Pancreatic islet grafting restores endogenous insulin production in type 1 diabetic patients, but long-term outcomes remain disappointing as a result of immunological destruction of allogeneic islets. In solid organ transplantation, donor-specific anti-HLA antibodies (DSA) are the first cause of organ failure. This retrospective multicentric study aimed at providing in-depth characterization of DSA response after pancreatic islet grafting, identifying the risk factor for DSA generation and determining the impact of DSA on graft function. Forty-two pancreatic islet graft recipients from the Groupe Rhin-Rhône-Alpes-Genève pour la Greffe d'Ilots de Langerhans consortium were enrolled. Pre- and postgrafting sera were screened for the presence of DSA and their ability to activate complement. Prevalence of DSA was 25% at 3 years postgrafting. The risk of sensitization increased steeply after immunosuppressive drug withdrawal. DSA repertoire diversity correlated with the number of HLA and eplet mismatches. DSA titer was significantly lower from that observed in solid organ transplantation. No detected DSA bound the complement fraction C3d. Finally, in contrast with solid organ transplantation, DSA did not seem to negatively affect pancreatic islet graft survival. This might be due to the low DSA titers, specific features of IgG limiting their ability to activate the complement and/or the lack of allogenic endothelial targets in pancreatic islet grafts.

Objective:To evaluate the dose-response relationship of 10, 20 and 40-mg ponesimod and long-term efficacy and safety of ponesimod 20 mg using an analysis of combined data from the phase 2 Core and Extension studies in relapsing-remitting multiple sclerosis (RRMS) patients.Methods:In the Core study, 464 patients were randomized (1:1:1:1): placebo (n=121), 10-mg (n=108), 20-mg (n=116), or 40-mg ponesimod (n=119) once-daily for 24 weeks. Patients who completed the Core study transitioned into the Extension study, which had treatment period 1 (TP1; up to 96 weeks), TP2 and TP3 (up to 432 weeks). The 40-mg dose was discontinued due to low tolerability at the end of TP1 and 10-mg dose was subsequently discontinued due to lower benefit-risk profile vs 20 mg at the end of TP2. All patients received 10 or 20 mg during TP2, followed by 20 mg in TP3. Annualized relapse rate (ARR), 6-month confirmed disability accumulation (CDA), time to first confirmed relapse, MRI outcomes, and safety were evaluated.Results:A total of 435 patients received ≥1 dose of ponesimod (first randomized dose: 10 mg=139, 20 mg=145, 40 mg=151) at any time during the Core and/or the Extension study. As of 31 March 2019, 214 patients were still on ponesimod treatment. Median (range) of ponesimod exposure was 7.95 (0–9.36) years. Ponesimod 20-mg, from Core up to end of TP3, was associated with sustained low clinical activity (ARR for confirmed relapses: 0.154; at week 432, Kaplan-Meier estimate for confirmed relapse was 43.9% and 6-month CDA was 20.4%) and MRI disease activity, and over 64% of patients remained free of a confirmed relapse. Most common adverse events were nasopharyngitis (30%), headache (24%) and upper respiratory tract infection (21%).Conclusion:The effects on MS disease control were maintained with ponesimod 20 mg for approximately 8 years with no new safety concerns identified.Classification of evidence:This study provides Class IV evidence that in individuals with relapsing-remitting multiple sclerosis, long-term treatment with ponesimod 20mg was associated with sustained low annualized confirmed relapse rate (0.154 at week 432), with 64% of patients remaining relapse-free.Trial Registration Information:EudraCT Number 2008-006786-92 (Core study) and EudraCT Number 2009-011470-15 (Extension study)

ShcA is an adaptor protein that binds to the cytoplasmic tail of receptor tyrosine kinases and of the Low Density Lipoprotein-related receptor 1 (LRP1), a trans-membrane receptor that protects against atherosclerosis. Here, we examined the role of endothelial ShcA in atherosclerotic lesion formation. We found that atherosclerosis progression was markedly attenuated in mice deleted for ShcA in endothelial cells, that macrophage content was reduced at the sites of lesions, and that adhesion molecules such as the intercellular adhesion molecule-1 (ICAM-1) were severely reduced. Our data indicate that transcriptional regulation of ShcA by the zinc-finger E-box-binding homeobox 1 (ZEB1) and the Hippo pathway effector YAP, promotes ICAM-1 expression independently of p-NF-κB, the primary driver of adhesion molecules expressions. In addition, ShcA suppresses endothelial Akt and nitric oxide synthase (eNOS) expressions. Thus, through down regulation of eNOS and ZEB1-mediated ICAM-1 up regulation, endothelial ShcA promotes monocyte-macrophage adhesion and atherosclerotic lesion formation. Reducing ShcA expression in endothelial cells may represent an obvious therapeutic approach to prevent atherosclerosis.

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Chondrocyte hypertrophic differentiation, a key process in endochondral ossification (EO), is also a feature of osteoarthritis leading to articular cartilage destruction. ShcA (Src homology and Collagen A) is an adaptor protein that binds to the cytoplasmic tail of receptor tyrosine kinases. We found that deletion of ShcA in chondrocytes of mice inhibits hypertrophic differentiation, alters the EO process, and leads to dwarfism. ShcA promotes ERK1/2 activation, nuclear translocation of the master transcription factor for chondrocyte hypertrophy, RunX2, while maintaining the Runx2 inhibitor YAP1 in its cytosolic inactive form. This leads to hypertrophic commitment and expression of markers of hypertrophy, such as Collagen X. In addition, ShcA deletion in chondrocytes protects from age-related osteoarthritis development in mice. Our results reveal that ShcA integrates multiple stimuli which affect the intracellular signaling processes leading to the hypertrophic commitment of chondrocytes and osteoarthritis.

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