Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

Abstract

Parasite proteins containing repeats are essential invasion ligands, important for their ability to evade the host immune system and to induce immunosuppression. Here, the intrinsic suppressive potential of repetitive structures within parasite proteins was exploited to induce immunomodulation in order to establish self-tolerance in an animal model of autoimmune neurological disease.We tested the tolerogenic potential of fusion proteins containing repeat sequences of parasites linked to self-antigens. The fusion constructs consist of a recombinant protein containing repeat sequences derived from the S-antigen protein (SAg) of Plasmodium falciparum linked to a CD4 T cell epitope of myelin. They were tested for their efficacy to control the development of experimental autoimmune encephalomyelitis (EAE), In addition, we used the DO11.10 transgenic mouse model to study the immune mechanisms involved in tolerance induced by SAg fusion proteins.We found that repeated sequences of P. falciparum SAg protein linked to self-epitopes markedly protected mice from EAE. These fusion constructs were powerful tolerizing agents not only in a preventive setting but also in the treatment of ongoing disease. The tolerogenic effect was shown to be antigen-specific and strongly dependent on the physical linkage of the T cell epitope to the parasite structure and on the action of anti-inflammatory cytokines like IL-10 and TGF-β. Other mechanisms include down-regulation of TNF-α accompanied by increased numbers of FoxP3 + cells. This study describes the use of repetitive structures from parasites linked to defined T cell epitopes as an effective method to induce antigen-specific tolerance with potential applicability for the treatment and prevention of autoimmune diseases.

Tolerogenic Immunomodulation by PEGylated Antigenic Peptides

“…Beside dominant suppression mediated by Tregs, peripheral tolerance ( 3 ) also involves deletion of antigen-specific cells by activation-induced cell death ( 60 ) and anergy ( 4 ), e.g., failure of antigen-reactive cells to produce pro-inflammatory cytokines. The data of this study point to a partial deletion of antigen-specific effector cells upon injection of pOVA-PEG, as also found upon vaccination with multimerized T cell epitopes ( 61 ) and T cell epitopes linked to parasite-derived tandem repeats ( 17 ).…”

“…In a preceding study, a tolerogenic effect of peptide epitopes was only observed when the peptide was multimerized or coupled to a repetitive carrier protein, but not as native peptide ( 17 ). This let us hypothesize that just molecular size is an important parameter in the tolerogenic efficacy.…”

“…The efficacy of small peptides is restricted by their rapid excretion through the kidney or enzymatic degradation ( 14 ). This provoked further studies aiming to improve the tolerogenic potential of peptides by coupling to autologous cells ( 15 , 16 ), to carrier proteins ( 17 ), coupling to or encapsulation of peptides into different kinds of nanoparticles ( 18 – 21 ), and others as reviewed in ( 7 , 22 – 25 ).…”

Malaria Parasites: The Great Escape

“…However, this often leads to the production of mainly IgM and limited B cell memory (175). In addition, exposure to antigens containing repeated motifs can result in the suppression of an ongoing T cell response (176, 177). …”

Advances in Autoimmune Epilepsy Associated with Antibodies, Their Potential Pathogenic Molecular Mechanisms, and Current Recommended Immunotherapies

“…However, this direction is still worth trying since the clinical efficacy of existing immunotherapy to AE diseases has a distance to the ideal therapeutic expectation. As an example, taking advantage of the trait that repeated sequences from parasite are of essence to evade the host immune system, researchers linked repetitive structures from specific parasite proteins to defined self/T-cell epitopes together, tested and verified successfully the effectiveness to induce antigen-specific tolerance (169). …”