Indoleamine 2,3 dioxygenase contributes to transferable tolerance in rat red blood cell inducible model of experimental autoimmune haemolytic anaemia

Autoimmune haemolytic anaemia (AIHA) is caused by autoantibodies against 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 naïve mouse but a lymphocyte-mediated regulatory mechanism eventually
suppresses the production of autoantibodies specific for mouse RBC. Critically, this
tolerogenic response can be transferred to naïve mouse by splenocytes from rat
RBC immunized mouse. Here we investigate whether Indoleamine 2,3 dioxygenase
(IDO) or the initiators of IDO cascade, particularly CTLA-4 receptor and its soluble
isoform contribute to this tolerogenic mechanism. Splenocytes from experimental
AIHA mice were adoptively transferred 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
naïve recipients is dependent on 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.