Ph.D Thesis

Ph.D StudentAbraham Michal
SubjectThe Role of CD3 and Matrix Metalloproteinases (MMPs) in
Immune Regulation: Relevance to Multiple
DepartmentDepartment of Medicine
Supervisors PROF. Ariel Miller
DR. Sarah Shapiro


Multiple sclerosis (MS) is a chronic demyelination disease of the central nervous system (CNS) believed to be triggered by T cells which infiltrate into the CNS. This thesis concentrated on two elements, related to the complex pathological processes in MS: The MMPs, extracellular matrix degrading enzymes that are essential for transmigration into the CNS and immune activation via CD3 molecule. The study demonstrated the ability of Th1 cytokines to up-regulate MMPs activity, while Th2 cytokines down-regulate deleterious proteolytic activity. Th1 cells secrete higher levels of gelatinases (MMP2 and MMP9), and preferentially migrate, in comparison to Th2 cells. The present study demonstrates that anti-CD3 can induce a new type of human regulatory T cells in vitro. TaCD3 regulatory cells act by inhibiting a function associated with antigen presentation of DCs and require cell contact. Oral administration of anti-CD3 antibodies can induce oral tolerance and suppress experimental allergic encephalomyelitis (EAE). Oral administration of anti-CD3 induces a unique type of regulatory T cells characterized by the expression of latency associated peptide (LAP) on their cell surface that function in vivo by TGF-b- and IL-10- dependent mechanism. Thus, the study contributes to the better understanding of autoimmune diseases, such as MS, and suggests the implementation of several future therapeutic approaches, amongst them the use of inhibitors for Th1- related cytokines as well as specific MMPs-antagonists, capable of attenuating deleterious inflammatory and proteolytic activity. Another therapeutic approach is the oral administration of anti-CD3 as a treatment for T cell-mediated inflammatory and autoimmune diseases in humans.