Tolerance induction by monoclonal CD3 antibodies is dependent on indoleamine 2,3 dioxygenase (IDO) (56.5)

Abstract

Abstract Experimental data demonstrated that a short treatment with CD3 antibodies (CD3 Ab) promotes immune tolerance in primed hosts. Successful clinical transfer of this strategy has been achieved in autoimmune diabetes, and on this basis, CD3 Abs are currently under pharmaceutical development. The tolerogenic effect of CD3 Ab evolves in two consecutive phases: a first phase of “induction” during Ab treatment, involving transient T cell depletion as well as antigenic modulation and a second phase of “maintenance” that persists after CD3 Ab clearance and that correlates with the presence of active and transferable tolerance involving TGF-β dependent Tregs. We focused on the causal links relating the “induction” and “maintenance” phases of tolerance using spontaneously diabetic NOD mice and human CD3ϵ transgenic NOD mice, a novel preclinical model that we established. It is well known that abnormalities in dendritic cells (DCs) contribute to autoimmune diabetes in NOD mice, e.g. indoleamine 2,3 dioxygenase (IDO) induction in CD8+ DCs of NOD mice by IFN-γ is defective. Our results show that depletion of DCs or inhibition of IDO during CD3 Ab therapy abrogates the tolerogenic effect. TGF-β has been shown to induce IDO and we reported that remission from diabetes after CD3 Ab therapy is TGF-β-dependent. We propose that CD3 Ab mediated tolerance ensues from a local immune privilege in the pancreas driven by induction of TGF-β and tolerogenic DCs expressing IDO.