Soluble nano-materials made from immunogenic antigen and inhibitory peptide limits disease in a mouse model of autoimmunity.
Bradley P. Sullivan1, Joshua Sestak1, Sharadvi Thati1, Laura Northrup1, Brittany Rover2, and Cory J. Berkland1, 2, 3
1Department of Pharmaceutical Chemistry, School of Pharmacy, Department of Bioengineering Graduate Program, School of Engineering, and 3Department of Chemical and Petroleum Engineering, School of Engineering, The University of Kansas, Lawrence, Kansas.
Non-specific immunosuppression is a serious side effect associated with therapies used to treat patients with autoimmune disorders and patients receiving organ transplantation. Antigen specific immunotherapies (antigen-SIT) are being developed to increase drug efficacy, while reducing the risk of serious adverse reactions associated with global immunosuppression in these patients. We evaluated soluble antigen arrays (SAgAs) as novel antigen-SIT molecules that are covalently engrafted with multiple copies of immune-inhibitory peptide(s) and the causal disease antigen, proteolipid protein peptide (PLP), on the development of experimental autoimmune encephalomyelitis (EAE) in mice. We hypothesized that SAgA delivery of an inhibitory peptide (LABL) against intracellular adhesion molecule-1, an essential signaling receptor in immune cells, would inhibit EAE disease in mice. Treatment with SAgA engrafted with LABL (SAgALABL) or SAgA co-engrafted with both LABL and PLP (SAgALABL:PLP) reduced culture supernatant levels of the pro-inflammatory cytokines tumor necrosis factor alpha and interleukin-6 in PLP stimulated splenocytes from EAE mice. Of importance, cell viability and culture supernatant levels of interleukin-2 were not altered by either SAgA, suggesting that neither SAgA was acutely cytotoxic to all immune cells. In contrast, EAE-induced mice treated with SAgALABL showed worse clinical outcomes, whereas treatment of EAE-mice with SAgALABL:PLP inhibited disease. The data suggest that SAgALABL:PLP displaying both immunogenic antigen and inhibitory peptide(s) can inhibit pro-inflammatory cytokine production in PLP-stimulated splenocytes and can suppress disease progression in a mouse model of autoimmunity. Taken together, SAgAs might provide a novel platform to rationally design antigen-SIT for transplant patients and patients with autoimmune disorders.