Program

PO3-5-6

Beneficial effects of combination of tissue transglutaminase inhibitor and interleukin-15 inhibitor in ameliorating mucosal immune inflammatory response in experimental model of Celiac Disease

[Speaker] Rahul Singh:1
[Co-author] Ashutosh Singh:2, Kaushal K Prasad:1, Bikash Medhi:2, Rakesh Kochhar:1
1:GASTROENTEROLOGY, POSTGRADUATE INSTITUTE OF MEDICAL EDUCATION & RESEARCH, India, 2:PHARMACOLOGY, OSTGRADUATE INSTITUTE OF MEDICAL EDUCATION & RESEARCH, India

Background
Celiac disease (CD) is a polygenic, auto-inflammatory disease, activated by the exposure of a dietary gluten in individuals with the specific genetic background. With the help of a suitable animal model of CD, potential treatments could be administered and their effectiveness determined before clinical trials are conducted. The study intended to evaluate the efficacy of a combination of Cystamine (CysN), a tissue transglutaminase inhibitor and Ascorbate (Asc), an interleukin-15 inhibitor in an experimental model of CD.

Method
A total of 42 adult C57BL/6 mice were randomized into 7 groups
Group 1) control without treatment
Group 2) received 20 mg/kg of polyinosinic-polycytidylic acid (Poly I-C)
Group 3) treated with CysN 17.2 mg/d per o.s for 21 days
Group 4) treated with 20 mg/d Asc per o.s for 21 days
Group 5) treated with CysN and Asc at 17.2 mg/d and 20 mg/d per o.s respectively for 21 days
Group 6) treated with CysN and Asc at 8.6 mg/d and 10 mg/day per o.s respectively for 21 days
Group 7) treated with CysN and Asc at 34.4 mg/d and 40 mg/d per o.s respectively for 21 days.
Molecular parameters evaluated such as TG2 activity by immunohistochemistry, expression of Rae-1 (homolog of human MICA) by RT-PCR, interleukin-15, IFN-alpha & IFN-gamma expression by ELISA and histopathology.

Result
Histopathological study showed partial villous atrophy, Intraepithelial lymphocytosis and crypt hyperplasia in Poly I-C induced small intestinal inflammation group which was absent in group administered combinational doses. Immunohistochemistry of poly I-C group showed marked localization of TG2 protein in the small intestine which was absent in combinational doses group. Moreover, levels of IFN-alpha, IFN-gamma, and IL-15 are significantly decreased (P value equal to or more than 0.05) in the group administered combinational doses than poly I-C group. Gene expression of Rae-1 is significantly decreased in a group given combinational doses.

Conclusion
The combination therapy of CysN and Asc ameliorated the small intestinal tissue injury effectively than either agent alone.

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