Poster Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Checkpoint inhibitor induced diabetes has a distinct immune and endocrine profile to type 1 diabetes in NOD mice (#514)

Linda Wu 1 2 3 4 , Nicole Fewings 3 , Charmaine Cheung 3 , David Brown 1 3 4 , Roderick Clifton-Bligh 2 4 , Sarah Sasson 1 , Venessa Tsang 2 4 , Alexander Menzies 2 4 5 , Jenny Gunton 1 3 4
  1. Westmead Hospital, Ryde, NEW SOUTH WALES, Australia
  2. Royal North Shore Hospital, St Leonards, New South Wales, Australia
  3. Westmead Institute for Medical Research, Westmead, New South Wales, Australia
  4. University of Sydney, Camperdown, New South Wales, Australia
  5. Melanoma Institute Australia, North Sydney, New South Wales, Australia

Introduction

In recent years a novel form of autoimmune diabetes termed checkpoint inhibitor induced autoimmune diabetes (CIADM) has been identified in humans. It is distinct from type 1 diabetes (T1D) with different autoantibody expression and disease course. Analysis of the immunophenotype of CIADM is limited in humans by tissue availability.

 

Aims

To compare the phenotype of CIADM versus T1D, streptozocin-induced diabetes and controls using NOD mice.

 

Methods

NOD mice were allocated to one of four groups; controls (young and aged), spontaneous T1D, streptozocin-induced diabetes or anti-PDL1-Ab-induced diabetes (CIADM). Mice were monitored for diabetes and at cull pancreas was collected for histology or for islet-isolation. Pancreatic histology assessed beta-cell mass, alpha-cell mass and insulitis. Mass cytometry and flow cytometry were performed to assess local pancreatic immune activity. Splenocytes, serum and fresh stool were collected. Splenocytes from different groups were adoptively transferred to NOD-SCID immunocompromised mice which were monitored for development of diabetes.

 

Results

Anti-PDL1-Ab administration caused insulin-dependent diabetes in all treated NOD mice. Pancreatic histology confirmed significantly reduced beta-cell mass in the CIADM and streptozocin treated groups and moderate reduction in the classic T1D group versus controls. Alpha-cell mass was preserved in CIADM and T1D groups. Serum insulin/glucose ratio was significantly lower in CIADM and T1D groups than controls. Lipase was significantly higher in streptozocin-treated, CIADM and T1D mice and faecal fat lower in these groups suggestive of exocrine dysfunction. Flow cytometry demonstrated significant differences in beta-cell PD-L1 expression and proportion of key immune cells with T cell predominant responses in CIADM and T1D groups and neutrophil predominant responses in the streptozocin treated group.  IMC and adoptive transfer results are currently under analysis.

 

Conclusion

CIADM has a distinct immune, endocrine and exocrine profile to T1D and chemical induced diabetes in NOD mice.