Peptides and Proteins for Treatment and Suppression of Type 1 Diabetes

Abstract

Type-1 diabetes (T1D) is an autoimmune disease in which self-reactive immune cells infiltrate the islets in the pancreas to destroy -cells. One of many possible causes is that selfreactive T cells that are normally eliminated can escape from the thymus along with normal T cells. The escaped T cells can be activated in response to a low level of secondary selfantigens, which can lead to a major step for tissue self-recognition. For activation, T cells interact with antigen-presenting cells (APC) via formation of the immunological synapse, which has a “bull’s eye” structure at the membrane interface between both cells (Grakoui et al., 1999). The immunological synapse is composed of two segregated clusters of Signal-1 and Signal-2 molecular complexes. Signal-1 is generated by interaction between T-cell receptors (TCR) and antigen/multi histocompatibility complex-II (Ag/MHC-II). Signal-2 (costimulatory signal) can be delivered by a positive signal via B7/CD28 interactions or a negative signal via B7/CTLA-4 interactions. In addition, the CD40/CD154 costimulatory interaction between APC and T cells was found to induce an inflammatory immune response (Baker et al., 2008; Munro et al., 2007). Cell adhesion molecule interactions such as ICAM-1/LFA-1 interactions have also been categorized as a positive signal (Bromley et al., 2001; Grakoui et al., 1999). The positive costimulatory signal assists the induction of T-cell activation while the negative costimulatory signal suppresses T-cell activation (Bour-Jordan et al., 2011; Manikwar et al., 2011). The formation of the immunological synapse involves translocation of Signal-1 and Signal-2. Prior to the translocation process, Signal-1 is clustered at the periphery and Signal-2 is clustered at the center. Then, Signal-1 and Signal-2 switch places to establish the immunological synapse where Signal-1 is at the center (called central zone supramolecular activation complex or cSMAC) and Signal-2 is at the periphery (peripheral zone supramolecular activation complex or pSMAC) (Bromley et al., 2001; Grakoui et al., 1999). TCR on T cells recognize self-antigens presented on MHC-II molecules on the surface of APC for activation of self-reactive T cells to initiate autoimmune diseases. In T1D, glutamic acid decarboxylase-65 (GAD65), is one of the important self-antigens in humans, and is a reliable marker in overt diabetes (Tisch et al., 1998). Administration of GAD peptides in complete Freund’s adjuvant (CFA) into non-obese diabetes (NOD) mice triggers insulitis and destruction of -cells to cause diabetes (Liu et al., 1999; Tisch et al., 1999; Yoon et al., 1999). There is a correlation between islet expression of GAD enzymes and the development of T1D. Different types of MHC-II molecules such as I-Ag7 and I-Ag7.PD recognize different