An article published last week in Disease Models and Mechanisms by Dawn Smilek, MD, PhD, Mario Ehlers, MD, PhD, and Jerry Nepom, MD, PhD, provides a review of mechanisms involved in the disruption of tolerance to self-antigens in autoimmune disease, highlighting where those mechanisms can be targeted as a means of restoring tolerance and durably reversing autoimmune pathology. Given the complexity of pathways that contribute to autoimmune disease, effective and long-lasting treatment will likely require rational combinations of therapeutics that enhance regulatory components of the immune system, while diminishing antigen-specific effectors and the innate immune response. This approach is consistent with the ITN’s recently-launched PAUSE study in psoriasis, which will assess the combination of ustekinumab (anti-IL12/23) to first reduce T effector cells in the skin, followed by abatacept (CTLA-4 Ig) to prevent pathogenic re-activation of repopulating cells by means of co-stimulatory blockade. Other ITN trials in development will similarly use mechanistically-driven combination therapy approaches to tolerance.
