An IL-2 mutein engineered to promote expansion of regulatory T cells arrests ongoing autoimmunity in mice
Citations Over TimeTop 10% of 2020 papers
Abstract
Interleukin-2 (IL-2) controls the homeostasis and function of regulatory T (Treg) cells, and defects in the IL-2 pathway contribute to multiple autoimmune diseases. Although recombinant IL-2 therapy has been efficacious in certain inflammatory conditions, the capacity for IL-2 to also activate inflammatory effector responses highlights the need for IL-2-based therapeutics with improved Treg cell specificity. From a panel of rationally designed murine IL-2 variants, we identified IL-2 muteins with reduced potency and enhanced Treg cell selectivity due to increased dependence on the IL-2 receptor component CD25. As an Fc-fused homodimer, the optimal Fc.IL-2 mutein induced selective Treg cell enrichment and reduced agonism of effector cells across a wide dose range. Furthermore, despite being a weaker agonist, overall Treg cell growth was greater and more sustained due to reduced receptor-mediated clearance of the Fc.IL-2 mutein compared with Fc-fused wild-type IL-2. Preferential Treg cell enrichment was also observed in the presence of activated pathogenic T cells in the pancreas of nonobese diabetic (NOD) mice, despite a loss of Treg cell selectivity in an IL-2R proximal response. These properties facilitated potent and extended resolution of NOD diabetes with infrequent dosing schedules.
Related Papers
- → Direct evidence for the contribution of B cells to the progression of insulitis and the development of diabetes in non-obese diabetic mice(1997)176 cited
- → I-E+ nonobese diabetic mice develop insulitis and diabetes.(1993)127 cited
- → Elevated glucagon-like peptide-1 plasma levels, as a possible adaptive response, in diabetic NOD mice(2012)10 cited
- Studies on the thymus of non-obese diabetic (NOD) mice: effect of transgene expression.(1994)
- → Altered autoimmune response in NOD-Alox15null mice (99.13)(2009)