such as mice, rats, guinea pigs, and European rabbits, have long been used as models to improve our understanding of several human maladies. The primary goal of developing animal models for research is to create an experimental system in which the conditions occurring in humans are phenocopied as accurately as possible in the laboratory animal. The rabbit was the first animal model used in several immunological studies and was crucial, for example, for the development of the rabies vaccine by Louis Pasteur in 18811. The pioneering studies of rabies and syphilis conducted in rabbits continued to advance our understanding of these and other infectious diseases. Furthermore, the study of rabbit immunoglobulins established much of what is known about the structure, function and regulated expression of antibodies [reviewed in refs.2,3,4]. Although, rabbit was a major animal model used for the study of molecular immunology in the late 1980s, rabbits were increasingly replaced by rodents in the subsequent years5. Among the reasons for the increasing use of rodents, such as mice, instead of rabbits are reduced maintenance costs, small size, availability of inbred strains, ease of breeding, short reproductive cycle, high numbers of progeny, wide availability of commercial immunological reagents, and availability of many knockout (KO) and transgenic models6,7. However, rabbits have the advantage of an intermediate size between rodents and larger, more costly animal models, such as primates. The size of rabbits permits the ready sampling of blood and greater access to many cells and tissues from a single animal. Additionally, rabbits have a longer life span than that of rodents, and the immune system genes of rabbits are apparently more similar to those of the human immune system than are rodent genes8,9,10. Rabbits are also carriers or reservoirs of several pathogens that can cause zoonotic diseases. Some studies in mice found a lack of disease symptoms mimicking those of human infection. Additionally, the low-success rates in the translation of findings from some mouse studies to human diseases suggest that other animal models, such as rabbit, may often be more appropriate11,12. The rabbit is actively used as a laboratory model for several non-infectious conditions, including atherosclerosis13,14, intestinal immunity15, reproduction16, lupus17, arthritis18, cancer19, and Alzheimer’s disease20. The rabbit has also been increasingly used during the last two decades as a reliable animal model for many infectious diseases. In this essay, several examples, including viral, bacterial, and parasitic infectious diseases, are described in which rabbits provide a more reliable model for host-pathogen interactions than rodents for their human disease counterparts. Overview of the rabbit immune system, therapeutics, and co-evolution between host and viral pathogens The pre-immune antibody repertoire in young rabbits develops in two stages: first, with antibody heavy chain-encoding gene segments V (variable), D (diversity), and J (joining) rearrangements in bone marrow and, second, with immunoglobulin (Ig) gene diversification in gut-associated lymphoid tissue (GALT)21,22. In the bone marrow, one VH gene segment, VH1, is preferentially used for V(D)J gene rearrangements, whereas numerous kappa or lambda variable gene segments are used in VJ gene rearrangements of the light chain. After leaving the bone marrow and migrating to GALT, the B cells undergo proliferation and diversify their Ig genes by somatic hypermutation and gene conversion. Specific commensal microbes drive this B-cell expansion and Ig gene diversification through a mechanism that is not yet ful (...truncated)


This is a preview of a remote PDF: https://www.nature.com/articles/s12276-018-0094-1.pdf

Pedro J. Esteves, Joana Abrantes, Hanna-Mari Baldauf, Lbachir BenMohamed, Yuxing Chen, Neil Christensen, Javier González-Gallego, Lorenzo Giacani, Jiafen Hu, Gilla Kaplan, Oliver T. Keppler, Katherine L. Knight, Xiang-Peng Kong, Dennis K. Lanning, Jacques Le Pendu, Ana Lemos de Matos, Jia Liu, Shuying Liu, Ana M. Lopes, Shan Lu, Sheila Lukehart, Yukari C. Manabe, Fabiana Neves, Grant McFadden, Ruimin Pan, Xuwen Peng, Patricia de Sousa-Pereira, Ana Pinheiro, Masmudur Rahman, Natalie Ruvoën-Clouet, Selvakumar Subbian, Maria Jesús Tuñón, Wessel van der Loo, Michael Vaine, Laura E. Via, Shixia Wang, Rose Mage. The wide utility of rabbits as models of human diseases, Experimental & Molecular Medicine, 2018, Issue: 50, DOI: 10.1038/s12276-018-0094-1