Unswitched immunoglobulin M response prolongs mouse survival in prion disease

Abstract

Several studies have failed to demonstrate the presence of immune responses to infectious prions during the course of prion disease, reflecting the identical primary structure of normal and disease-associated isoforms and the widespread expression of the normal cellular form of prion protein, PrPC, leading to B- and/or T-cell tolerance of disease-associated isoforms and also possibly because antigen-presenting cells are unable to process the highly aggregated, detergent-insoluble, protease-resistant form, PrPSc. Under certain circumstances, PrPSc can be revealed to the immune system in immunogenic form, and it has been shown previously that anti-PrP antibodies can be induced to prions immunoadsorbed to Dynabeads using specific anti-PrP monoclonal antibodies, even in PrP-sufficient mice. This study demonstrated in a murine scrapie model that PrP–Dynabeads effectively stimulated the immune system to produce anti-PrP IgM antibodies over prolonged periods after repeated immunization. It was also shown that these immune responses prolonged incubation times in murine scrapie.

PrP-specific camel antibodies with the ability to immunodetect intracellular prion protein

“…Brains from terminally ill scrapie-infected wild-type (WT) FVB/N mice were homogenized in PBS (10 % w/v) using an Ultra Turrax tissue homogenizer (SIS) as described previously (Tayebi et al, 2009) Immunization of camels with PrP Sc -Dynabeads. All procedures involving animals were carried out under a project and personal licence authority issued in accordance with The Animals (Scientific Procedures) Act 1986 and approval by the Institutional Ethics Committee.…”

“…In more recent work (Tayebi et al, 2009), we have demonstrated that active immunization with non-denatured PrP Sc results in considerable prolongation of the incubation period and delayed onset of clinical prion disease in mice. Importantly, this study demonstrated that immunization with non-denatured PrP Sc predominantly elicits serum IgM.…”

The Tyr-Tyr-Arg Prion-Specific Epitope: Update and Context

“…However, this approach normally results in the production of IgM Abs (Tayebi et al 2004(Tayebi et al , 2009(Tayebi et al , 2011Nikles et al 2005 ;Buchholz et al 2006 ) . IgM Abs is not as useful as IgG Abs in diagnostic applications due to low af fi nity, and they are not as useful in therapeutic applications for the following reasons: IgM cannot cross the blood-brain barrier, they diffuse through the tissues poorly, they provide only short-lived immunity, and they can cause the inappropriate activation of 3Cb complement.…”

“…Unfortunately, the exposure of PrP null mice to PrP Sc proteins without the use of harsh adjuvants, carriers, or Virus Like Particles (VLPs), etc., regularly induces the production of IgM Ab in mice (Tayebi et al 2004(Tayebi et al , 2009(Tayebi et al , 2011Nikles et al 2005 ;Buchholz et al 2006 ) . This seemingly default tendency of the murine immune system to produce IgM upon exposure to PrP…”

Advances in the development of antibody-based immunotherapy against prion disease

“…84 Another study showed that PrPDynabeads stimulated the immune system in a murine scrapie model to produce anti-PrP immunoglobulin (Ig) M antibodies and prolonged onset after repeated immunization. 85 Some research groups have used truncated prion peptides as immunogens for the production of antibodies. However, though many modified truncated prion peptides induce an antibody response in animal models, only a few delay onset and slow progression of the disease.…”