Rabbit Model for Human Disease Study

Biomarker expression patterns in Bovine, Canine, Porcine and Avian.

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For most researchers in immunology, rabbits are thought of as production platforms for polyclonal antibodies and more recently recombinant proteins. Developments in recent years have however shown that the rabbit represents a valuable experimental animal. For some diseases it could become the model of choice for the translational medicine research. This mini-review will look at some of the potential disease areas.

Atherosclerosis

Atherosclerosis is mainly a disease of humans, primates, and pigs but can be induced in other species. Several species have been used as a model organism, using genetic manipulations or diet to induce atherosclerosis.

The rabbit hypercholesterolemia model that induces atherosclerosis by feeding rabbits a high-cholesterol diet is perhaps the most well-know of the models, resulting in notable vascular lesions after only a few weeks. This model is very useful as it has been found to be highly reproducible with minimal variation between animals and transferable between laboratories. A further model, referred to as normolipemic, causes atherosclerotic lesions through indwelling aortic polyethylene catheter, balloon angioplasty or nitrogen exposure. Some laboratories used a combination of these two methods.

Eye Research and Ocular Cancer

Key advantages to using rabbits as experimental models for ophthalmic research are the size of the rabbit eye, a large body of accumulated data on the anatomy and physiology of the rabbit eye, and most importantly its similarity to the human eye (Gwon 2008).

The rabbit model is most often used to study surgical interventions such as cataract removal, intraocular lens insertion, corneal transplantation, laser refractive procedures, glaucoma shunt implantation, and intra-vitreal drug delivery.

Uveal melanoma (UM) is the most frequent primary intraocular tumor in adults (Singh and Topham 2003) and differs from cutaneous melanoma in several aspects. They are caused by genetic mutations, however while cutaneous melanoma mutations are frequently found in the BRAF gene, many UM causing mutations originate in either GNAQ or GNA11 (Van Raamsdonk et al. 2009, Van Raamsdonk et al. 2010). To date several UM cell lines have been used in rabbits to study the cancer.

A novel model of retinoblastoma, induced by injection of cultured human retinoblastoma cells into the sub-retinal space of immunosuppressed rabbits, results in intraocular tumors after one week. These tumors are significantly similar to those occurring in humans. The tumors are maintained for up to eight weeks and able to develop viable vitreal tumor seeds, already at mid-sized stage. This is an advantage as vitreous seeds only develop very late in mouse models; failure to eliminate these is considered to be the cause of treatment failures in humans. The rabbit model presents itself as an appropriate model for testing novel chemotherapeutics.

Further areas of research using the rabbit eye as a model include retinal detachment and proliferative vitreoretinopathy (PVR), retinoblastoma, and retinitis pigmentosa (RP). PVR is characterized by an abnormal wound healing process that occurs after retinal detachment or other ocular trauma, exhibiting excessive inflammation within the eye. So far PVR is treated by vitrectomy or non-specific pharmacological suppression of cell proliferation; these are not ideal. Research focused on elucidating intra-ocular inflammation is needed. The rabbit PVR model is key to underpinning that effort.

Infectious Diseases

There are a several human infectious diseases for which rabbits have been considered as a model, among them:

• HIV1 infection and AIDS
• HTLV1 infection and adult T-cell leukemia–lymphoma
• Papillomavirus infection
• Ocular Herpes Infection
• Tuberculosis
• Syphilis

The model for tuberculosis is perhaps the best fitting model with the least compromises. Tuberculosis (TB) is still a major cause of morbidity and mortality; this applies specifically in some developing countries. The lack of an effective vaccine, increasing drug resistance, and high cost of long-term treatments mean that tuberculosis has not been effectively controlled. It is estimated that nine million new cases occurred annually, worldwide; leading to one and a half million deaths.

In healthy individuals T cells and macrophages are the main line of defense against M. tuberculosis through the formation of granulomas. Immunocompromised patients lack or have poorly formed granulomas. However, bacteria may become dormant inside granulomas leading to latent infections. To investigate, three animal models have been considered for TB research: rabbits, guinea pigs, and mice. While mice have advantages in the lab, they are relatively resistant to tuberculosis infection. Next in susceptibility are rabbits, with guinea pigs showing even more susceptibility to infection than mice and rabbits. However, rabbits are significantly susceptible to the M. bovis bacterium which also delivers a pathology more relevant to the human TB than the mouse or guinea pig model. The advantage in rabbits is they are also the only experimental model in which pulmonary cavitation occurs and arrested infection occurs. Both aspects closely related to human TB.

The pulmonary cavities are a reservoir of bacteria containing large populations of M. tuberculosis and the rabbit model can be used to mimic human transmission. The immune system of the rabbit is able to control infection such that a latent infection occurs, a state seen in humans. This gives the impression of controlling TB infection so effectively that the bacterial load seems to have been completely cleared.

In humans reactivation from a latent state is spontaneous, rabbits require immunosuppression for reactivation. This achieved through corticosteroid immunosuppression. Rabbits with latent TB infection did demonstrate the appropriate immune response, activation of T cells and macrophages and increases in TNFalpha levels. These features make rabbit an important model for the study of human latent TB.

To help you to advance your research in rabbits, whether as a model organism or investigating the rabbit immune response in its own right, Bio-Rad supplies key antibodies against cell markers and cytokines to investigate lapine T cells and their immune responses.

Cell Markers

Cytokines

These cytokines can be assayed in ELISA using a capture, a biotinylated detection antibody, and a recombinant standard.

References

• Badimon L et al. (2008). Models of behavior: cardiovascular. In Sourcebook of models for biomedical research Conn, P.M. ed. (New York City, USA, Humana Press), pp. 361-368.
• Bosze Z and Houdebine LM (2006). Application of rabbits in biomedical research: a review. World Rabbit Sci 14, 1-14.
• Gwon A (2008). The rabbit in cataract/IOL surgery. Animal models in eye research, Tsonis P.A., ed. (Amsterdam, Netherlands, Elsevier), pp. 184-204.
• Kónya A et al. (2008). Animal models for atherosclerosis, restenosis, and endovascular aneurysm repair. In Sourcebook of models for biomedical research, Conn, P.M. ed. (New York City, USA, Humana Press), pp. 369-384.
• Singh AD and Topham A (2003). Incidence of uveal melanoma in the United States: 1973–1997. Ophthalmology 110, 956–961.
• Van Raamsdonk CD et al. (2009). Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457, 599–602.
• Van Raamsdonk CD et al. (2010). Mutations in GNA11 in uveal melanoma. N Engl J Med 363, 2191–2199.