Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypophysitis is a chronic inflammation of the pituitary gland of unknown (primary forms) or recognizable (secondary forms) etiology, such as the use of ipilimumab in cancer immunotherapy. Ipilimumab, which blocks the T cell inhibitory molecule CTLA-4 (cytotoxic T lymphocyte antigen-4), induces hypophysitis in about 4% of patients through unknown mechanisms. We first established a model of secondary hypophysitis by repeated injections of a CTLA-4 blocking antibody into SJL/J or C57BL/6J mice, and showed that they developed lymphocytic infiltration of the pituitary gland and circulating pituitary antibodies. We next assessed the prevalence of pituitary antibodies in a cohort of 20 patients with advanced melanoma or prostate cancer, 7 with a clinical diagnosis of hypophysitis, before and after ipilimumab administration. Pituitary antibodies, negative at baseline, developed in the 7 patients with hypophysitis but not in the 13 without it; these antibodies predominantly recognized thyrotropin-, follicle-stimulating hormone-, and corticotropin-secreting cells. We then hypothesized that the injected CTLA-4 antibody could cause pituitary toxicity if bound to CTLA-4 antigen expressed "ectopically" on pituitary endocrine cells. Pituitary glands indeed expressed CTLA-4 at both RNA and protein levels, particularly in a subset of prolactin- and thyrotropin-secreting cells. Notably, these cells became the site of complement activation, featuring deposition of C3d and C4d components and an inflammatory cascade akin to that seen in type II hypersensitivity. In summary, the study offers a mechanism to explain the pituitary toxicity observed in patients receiving ipilimumab, and highlights the utility of measuring pituitary antibodies in this form of secondary hypophysitis.
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PMID:Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. 2469 85

BACKGROUND Ipilimumab is a therapeutic human monoclonal antibody that targets the T-cell inhibitory molecule, cytotoxic T-lymphocyte antigen-4 (CTLA-4), and is classified as an immune checkpoint inhibitor that has been shown to improve prognosis in patients with advanced melanoma. However, several immune-related adverse events have been reported to be associated with ipilimumab Treatment. A case of acute exacerbation of chronic adrenal insufficiency is presented that highlights that glucocorticoid dosage for patients undergoing steroid treatment at the time of ipilimumab treatment has yet to be established. CASE REPORT A 50-year-old Japanese woman was diagnosed with malignant melanoma on the sole of her right foot. During her second course of ipilimumab treatment, she developed acute adrenal insufficiency caused by isolated adrenocorticotropic hormone (ACTH) deficiency, which required treatment with oral hydrocortisone. However, the symptoms of her adrenal insufficiency worsened, and she commenced treatment with 12 courses of nivolumab, a therapeutic human monoclonal antibody that blocks programmed cell death protein 1 (PD-1) on the surface of T-cells. She did not require corticosteroid support during nivolumab treatment. CONCLUSIONS This case report highlights the risk of exacerbating adrenal insufficiency during treatment with ipilimumab. The differences in clinical outcome in this patient between ipilimumab and nivolumab treatment might be explained by the different mechanisms between ipilimumab and nivolumab on immune function.
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PMID:A Case of Acute Exacerbation of Chronic Adrenal Insufficiency Due to Ipilimumab Treatment for Advanced Melanoma. 3067 13