Interference with tolerance induction in vivo by inhibitors of prostaglandin synthesis |
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| Authors: | W V Scheuer M V Hobbs W O Weigle |
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| Affiliation: | 1. Division of Gastroenterology, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada;2. Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA;3. Institute of Liver Studies, King''s College Hospital Foundation Trust, London UK;4. Unite d’Hepatologie et de Transplantation Hepatique, Centre Hospitalier Universitaire Henri-Mondor, Service d’Hepatologie et de Gastroenterologie, Universite Paris-Est Creteil, Val-de-Marne, Paris, France;5. Hepatology & Liver Intensive Care, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, University Paris Diderot, Clichy, France;6. Department of Gastroenterology and Hepatology, Medical University of Vienna, Austria;7. Department of Gastroenterology/Hepatology, Endocrinology and Nephrology, Klinikum Klagenfurt am Wörthersee, Austria;8. Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, ON, Canada;9. Hospital Saint Luc, Universite de Montreal, Montreal, QC, Canada;10. Division of Gastroenterology and Hepatology, Department of Transplant Hepatology, Mayo Clinic, Phoenix, AZ, USA;11. Division of Infectious Diseases, Georgetown University, Washington, DC, USA;12. Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA;13. Universite Catholique de Louvain, Brussels, Belgium;14. Gilead Sciences, Inc., Foster City, CA, USA;15. Division of Gastroenterology and Hepatology, University of California, San Francisco, CA, USA;16. Department of Gastroenterology, University of Torino, Torino, Italy;17. Department for Gastroenterology and Hepatology, University Hospital Zurich, Switzerland;2. Networking Biomedical Research Centre in Hepatic and Digestive Diseases (CIBEREHD), Spain;3. Department of Medicine, Universitat de València, Valencia (Spain);4. Instituto de Investigación Sanitaria, Hospital Universitari i Politècnic La Fe, Valencia (Spain) |
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| Abstract: | Prostaglandins (PG) have been implicated as modulators of both humoral and cellular immune responses. In order to evaluate a possible role for PG in tolerance, the effect of inhibitors of prostaglandin synthesis on tolerance induction and circumvention has been investigated. Injection of deaggregated human gamma-globulin (DHGG) into A/J mice leads to unresponsiveness to a subsequent challenge with immunogenic aggregated human gamma-globulin (AHGG). Administration of indomethacin (IM) or acetylsalicylic acid (ASA) shortly before and after DHGG injection prevents tolerance induction. PGE2 reverses the tolerance overriding effect provided by IM. IM is not able to overcome unresponsiveness when given 10 and 20 days after tolerance induction, at a time point when both T and B lymphocytes are tolerant. As previously shown, lipopolysaccharide (LPS) both inhibits the induction of tolerance to HGG and circumvents tolerant T helper cells late in tolerance when competent B cells are present. In contrast, IM is unable to circumvent T-helper cell tolerance when given at Day 60 after tolerogen, when B cells (but not T cells) are responsive. Furthermore, LPS acts as an adjuvant, B-cell mitogens, inducer of polyclonal Ig secretion, and primes mice when given with tolerogen, while IM has none of these properties. These results indicate a difference between the effects of IM and LPS on tolerance and a possible role of PG in DHGG-mediated tolerance induction. |
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