Circulating CD4+PD-1+ and CD8+PD-1+ T cells are profoundly decreased at the onset of fulminant type 1 diabetes and are restored by treatment, contrasting with CD4+CD25+FoxP3+ regulatory T cells

Iijima, Toshie; Kato, Kuniki; Jojima, Teruo; Tomotsune, Takanori; Fukushima, Maiko; Suzuki, Kunihiro; Aso, Yoshimasa

doi:10.1016/j.diabres.2017.07.036

Cited by 17 publications

(13 citation statements)

References 9 publications

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“…PD-1, an inhibitory co-stimulatory molecule found on activated T cells, has been recently reported as playing a role in the pathogenesis of T1D. Failure of PD-1 upregulation upon T-cell receptor stimulation [21] and profound reductions in circulating CD4+PD-1+ and CD8+PD-1+ T cells were observed at the onset of the disease [22]. PD-1 is also reported to play a role in animal models of T1D [23].…”

Section: Discussionmentioning

confidence: 99%

Fulminant type 1 diabetes associated with Isolated ACTH deficiency induced by anti-programmed cell death 1 antibody—insight into the pathogenesis of autoimmune endocrinopathy—

et al. 2019

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Therapeutic blocking antibodies against programmed death 1 (PD1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) are applied for advanced cancer therapy, but induce a wide range of immune-related adverse events. In our recent case of a 52-year-old female doctor suffering from breast cancer having metastasized to the lung and liver, it was decided to use nivolumab to prevent the disease progressing after excisional surgeries and multiple chemotherapies. One month after completing the nivolumab course, fatigue, hypoglycemia and hypotension developed and isolated ACTH deficiency (IAD) was diagnosed. A further month later, under steroid supplementation, hyperglycemia emerged alongside thirst and polydipsia, prompting a diagnosis of fulminant type 1 diabetes (FT1D). Her susceptibility to type 1 diabetes was examined by HLA haplotype and CTLA4 gene polymorphism analyses. Polymorphisms CT60G>A and +49G>A in CTLA4 both generated a GG genotype. Our patient manifested one of the rarest combinations of autoimmune disease induced by nivolumab. Whereas the HLA haplotype was unsusceptible to autoimmune type 1 diabetes, polymorphisms of CTLA4, the antibody of which frequently causes hypophysitis, were susceptible to FT1D. Peripheral modulation of activated T cells, mainly by PD-1 antibodies, induced FT1D associated with IAD in patients with CTLA4 polymorphism. This case reveals hints of the T-cell etiology in T1D and evidence of CTLA4 involvement in IAD.

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Section: Discussionmentioning

confidence: 99%

Fulminant type 1 diabetes associated with Isolated ACTH deficiency induced by anti-programmed cell death 1 antibody—insight into the pathogenesis of autoimmune endocrinopathy—

et al. 2019

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“…Animal studies have revealed that PD-1/PD-L1 deficiency or blockade activates T cells infiltrating into islets and results in selective beta-cell destruction in non-obese diabetic (NOD) mouse models (7,8). Evidence also shows decreased PD-1 expression in circulating T cells in patients with new-onset type 1 diabetes following anti-PD-1 and anti-PD-L1 treatment (9,10). By contrast, several proinflammatory cytokines, especially tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interferon gamma (IFN-γ), have been shown to play important roles in developing type 1 diabetes at the level of both the immune response and targeting beta-cells (11).…”

Section: Discussionmentioning

confidence: 99%

Sintilimab-Induced Autoimmune Diabetes in a Patient With the Anti-tumor Effect of Partial Regression

et al. 2020

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Context: Immune checkpoint blockades (ICBs) have been approved widely to treat various malignancies. Autoimmune diabetes mellitus, which can be caused by programmed cell death protein 1 (PD-1) inhibitors, is rare. Sintilimab, a monoclonal anti-PD-1 antibody, has been approved in China for the treatment of Hodgkin's lymphoma and was used in our clinical trial for patients with unresectable hepatocellular carcinoma (HCC). Case Presentation: We present the first case of autoimmune diabetes during Sintilimab treatment in a patient with unresectable HCC, accompanied by a remarkable anti-tumor effect of partial regression. A 56-year-old male with typical symptoms presented with diabetic ketoacidosis (DKA) at 24 weeks after Sintilimab initiation. His fasting plasma glucose level was 22.2 mmol/L, HbA1c was 7.8%, fasting insulin was 1.5 mIU/L, and fasting C-peptide was 1.12 ng/mL, which further decreased to 0.21 ng/mL 4 days later. The patient was diagnosed with new-onset diabetes mellitus using the oral glucose tolerance test. The anti-glutamic acid decarboxylase 65 antibody, anti-islet cell antibody, and anti-insulin antibody tests were all negative. For the type 1 diabetes-associated alleles of human leukocyte antigen (HLA) class I and II, the most relevant type was identified as HLA-A * 0201. A diagnosis of PD-1 inhibitor-induced autoimmune diabetes was made. After rectification of DKA, he was treated with insulin therapy daily, which has since controlled his plasma glucose well. Thereafter, Sintilimab was been continued with sustained therapeutic effect. Conclusion: Due to unpredictability of this rare immune related adverse event (irAE), diabetes-related autoantibodies and C-peptide are recommended to be tested before immunotherapy, and plasma glucose monitoring should be performed. After plasma glucose is well controlled using insulin therapy, PD-1 inhibitor treatment might be continued, especially when the immunotherapy is effective.

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“…A recent investigation conducted by Iijima et al ( 92 ) studied for the first time the expression of PD-1 in circulating CD4 + and CD8 + T cells from fulminant T1D onset to 12 weeks after initiation of treatment. A consistent reduction was observed in circulating CD4 + PD-1 + and CD8 + PD-1 + T cells at the onset of fulminant T1D in two subjects with diabetic ketoacidosis (DKA) caused by T1D.…”

Section: Evidences Of Pd-1 and Treg Involvement In Autoimmunitymentioning

confidence: 99%

Inhibitory Receptors and Pathways of Lymphocytes: The Role of PD-1 in Treg Development and Their Involvement in Autoimmunity Onset and Cancer Progression

2018

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Regulatory T (Treg) cells represent a subpopulation of suppressor CD4+ T cells critically involved in the establishment of peripheral tolerance through the inhibition of effector T (Teff) cells and the suppression of the immune-mediated tissue destruction toward self-antigens. Treg generation, their suppressive properties and also Treg-Teff cell interactions could be modulated at least in part by programmed cell death-1 (PD-1) expression on their surface and through binding between PD-1 and programmed cell death ligand-1 (PD-L1). Defects involving PD-1 and Tregs can lead to the development of pathological conditions, including autoimmune disorders or promote cancer progression by favoring tumor evasion from the host immune response. At the same time, PD-1 and Tregs could represent attractive targets for treatment, as demonstrated by the therapeutic blockade of PD-L1 applied for the management of different cancer conditions in humans. In the present Review, we focus specifically the role of PD-1/PD-L1 on Treg development and activity.

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Circulating CD4+PD-1+ and CD8+PD-1+ T cells are profoundly decreased at the onset of fulminant type 1 diabetes and are restored by treatment, contrasting with CD4+CD25+FoxP3+ regulatory T cells

Cited by 17 publications

References 9 publications

Fulminant type 1 diabetes associated with Isolated ACTH deficiency induced by anti-programmed cell death 1 antibody—insight into the pathogenesis of autoimmune endocrinopathy—

Fulminant type 1 diabetes associated with Isolated ACTH deficiency induced by anti-programmed cell death 1 antibody—insight into the pathogenesis of autoimmune endocrinopathy—

Sintilimab-Induced Autoimmune Diabetes in a Patient With the Anti-tumor Effect of Partial Regression

Inhibitory Receptors and Pathways of Lymphocytes: The Role of PD-1 in Treg Development and Their Involvement in Autoimmunity Onset and Cancer Progression

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