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. 2018 Feb;61(2):389-398. doi: 10.1007/s00125-017-4459-0. Epub 2017 Oct 13.


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 CD3ε (also known as CD3E) chain (NOD-huCD3ε) were treated for recent-onset diabetes with oral givinostat, subtherapeutic doses of humanised CD3 antibodies (otelixizumab, 50 μg/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-huCD3ε 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-1β, IL-6, TNF-α). Importantly, the otelixizumab + givinostat combination strongly improved the metabolic status of NOD-huCD3ε 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.

Keywords: Beta cells; Glucose tolerance; HDACi; Human CD3 antibodies; Humanised NOD mice; Insulin secretion; Type 1 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Cells, Cultured
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Diabetes Mellitus, Type 1 / metabolism
  • Female
  • Flow Cytometry
  • Histone Deacetylase Inhibitors / blood
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Immunotherapy / methods*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Interferon-gamma / blood
  • Interleukin-10 / blood
  • Interleukin-1beta / blood
  • Interleukin-6 / blood
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • T-Lymphocytes / physiology*
  • Tumor Necrosis Factor-alpha / blood


  • Antibodies, Monoclonal, Humanized
  • Histone Deacetylase Inhibitors
  • Interleukin-1beta
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interferon-gamma
  • otelixizumab