APL1, an altered peptide ligand derived from human heat-shock protein 60, increases the frequency of Tregs and its suppressive capacity against antigen responding effector CD4 + T cells from rheumatoid arthritis patients

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by a chronic relapsing-remitting joint inflammation. Perturbations in the balance between CD4 + T cells producing IL-17 and CD4 + CD25 high FoxP3 + Tregs correlate with irreversible bone and cartilage destruction in RA. APL1 is an altered peptide ligand derived from a CD4+ T-cell epitope of human HSP60, an autoantigen expressed in the inflamed synovium, which increases the frequency of CD4 + CD25 high FoxP3+ Tregs in peripheral blood mononuclear cells from RA patients. The aim of this study was to evaluate the suppressive capacity of Tregs induced by APL1 on proliferation of effector CD4+ T cells using co-culture experiments. Enhanced Treg-mediated suppression was observed in APL1-treated cultures compared with cells cultured only with media. Subsequent analyses using autologous crossover experiments showed that the enhanced Treg suppression in APL1-treated cultures could reflect increased suppressive function of Tregs against APL1-responsive T cells. On the other hand, APL1-treatment had a significant effect reducing IL-17 levels produced by effector CD4+ T cells. Hence, this peptide has the ability to increase the frequency of Tregs and their suppressive properties whereas effector T cells produce less IL-17. Thus, we propose that APL1 therapy could help to ameliorate the pathogenic Th17/Treg balance in RA patients.

Biodistribution and pharmacokinetic profiles of an altered peptide ligand derived from heat-shock proteins 60 in Lewis rats

“…Previously, we showed that CIGB-814 induced regulatory properties associated with inhibition of inflammation in several experimental models (Domínguez et al 2011;Barberá et al 2016;Lorenzo et al 2017).…”

“…This peptide increased the frequency of Treg and their suppressive capacity against antigen responding effector CD4 + T cells from RA patients. In addition, this peptide inhibits significantly IL-17 levels produced by effector CD4 + T cells from peripheral blood mononuclear cells (PBMCs) of RA patients (Kim et al 2016;Barberá et al 2016).…”

Immune tolerance therapies for autoimmune diseases based on heat shock protein T-cell epitopes

“…In the preclinical models, the peptide called APL1 was able to increase the percentage of CD4 þ CD25 þ FoxP3 þ Treg cells in vivo after inoculation into BALB/c mice and in the rat adjuvant arthritis model, where it was able to control histological damage and clinical signs of arthritis, an effect that was associated with increased proportions of FoxP3 þ Tregs in the spleen. Furthermore, the APL1 induced Tregs ex vivo in PBMCs obtained from RA patients [61].…”

Heat shock proteins in the therapy of autoimmune diseases: too simple to be true?

“…For instance, immunization with bacterial ( Mycobacterium tuberculosis ) or mammalian Hsp60 ameliorated or suppressed various experimental models of autoimmune diseases, e.g., adjuvant arthritis, collagen-induced arthritis, diabetes type I, or atherosclerosis in a Th2- and/or Treg-dependent way (van Eden et al 2005a , b ; Landstein et al 2015 ). Moreover, an altered peptide ligand (APL) derived from a CD4+ T cell epitope of human Hsp60 inhibited the course of murine arthritis, similarly to methotrexate (Lorenzo et al 2017 ), and increased the percentage of Treg or downregulated the secretion of pro-inflammatory IL-17 in peripheral blood mononuclear cell cultures from RA patients (Barberá et al 2016 ). Further, artificial induction of Hsp70 expression or administration of bacterial or murine Hsp70-derived peptides prevented inflammatory damage in experimental autoimmune arthritis models in a Treg- and/or IL-10-dependent way (van Eden et al 2005a , b ; Stocki and Dickinson 2012 ; Borges et al 2012 ; van Herwijnen et al 2012 ; van Eden et al 2013a , b ).…”