Tregitope: Immunomodulation Powerhouse

Abstract

IVIG is frequently used in the 'pre-conditioning' regimens for higher risk transplants; its effects are attributed in part to induction of Tregs. We have identified regulatory T cell (Treg) epitopes, now known as Tregitopes, in IgG, the main component of intravenous immunoglobulin therapy (IVIg). Tregitopes provide one explanation for the expansion and activation of Treg cells following IVIg treatment. Tregitopes are peptides that exhibit high affinity binding to multiple human HLA Class II DR; they are conserved across IgG isotypes and mammalian species. In vitro and in vivo, for human PBMC and in animal models, Tregitopes activate Tregs. Studies to delineate the mechanism of action have shown that Tregitopes' effects are very similar to IVIg in vitro. Here we demonstrate that Tregitopes induce Tregs to produce IL-10, leading to modulation of dendritic cell phenotype (down-regulation of Class II, CD80 and CD86 and up-regulation of ILT3), and describe the effects of Tregitopes in the ABM-TCR-transgenic skin transplantation model. The discovery of Tregitopes in IgG and other autologous proteins may contribute to improved understanding of the mechanism of action of IVIg and lead to the application of these powerful immunomodulators to improve transplantation success and suppress autoimmune disease, in the future.

Unraveling molecular determinants of manual therapy: an approach to integrative therapeutics for the treatment of fibromyalgia and CFS/ME

“…Moreover, load-independent changes were also evidenced on the non-CCL treated contralateral limb, indicating a systemic response of the massage-mimetic treatment [46]. From the 47% of the functional gene ontology clusters associating with immune response after CCL, the authors validated the chemokine (C-C motif) receptor CCR2, a critical regulator of skeletal muscle regeneration [47,48]; the leukocyte immunoglobulin like receptor B4 (Lilrb4), alias ILT3, thought to control inflammatory responses and limit autoreactivity through Treg enhancement [49]; the major histocompatibility complex (class II) molecule Cd74, an important regulator of immunity and inflammation with an impact on the cell endosomal compartment [50]; and the lysozyme 2 (Lyz2) gene involved in activities such as reducing the presence of proinflammatory cytokines (TNF-α, IL-6, INF-γ, IL-8 and IL-17) while increasing levels of anti-inflammatory cytokines (IL-4 and TGF-β) [51]; by the cost-effective alternative approach RT-qPCR (real time polymerase chain reaction after retrotranscription) which entitles a rather easy implementation of molecular marker monitorization in follow-up studies. All these molecular changes appeared unaffected in low load treatments (1.4 N) and upregulated by medium load treatments (4.5 N) indicating that a minimum pressure is required to register the effect.…”

“…The evidence obtained from animal experimentation using mimetic devices is considered valuable but incomplete. Although the response to MT maneuvers at the molecular level is clear, for example the tolerance associated marker ILT3, which could benefit autoimmune diseases [49] appears induced by medium load pressure treatments [46], and many miRNAs respond to certain compressive loads [73], the current paucity of information limits the potential of adapting MT to particular health problems.…”

Engineering antigen-specific immunological tolerance

“…In mouse models of autoimmunity and allograft transplantation, the so-called 'Tregitopes' are co-administered with soluble antigenic peptides to drive Treg activation and IL-10 expression, in an FcRn-mediated mechanism that is postulated to recapitulate the therapeutic mode of action behind intravenous immunoglobulin (IVIg) therapy [17].…”

“…Non-optimal ex vivo expansion may lead to the generation of exhausted cells, potentially explaining why relapse of the disease was Engineering immunological tolerance Kontos, Grimm and Hubbell 85 (a) [3] (a) [7] (e) [10] (b) [4] Soluble peptides / APL (f) [12,13,14,15,16,17] DNA vaccine (l) [22,23] Tregitopes (h) [16,17,41] CD28 CD80/CD86 (c) [5] (d) [8,9] (b) [4] (i) [21] (i) [18,19,20] : antigen : epitope from antigen Nanoparticle (g) [33,34,35] MHC II TCR Liposome Apoptotic cell (j) [28,29,30], (k) [31,32] BCR Current Opinion in Immunology…”

Intravenous immunoglobulins in liver transplant patients: Perspectives of clinical immune modulation

“…This mechanism is currently suggested to be crucial for IVIginduced restoring of imbalanced immune homeostasis [55] . Regulatory T cell epitopes (Tregitopes) on IgG have been recently identified to trigger the interaction between Tregs and IVIg [56] .…”