Year: 2006
Type: article
Abstract: By definition, amyloids regardless of primary sequence of the subunit, share common structural features. Encouraged by the previous identification of anti–amyloid mAbs that recognize multiple amyloids and data showing that anti–amyloid antibodies can enhance clearance of light chain amyloid in mice, we tested the hypothesis that immunization with heterologous amyloids (hAs) formed from peptides that lack homology to any human or mouse protein could induce a generic anti–amyloid response. We find that vaccination of mice with hAs induces a robust anti–amyloid Ab response and that the anti–amyloid Abs are capable of recognizing multiple amyloids regardless of subunit. Our original rationale for this approach was largely driven by trying to avoid a harmful T–cell response. In most cases, we are immunizing with amyloids composed of subunits lacking homology to human or mouse proteins; thus MHC presentation and activated T–cells would be targeting non–self peptides. Furthermore, we find that amyloids formed from a 6 amino acid peptide induce a generic anti–amyloid response. In this latter case, sequence homology becomes less of an issue; such small peptides theoretically lack the ability to bind to MHC. We had originally speculated that such an approach might avoid self–tolerance issues and induce a stronger anti–amyloid immune response than fAβ42 vaccination. However, this speculation was largely based on the idea that an anti–amyloid response was induced by a thymus dependent (TD) mechanism. Current data suggests that amyloid is not a TD antigen but a thymus independent type 2 (TI2) antigen. The rules or immune recognition of a TI2 antigen are distinct from those for TD responses, and little is known about self–tolerance with respect to TI2 responses. By definition, TI2 antigens do not require help from αβ T–cells or antigen presentation by MHC class II. Therefore, to determine if fAβ42 and hAs are TI2 antigens, we are currently vaccinating TcR αβ knockout mice and MHC class II knockout mice with several hAs and fAβ42. This novel approach enables testing of the hypothesis that immunotherapy targeting amyloid and, potentially, a preamyloid aggregate is beneficial in mouse models of AD.
Source: Alzheimer s & Dementia
Authors: Pritam Das, Rudi Hrncic, Todd Golde
Institutions: Mayo Clinic, Mayo Clinic in Florida
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W3023012977