title: Indoleamine 2,3 dioxygenase contributes to transferable tolerance in rat red blood cell inducible model of experimental autoimmune haemolytic anaemia.
abstract: Autoimmune haemolytic anaemia (AIHA) is caused by autoantibodies against red blood cell (RBC) surface antigens that render RBC susceptible to Fc-mediated phagocytosis and complement-mediated lysis. Experimental AIHA can be induced by injection of rat RBC to naive mice, but a lymphocyte-mediated regulatory mechanism eventually suppresses the production of autoantibodies specific for mouse RBC. Critically, this tolerogenic response can be transferred to naive mice by splenocytes from the rat RBC-immunized mouse. Here we investigate whether indoleamine 2,3 dioxygenase (IDO) or the initiators of IDO cascade, including the cytotoxic T lymphocyte antigen (CTLA)-4 receptor and its soluble isoform, contribute to this tolerogenic mechanism. Splenocytes from experimental AIHA mice were transferred adoptively to naive mice under the cover of anti-CTLA-4, anti-soluble CTLA-4 antibodies or IDO inhibitor 1-methyl tryptophan (1-MT). Recipient mice were immunized with rat RBC and levels of antibody against self-RBC and rat-RBC were monitored. Our results indicate that transfer of tolerance to naive recipients is dependent upon IDO-mediated immunosuppression, as mice receiving previously tolerized splenocytes under the cover of 1-MT were refractory to tolerance and developed haemolytic disease upon further challenge with rat RBC. Initiators of IDO activity, CTLA-4 or soluble CTLA-4 did not mediate this tolerogenic process but, on their blockade, boosted antigen-specific effector immune responses.
authors.affiliation: Section of Immunology and Infection, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK. l.dahal@abdn.ac.uk
authors.forename: L N
authors.initials: LN
authors.lastname: Dahal
authors.forename: L S
authors.initials: LS
authors.lastname: Hall
authors.forename: R N
authors.initials: RN
authors.lastname: Barker
authors.forename: F J
authors.initials: FJ
authors.lastname: Ward
mesh_terms: D000069594:Abatacept; D019264:Adoptive Transfer; D000744:Anemia, Hemolytic, Autoimmune / Q000201:enzymology* / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000276:immunology; D007114:Immunization; D018796:Immunoconjugates / Q000276:immunology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000502:physiology*; D007518:Isoantibodies / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017207:Rats, Sprague-Dawley; D017634:Self Tolerance; D013045:Species Specificity; D013154:Spleen / Q000166:cytology; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007518:Isoantibodies; D000069594:Abatacept; D014364:Tryptophan; C525396:1-methyltryptophan