Abstract
In recent years, our knowledge about immunoregulation and autoimmunity has significantly advanced, but nontoxic and more effective treatments for different inflammatory and autoimmune diseases are still lacking. Oral tolerance is of unique immunologic importance because it is a continuous natural immunologic event driven by exogenous antigen and is an attractive approach for treatment of these conditions. Parenteral administration of anti-CD3 monoclonal antibody is an approved therapy for transplantation in humans and is effective in autoimmune diabetes. Orally administered anti-CD3 monoclonal antibody is biologically active in the gut and suppresses experimental models of autoimmune diseases. Orally delivered antibody does not have side effects including cytokine release syndromes, thus oral anti-CD3 antibody is clinically applicable for chronic therapy. Here we review findings that identify a novel and powerful immunologic approach that is widely applicable for the treatment of human autoimmune conditions.
Highlights
Understanding how the immune system balances between tolerance and protective immunity is still a key challenge in immunology
An experimental system that has been frequently used for the study of Tcell function in oral tolerance is the use of TCR transgenic (Tg) mice in which all T cells have a common TCR
We found that oral anti-CD3 ameliorates disease in other autoimmune and inflammatory diseases including streptozocin-induced [30] and nonobese diabetic (NOD) autoimmune diabetes, type 2 diabetes in the Ob/Ob mouse [32], lupus prone SNF1mice [33], and collagen-induced arthritis [34]
Summary
Understanding how the immune system balances between tolerance and protective immunity is still a key challenge in immunology. Using TCR Tg mice, we administered the cognate antigens myelin basic protein (MBP) and ovalbumin (OVA) and investigated how oral administration of an antigen-affected specific Tcell subsets In these studies, we demonstrated the dosedependent induction of Tregs in MBP TCR Tg mice [5] and deletion following high-dose oral administration of OVA in OVA TCR Tg mice [6]. The CD4+ cells from OVA TCR Tg fed animals had greater suppressive properties in vitro than natural Tregs, mediated suppression in part by both TGF-β and IL-10, and presented increased expression of CTLA-4, a molecule known to be involved in Treg activity [6, 10] These findings demonstrated that oral antigen could induce/expand Tregs, administration of OVA to OVA TCR Tg mice is dependent on TCR Tg mice and not translatable to humans.
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