| First Author | Besançon A | Year | 2018 |
| Journal | Diabetologia | Volume | 61 |
| Issue | 2 | Pages | 389-398 |
| PubMed ID | 29030662 | Mgi Jnum | J:257622 |
| Mgi Id | MGI:6120000 | Doi | 10.1007/s00125-017-4459-0 |
| Citation | Besancon A, et al. (2018) Oral histone deacetylase inhibitor synergises with T cell targeted immunotherapy to preserve beta cell metabolic function and induce stable remission of new-onset autoimmune diabetes in NOD mice. Diabetologia 61(2):389-398 |
| abstractText | AIM/HYPOTHESIS: Combination therapy targeting the major actors involved in the immune-mediated destruction of pancreatic beta cells appears to be an indispensable approach to treat type 1 diabetes effectively. We hypothesised that the combination of an orally active pan-histone deacetylase inhibitor (HDACi: givinostat) with subtherapeutic doses of CD3 antibodies may provide ideal synergy to treat ongoing autoimmunity. METHODS: NOD mice transgenic for the human CD3epsilon (also known as CD3E) chain (NOD-huCD3epsilon) were treated for recent-onset diabetes with oral givinostat, subtherapeutic doses of humanised CD3 antibodies (otelixizumab, 50 mug/day, 5 days, i.v.) or a combination of both drugs. Disease remission, metabolic profiles and autoreactive T cell responses were analysed in treated mice. RESULTS: We demonstrated that givinostat synergised with otelixizumab to induce durable remission of diabetes in 80% of recently diabetic NOD-huCD3epsilon mice. Remission was obtained in only 47% of mice treated with otelixizumab alone. Oral givinostat monotherapy did not reverse established diabetes but reduced the in situ production of inflammatory cytokines (IL-1beta, IL-6, TNF-alpha). Importantly, the otelixizumab + givinostat combination strongly improved the metabolic status of NOD-huCD3epsilon mice; the mice recovered the capacity to appropriately produce insulin, control hyperglycaemia and sustain glucose tolerance. Finally, diabetes remission induced by the combination therapy was associated with a significant reduction of insulitis and autoantigen-specific CD8(+) T cell responses. CONCLUSIONS/INTERPRETATION: HDACi and low-dose CD3 antibodies synergised to abrogate in situ inflammation and thereby improved pancreatic beta cell survival and metabolic function leading to long-lasting diabetes remission. These results support the therapeutic potential of protocols combining these two drugs, both in clinical development, to restore self-tolerance and insulin independence in type 1 diabetes. |
