Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody

Shintaro Iwama, Alessandra De Remigis, Margaret K. Callahan, Susan F. Slovin, Jedd D. Wolchok, Patrizio P Caturegli

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number230ra45
JournalScience Translational Medicine
Volume6
Issue number230
DOIs
StatePublished - Apr 2 2014

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CTLA-4 Antigen
Blocking Antibodies
Antibodies
Pituitary Gland
Thyrotropin
Endocrine Cells
Complement Activation
Follicle Stimulating Hormone
Inbred C57BL Mouse
Prolactin
Immunotherapy
Adrenocorticotropic Hormone
Hypophysitis
Melanoma
Prostatic Neoplasms
Hypersensitivity
RNA
Inflammation
T-Lymphocytes
Antigens

ASJC Scopus subject areas

  • Medicine(all)

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Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. / Iwama, Shintaro; De Remigis, Alessandra; Callahan, Margaret K.; Slovin, Susan F.; Wolchok, Jedd D.; Caturegli, Patrizio P.

In: Science Translational Medicine, Vol. 6, No. 230, 230ra45, 02.04.2014.

Research output: Contribution to journalArticle

Iwama, Shintaro ; De Remigis, Alessandra ; Callahan, Margaret K. ; Slovin, Susan F. ; Wolchok, Jedd D. ; Caturegli, Patrizio P. / Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. In: Science Translational Medicine. 2014 ; Vol. 6, No. 230.
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