Reestablishing T Cell Tolerance by Antibody-Based Therapy in Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing b cells are selectively destroyed. b cell-specific T cells are considered to be the major mediators of pathology. Accordingly, most immunotherapies tested in the clinic to date have focused on reestablishing self-tolerance within the T cell compartment. Monoclonal antibodies (Ab) targeting a variety of lymphocyte surface proteins have demonstrated benefits in preclinical and clinical settings. Indeed, the use of Ab to target T cells directly or indirectly has proven to be an effective strategy to rapidly suppress b cell autoimmunity and establish tissue-specific, long-term tolerance in rodent T1D models. In this review, we describe a number of these Ab-based immunotherapies, discuss associated immune regulatory mechanisms, and highlight results obtained in T1D clinical trials.

Antibody Binding to CD4 Induces Rac GTPase Activation and Alters T Cell Migration

“…Diabetogenic CD4 + and CD8 + T cells are stimulated by β cell-antigen laden APC in the draining pancreatic lymph nodes (PLN), and then traffick to the islets to mediate inflammation and ultimately β cell destruction (1-4). To date, most immunotherapies have focused on targeting T cells as a means to prevent and/or treat T1D (5-11). We and others have applied Ab specific for CD4 and CD8 to manipulate coreceptor molecule signaling and the activity of pathogenic CD4 + and CD8 + T cells, as well as Foxp3-expressing regulatory CD4 + T cells (12-17).…”