Welcome to the 13th International Congress on Autoimmunity interactive program
OPENING REMARKS IN HONOR OF LATE PROF. MORTON SCHEINBERG (ID 908)
THE EFFECTS OF CANNABIDIOL IN COVID-19 PATIENTS (ID 907)
IS041 - TARGETING B CELLS IN MULTIPLE SCLEROSIS (ID 909)
Abstract
Abstract Body
Increasing evidence suggests that B cells contribute to both regulation of normal autoimmunity and the pathogenesis of immune mediated diseases including multiple sclerosis (MS). B cells in MS are skewed towards a pro-inflammatory profile and contribute to its pathogenesis by antibody production, antigen presentation, stimulation and activation of T cells, production of pro-inflammatory cytokines, formation of ectopic germinal centers under the meninges that drive cortical pathology and contribute to neurological disability, and probably by carrying the Epstein-Barr virus (EBV).
The recent interest in the key role of B cells in MS has primarily been evoked by the profound anti-inflammatory effects of rituximab observed in patients with relapsing MS. This has been reaffirmed by clinical trials with less immunogenic and more potent humanized and fully human B cell-depleting mAbs targeting CD20, namely ocrelizumab and ofatumumab, and the novel glycoengineered mAb ublituximab. Ocrelizumab is the first disease-modifying drug that has shown efficacy also in primary-progressive MS, and is currently approved for both indications. Another promising approach is the inhibition of Bruton's tyrosine kinase (BTK), a key cytoplasmic enzyme that mediates B and myeloid cell activation and survival, by agents such as evobrutinib, tolebrutinib, phenebrutinib and orelabrutinib. On the other hand, targeting B cell cytokines with the fusion protein atacicept paradoxically increased MS disease activity, probably by augmenting memory B cells. Finally, essentially all other approved therapies for MS, some of which have been designed to target T cells, have some effects on B cells that may contribute to their therapeutic activity.
JAK-INHIBITORS: DO WE NEED THEM? (ID 910)
NEW DRUGS IN SLE: WHAT SHOULD WE EXPECT? (ID 912)
CAN THE TREATMENT WITH EPIDERMAL GROWTH FACTOR REPRESENT A NOVEL THERAPEUTIC STRATEGY FOR THE TREATMENT OF AUTOIMMUNE DISEASES (ID 914)
THE ROLE OF BONE MARROW IN THE PATHOGENESIS OF SLE (ID 915)
O099 - DEVELOPMENT OF NOVEL THERAPEUTIC OPTIONS FOR INFLAMMATORY BOWEL DISEASES TARGETING AUTOPHAGY DYSFUNCTIONS (ID 70)
Abstract
Background and Aims
Safe and targeted medicines to effectively treat inflammatory bowel diseases (IBDs) are still awaited. Autophagy, a vital self-eating process involved in cellular homeostasis, provides a potential avenue for treating IBDs as several autophagy-related genes are associated with IBD risk. The therapeutic peptide P140 developed in our team is currently being evaluated in phase III clinical trials for lupus. It targets key elements of chaperone-mediated autophagy, which is hyperactivated in lupus. The “correcting” effect of P140 on autophagy results in weaker signaling of autoreactive T and B cells, leading to an improvement of pathophysiological conditions. Hence, we aim to analyze the therapeutic effects of P140 in animal IBD models.
Methods
Susceptible mice have been induced with dextran sulphate sodium (DSS) or trinitrobenzene sulphonic acid (TNBS) colitis and treated with P140 peptide following therapeutic protocols. The clinical course of the colitis has been monitored and animals were sacrificed for pathological and molecular analyses.
Results
Treatment with P140 peptide alleviates the clinical activity markers and repair the intestinal histo-morphological damages in DSS and TNBS colitis.
Conclusions
P140 exerts protective effects on the clinical course of chemically induced colitis. The molecular and cellular mechanisms behind this protection are currently investigated, with a special focus on autophagy.
O100 - NOVEL MOLECULAR TARGET AND THERAPEUTIC FOR THE TREATMENT OF AUTOIMMUNE DIABETES (ID 12)
Abstract
Background and Aims
Autoimmune diabetes involves T cell-mediated destruction of pancreatic beta cells resulting in hyperglycemia. Increased glucose flux enhances O-GlcNAcylation, an intracellular posttranslational modification of nucleo-cytoplasmic proteins. We found that hyperglycemia increases O-GlcNAcylation of NF-kappaB subunit c-Rel at serine residue 350 and enhances the transcription of pro-autoimmune cytokines, IL-2, IFNG and GM-CSF in T cells. Our recent results show that the regulatory effect of c-Rel O-GlcNAcylation is gene dependent and it suppresses the transcription of forkhead box P3 (FOXP3) that controls Treg cell development and function. Hence, blocking the function of O-GlcNAcylated c-Rel will have benefits in controlling autoimmune diabetes by diminishing the T cell-mediated autoimmunity.
Methods
We developed a novel peptoid, called OGC350, by molecular modeling and de novo synthesis, and studied its potential to bind to O-GlcNAcylated c-Rel and block its function.
Results
We found that OGC350 treatment significantly decreased T cell receptor-induced, O-GlcNAcylation-dependent expression of proautoimmune cytokines and enhanced FOXP3 expression in T cells. OGC350 treatment selectively affected autoimmunity-associated genes and did not exhibit toxicity on survival or proliferation of T cells.
Conclusions
This study reveals c-Rel S350 O-GlcNAcylation as a novel molecular mechanism inversely regulating proautoimmune gene expression and immunosuppressive FOXP3 expression in T cells with potential therapeutic implications to treat type 1 diabetes. Broad inhibition of hexosamine biosynthetic pathway or NF-kappaB will cause many side effects due to their ubiquitous importance in multiple biological functions. Therefore, inhibitors of O-GlcNAcylated NF-kappaB c-Rel function may prove long-sought-after specific molecular therapeutic to diminish autoimmunity in type 1 diabetes.
O101 - DISTINCT DRUG-SURVIVAL PROFILING OF SECOND BIOLOGICS THERAPY IN RHEUMATOID ARTHRITIS (ID 193)
Abstract
Background and Aims
Tailoring second-line biologics-therapy in rheumatoid arthritis (RA) by comparing and profiling TNF-inhibitor (TNFi) and biologics of different mode of action (BDMA- rituximab, abatacept, tocilizumab) after the first-line TNFi.
Methods
In this retrospective-observational study conventional-statistical and machine-learning approach were applied to interrogate RA-patients who were initiated (between-2007-2018) on second-line biologics-therapy. Primary-outcome was discontinuation of treatment due to primary- or secondary-failure and adverse drug-reactions.
Results
During the observation-period, 213 (TNFi-n=122, BDMA-n=91) of 435 patients discontinued their second-line biologics (median drug-survival-time 32months, 95%CI 31-35months). As second-line, BDMA reduced the risk of treatment-discontinuation [Hazard-ratio/HR-0.63 (95%CI 0.48-0.83, p<0.001)] compared to TNFi (FIGURE-1A). Better drug-survival of BDMA was only observed in the seropositive-patients ([HR-0.52 (95% CI 0.38-0.73, p<0.001](FIGURE-1B), not in seronegative-group [HR-1.04 (95%CI 0.63-1.73, p=0.8]. Adjusted by propensity-score, all 3- of the BDMAs were associated with risk reduction of treatment-discontinuation in seropositive-RA [(rituximab-HR 0.45 (95%CI 0.29-0.72, p<0.001, abatacept-HR 0.51 (95%CI 0.30-0.86, p=0.012), and tocilizumab-HR 0.56 (95%CI 0.30-0.97, p=0.044)]. Uncovered by the survival-tree model, previous exposure of monoclonal-TNFi as first-line therapy was associated with poorer drug-survival in BDMA-treated seropositive-patients with HR of 1.81 (95%CI 1.08-3.05, p=0.025)] compared to etanercept(FIGURE-1C). Drug-survival of BDMA was not superior to TNFi (FIGURE-1D) when the first-line TNFi was discontinued within 2years after initiation (HR-0.82, 95%CI 0.47-1.44, p=0.49).
Conclusions
Seropositive-RA patients demonstrated better drug-survival to BDMA, specially if they were treated with etanercept as the first-line. However in seronegative-patients or if the first-line TNFi was discontinued within 2years of initiation, BDMA was not better than TNFi. Further prospective studies are required to confirm these findings.