Targeting of tolerogenic dendritic cells towards heat‐shock proteins: a novel therapeutic strategy for autoimmune diseases?

Lin

et al. 2019

IJMS

Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease of unknown etiology. It is characterized by the presence of rheumatoid factor and anticitrullinated peptide antibodies. The orchestra of the inflammatory process among various immune cells, cytokines, chemokines, proteases, matrix metalloproteinases (MMPs), and reactive oxidative stress play critical immunopathologic roles in the inflammatory cascade of the joint environment, leading to clinical impairment and RA. With the growing understanding of the immunopathogenic mechanisms, increasingly novel marked and potential biologic agents have merged for the treatment of RA in recent years. In this review, we focus on the current understanding of pathogenic mechanisms, highlight novel biologic disease-modifying antirheumatic drugs (DMRADs), targeted synthetic DMRADs, and immune-modulating agents, and identify the applicable immune-mediated therapeutic strategies of the near future. In conclusion, new therapeutic approaches are emerging through a better understanding of the immunopathophysiology of RA, which is improving disease outcomes better than ever.

Section: Part Ii: Current Immune Target Therapy and On-going Immunmentioning

confidence: 99%

Immunopathogenic Mechanisms and Novel Immune-Modulated Therapies in Rheumatoid Arthritis

Lin

et al. 2019

IJMS

Journal of Immunology Research

“…However, CIA mice receiving the transfer of STAT3ca-transduced DCs displayed a significantly stronger reduction of CIA manifestation in comparison with those mice receiving DCs treated with vitamin D3 (data not shown). Although a number of studies have shown that tolerogenic DCs need to be pulsed with a disease-relevant autoantigen to induce an anti-inflammatory effect in autoimmune disorders, another group of studies has suggested that nonloaded tolerogenic DCs might take up relevant autoantigens in vivo and exert a therapeutic effect dampening inflammation [50, 51]. Thereby, whether the loading of tolerogenic DCs with autoantigens is necessary or not to attenuate inflammation in autoimmune disorders remains controversial.…”

Section: Resultsmentioning

confidence: 99%

STAT3 Activation in Combination with NF-KappaB Inhibition Induces Tolerogenic Dendritic Cells with High Therapeutic Potential to Attenuate Collagen-Induced Arthritis

Prado

Ugalde

González

et al. 2019

Dendritic cells (DCs) have the ability to induce tolerance or inflammation in response to self-antigens, which makes them fundamental players in autoimmunity. In this regard, immunogenic DCs produce IL-12 and IL-23 favouring the acquisition of Th1 and Th17 inflammatory phenotypes, respectively, by autoreactive CD4+ T-cells, thus promoting autoimmunity. Conversely, tolerogenic DCs produce IL-10 and TGF-β, inducing the generation of CD4+ T-cells with suppressive activity (Treg), which promote tolerance to self-constituents. Previous studies have shown that STAT3 signalling in DCs attenuates the production of proinflammatory cytokines, whilst NF-κB activation promotes it. In this study, we aimed to generate DCs displaying strong and constitutive tolerogenic profile to be used as immunotherapy in autoimmunity. To this end, we transduced bone marrow-derived DCs with lentiviral particles codifying for a constitutively active version of STAT3 (constitutively active STAT3 (STAT3ca)) or with a constitutive repressor of NF-κB (IκBα superrepressor (IκBαSR)), and their therapeutic potential was evaluated in a mouse model of arthritis induced by collagen (CIA). Our results show that STAT3ca transduction favoured the production of the anti-inflammatory mediator IL-10, whereas IκBαSR transduction attenuated the expression of the proinflammatory cytokine IL-23 in DCs. Moreover, both STAT3ca-transduced and IκBαSR-transduced DCs separately exerted a mild but significant therapeutic effect reducing the severity of CIA development. Furthermore, when DCs were transduced with both STAT3ca and IκBαSR together, they reduced CIA manifestation significantly stronger than when transduced with only STAT3ca or IκBαSR separately. These results show STAT3 and NF-κB as two important and complementary regulators of the tolerogenic behaviour of DCs, which should be considered as molecular targets in the design of DC-based suppressive immunotherapies for the treatment of autoimmune disorders.

Human Vaccines & Immunotherapeutics

“…We are planning now a phase I-II, unblinded, longitudinal study with RA patients in remission or with low disease activity under conventional therapy. 33 In our case the dexamethasone and Vit D3 tolerized DC will be loaded with a well-characterized HSP70 derived peptide, which is called HSP70-B29. 34 Peptide HSP70-B29 is conserved, and T cells were shown to cross-respond between the microbial and the self-peptide both in mice and in humans.…”

Section: Therapeutic Tolerancementioning

confidence: 99%

Vaccination against autoimmune diseases moves closer to the clinic

Eden

2019

Self Cite

Biologicals, e.g. TNF inhibitors, have improved dramatically the efficacy of medical interventions in autoimmune diseases, such as in rheumatoid arthritis (RA). However, although progressive inflammation can be halted in this way, no drug-free remissions or lasting cures are reached. For this to become real, therapies based on induction antigen-specific immune tolerance are sought. This review describes mechanisms of tolerance and the current possibilities for induction of therapeutic tolerance through antigen-specific vaccination approaches. And despite the fact that for various diseases the search for appropriate autoantigens is ongoing, pioneering studies are now already developed that use more broadly inflammation associated antigens. Through their capacity to preferentially induce regulatory T cells, heat shock proteins are an attractive source of such broadly inflammation associated antigens.