Immunomodulation

Abstract

The underlying pathogenesis of prion diseases (prionoses) is related to an autocatalytic conformational conversion of PrP^C (C for cellular) to a pathological and infectious conformer known as PrP^Sc (Sc for scrapie) or PrP^Res (Res for Proteinase K resistant) Colby (Cold Spring Harb Perspect Biol 3:a006833, 2011). Currently, all prion diseases are without effective treatment and are universally fatal [Trevitt and Collinge (Brain 129:2241–2265, 2006); Muller-Schiffmann and Korth (BioDrugs 22:45–52, 2008); Brazier et al. (Expert Rev Anti Infect Ther 7:83–105, 2009); Li et al. (Immunotherapy 2:269–282, 2010); Wisniewski and Goni (Expert Rev Vaccines 9:1441–1452, 2010)]. The conformational change of PrP in prion diseases is associated with a negative gain of function; however, prion-like protein conformational changes are increasingly being recognized as a normal biological trait in mammals and lower species [Tuite and Serio (Nat Rev Mol Cell Biol 11:823–833, 2010); Hou et al. (Cell 146:448–461, 2011); Moresco (Cell Res 21:1643–1645); Si et al. (Cell 140:421–435, 2010); Wickner (Semin Cell Dev Biol, 22:469, 2010)]. The growing understanding of these protein conformational changes in biological processes opens the possibility of therapeutic targeting, when this phenomenon occurs in association with disease. The past experience with bovine spongiform demic of chronic wasting disease (CWD), has highlighted the need to develop prophylactic and/or therapeutic approaches. In Alzheimer’s disease (AD), also a conformational neurodegenerative disorder, both passive and active immunizations have been shown to be highly effective in model animals at preventing disease and cognitive deficits, with emerging data from human trials suggesting that this approach can partially ameliorate amyloid plaque and tau pathology [Selkoe (Nat Med 17:1060–1065, 2011); Wisniewski and Boutajangout (Brain Struct Funct 214:201–218, 2010)]. Human prion diseases are most commonly sporadic; hence the therapeutic need is primarily to stop progression; however, in animals the ­majority of prionoses are infectious and the emphasis is on prevention of transmission. These infectious prionoses are typically acquired via the alimentary tract as a major portal of infectious agent entry. This makes mucosal immunization a potentially attractive method to produce a local immune response that partially or completely prevents prion entry across the gut barrier, whilst at the same time producing a modulated systemic immunity that is unlikely to be associated with toxicity. Nevertheless, this same approach has the potential to be used to retard or ameliorate human familial prionoses, when given years ahead of the expected onset of disease. A critical factor in any immunomodulatory approach aimed at a self-antigen is the need to finely balance an effective humoral immune response with potential autoimmune toxicity. Our results using an attenuated Salmonella vaccine strain expressing the prion protein showed that mucosal vaccination can protect against prion infection from a peripheral source, suggesting the feasibility of this approach. The current epidemic of CWD, with its potential to spread to human populations, emphasizes the importance of developing such immunomodulatory approaches more fully.