Utilizing Antigenic Peptide and Adhesion Molecule Conjugates to Suppress Autoimmune Disease in Animal Models

Abstract

Peptides and proteins have been used as carriers to target and deliver molecules to sites of action. Conjugating a drug to a macromolecule offers the unique advantage of being able to target drug to a specific cell surface receptor with high affinity, thereby increasing efficacy and reducing side effects. Furthermore, conjugations between two different peptides, or between peptide and protein, that have activities to modulate two receptors have shown promising results in suppressing autoimmune diseases in animal models. Therefore, the objective of the dissertation was to explore the possibility of selectively targeting peptide and protein conjugates to antigen presenting cells to suppress autoimmune diseases. The I-domain of leukocyte function associated antigen-1 (LFA-1) conjugated to antigenic PLP139-151 peptide (IDAC-3) suppressed experimental autoimmune encephalomyelitis (EAE) when delivered in a vaccine-like manner by shifting the immune balance away from Th17-mediated pathology by increasing involvement of T-reg cells (Chapter 2). PLP139-151 conjugated to LABL adhesion peptide (Ac-PLP-BPI-NH2-2) was formulated in a colloidal gel for a one-time subcutaneous administration to suppress EAE. A vaccine-like administration of the peptide conjugate suppressed EAE as well as the relapse. In vitro cytokine studies suggested that the mechanism of suppression was due to the shift of the immune balance away from a Th17-mediated response (Chapter 3). The utility of BPI to target other autoimmune diseases such as collagen-induced arthritis (CIA) was also investigated. Here, collagen type II peptides were conjugated to LABL (CII-BPI). It was found that suppression of disease is dependent upon the sequence of the antigen, and that the mechanism of disease suppression was linked to a shift in the immune balance from a proinflammatory to a regulatory response (Chapter 4).