From February 2000 to August 2008, The Gutsy Group provided $131,250 to fund the St. Vincent’s Hospital Immunology Centre Mouse Model. This project centred on a mouse model that mimicked human ulcerative colitis.
The research was carried out under the direction of Professor Tony dApice, Professor of Immunology at St. Vincent’s Hospital. The Professor’s main research was humanising mice and pigs so animal kidneys may be successfully transplanted into humans in the future. Mice were therefore inserted with the human gene 1-2 fucosyltransferase in the course of different research. Unexpectedly, and through serendipity, these mice developed colitis. As a result, this event enabled extensive research into the mechanism of the colitis to be performed on this animal model over the next nine years.
This research was conducted by four research fellows being Dr Ashley Miller, Dr Steven Brown, Dr Greg Moore and Dr Mark Lust, all of whom were awarded PhDs for their research, and three of the researchers received gold medals for this research into gastroenterology. Through this research it was demonstrated that these mice had abnormal thymus glands with consequent major effects on the immune system, a world first.
The Mouse Model of Ulcerative Colitis
In the transgenic Mouse Model of Ulcerative Colitis (hFUT1), the human gene for Alpha 1 -2 fucosyltransferase, inserted into the normal DNA of the mouse, produced spontaneous colitis that was similar to the human disease, ulcerative colitis. The mice developed severe diarrhoea, wasting and early death.
As a result of extensive research with the model, it was found that this genetic manipulation changed the type and shape of the sugar molecules that protruded from the surface of many cells, including lymphocytes, which are the major cells that control immunity. It was found that this abnormality caused:
- Chronic inflammation of the colon
- Defect in the mucus produced by the colon (mucus is thought to be a factor in preventing bacteria from invading the wall of the colonoscopy)
- Aberrant development of lymphocytes. Immature lymphocytes are processed by the thymus gland, which lies in front of the heart. Normal lymphocytes pass through the thymus, and have a number of sugar molecules attached to their surface, and then circulate back into the tissues of the body so they can carry out their normal immune function. In this mouse model the thymus gland was small and under-developed, (atrophic), and consequently the lymphocytes had abnormal surface markers, and therefore loss of their normal immune function.
This is the first time that an animal model of colitis had been developed due to a thymic abnormality.
It was found that the colitis in this model could be reversed by irradiating the mice, and transplanting normal immune system using bone marrow from a normal mouse. Furthermore, if the abnormal mice were bred in a germ-free environment, (have no bacteria in the gut), they did not develop colitis.
Finally, many experiments were performed to detect coagulation abnormalities, but no significant defects were identified.
Further information can be found in the articles published in the Inflammatory Disease Journal
Brown, S.J., Miller A.M., Cowan P.J., Slavin J, Connell W.R.,. Moore G.T., Bell S., Elliott P.R., Desmond P.V., dApice A.J., Altered Immune System Glycosylation Causes Colitis in Alpha1,2-fucosyltransferase Transgenic Mice, Inflammatory Bowel Disease 2004 Sep; 10(5):546-56.
Moore, G.T., Brown, S.J., Winterhalter A.C., Lust M., Salvaris E.J., Selan C., Nandurkar H.H, Desmond P.V., Cowan P.J., dApice A.J., Glycosylation Changes in hFUT1 Transgenic Mice Increase TCR Signaling and Apoptosis Resulting in Thymocyte Maturation Arrest, Mol. Immunology 2008 Apr; 45(8):52401-2410.