Autoantigen-targeted therapy reinforces impaired central tolerance in autoimmune mice (THER5P.916)

Abstract

Immune tolerance breakdown precedes autoimmune disease. Receptor editing is an immune tolerance mechanism that alters BCR specificity to combat frequent autoreactivity in the developing B cell repertoire. Much of what is known about receptor editing derives from multivalent antigens, or soluble antigens which interact with the BCR with supra-physiologic affinity (1010 M-1). A system was therefore developed in which the BCR interacts with insulin autoantigen with a more physiologic affinity (107 M-1) to better reflect B cells that arise in the developing bone marrow repertoire. Surprisingly, circulating insulin was found to elicit receptor editing in non-autoimmune mice. This process occurred less efficiently in the type 1 diabetes-prone NOD strain, consistent with enhanced anti-insulin B cell escape into the periphery from the bone marrow observed in this strain. Receptor editing efficiency was enhanced by treatment with an insulin-targeting mAb that selectively eliminates anti-insulin B lymphocytes and prevents type 1 diabetes. A F(ab’)2 of this antibody also depleted developing anti-insulin B lymphocytes, confirming receptor editing as a central tolerance mechanism targeted by this approach. These studies show that a small protein hormone of modest affinity elicits receptor editing, but with less efficiency in the context of autoimmunity. This defect can be overcome with autoantigen-targeted therapy, which offers promise for the treatment of autoimmune disease.