Abstract
Disclosure: P. Houeiss: None. S. luce: None. C. Boitard: None. Anti-PD1 is an immune checkpoint inhibitor that has revolutionized cancer treatment. It blocks the interaction between PD1, a receptor on the surface of activated or exhausted T cells, and its ligands PDL1 and PDL2, to inhibit the immune response. However, anti-PD1 induces T1D in 0.4-2% of patients raising questions about the risk factors and the mechanisms behind T1D development. Since the pancreas of these patients is inaccessible, we focus on autoimmune diabetes induction in a transgenic mouse model modified to express the T1D susceptibility genes HLA-DQ8, HLA-A2.1 and the human preproinsulin and on identifying new targets to prevent or treat this disease. Thus, 8 to 12 weeks old mice were treated initially with 500 micrograms of anti-PD1 followed by 250 micrograms every other day for 10 days. Control mice received 6 injections of PBS. Mice were followed up for evidence of hyperglycemia for 60 days. Cells and tissues from the pancreas, and the spleens were isolated 15-, 30- or 60-days post-treatment initiation and analyzed by flow cytometry and immunohistochemistry. Although diabetes incidence in treated mice was 14% (n=14), insulitis incidence progressively increased over time reaching 86% on D60 (p=0.005). On Day 15, in the spleen, a significant 10% increase of CD4(+)Foxp3(+)CD25(-) T cells at the expense of the CD4(+)Foxp3(-) T cells were seen in the treatment group as compared to the control (37.1±4.25 vs 26±3.5, p<0.01, n=5 per group). In the treatment group, PD1 expression significantly increased on CD4(+)Foxp3(+) T cells whereas PDL1 expression increased on CD4(+)Foxp3(-) and CD8(+) T cells (p<0.01). On D30, in the pancreas, infiltrates show positive staining for F4/80(+), CD4(+) and CD8(+) T cells with scarce foxp3(+) T cells. While the absolute percentage of CD4(+)Foxp3(+) T cells increased in the insulitis and diabetes group, their percentage among CD3(+) T cells decreased in the insulitis (10.2%) and diabetes group (3.9%) as compared to the control group (13.5%). Infiltrates were concentrated around the islets and the efferent and afferent vessels, and extended to the exocrine pancreas, leading to secondary acinar destruction. In the pancreatic infiltrates from anti-PD1 treated mice, we noted a significant increase in CD4(+) T cells recognizing Ins(13-21) monomers as compared to the negative control. PD1 blockade induced an insulitis characterized by a Treg to effector T cells imbalance. Thus, it acted on the early phase of T1D. In conclusion, this model describes a new T1D endotype that shares similarities with ICI induced diabetes in patients. Presentation: 6/2/2024