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Immune checkpoint molecules soluble program death ligand 1 and galectin-9 are increased in pregnancy.

ABSTRACT: Pregnancy requires balance between tolerance to the haploidentical fetus and the mother's ability to mount immune responses. There are parallels to this phenomenon that occur in metastatic cancer. We assessed soluble program death ligand-1 soluble PD-L1 (sPD-L1) and galectin-9 in the blood of pregnant women during gestation as these molecules are highly involved in immune suppression during cancer.Maternal blood was collected from 30 primigravida women at monthly intervals during pregnancy, delivery and 6-week post-partum. Blood was analyzed for sPD-L1 and galectin-9 concentrations by ELISA. Term placentas were collected in formalin and IHC was completed for PD-L1 and galectin-9 expression.Maternal blood levels of sPD-L1 (0.438 ng/mL) and galectin-9 (1976 pg/mL) were elevated early in normal pregnancies compared to non-pregnant controls (0.242 ng/mL and 773 pg/mL, respectively). sPD-L1 increased throughout gestation, whereas galectin-9 remained elevated until parturition; both proteins returned to control levels post-partum. Women carrying male fetuses had significantly higher galectin-9 levels, but not sPD-L1, than those carrying females (2263 pg/mL vs 1874 pg/mL; P = .0005). Trophoblast cells of the term placenta coexpress galectin-9 and PD-L1.Immune-regulatory molecules galectin-9 and sPD-L1 increased during pregnancy and may play a role in immune tolerance that is critical for the fetus.

SUBMITTER: Enninga EAL

PROVIDER: S-EPMC5814874 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

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Immune checkpoint molecules soluble program death ligand 1 and galectin-9 are increased in pregnancy.

Enninga Elizabeth Ann L EAL Harrington Susan M SM Creedon Douglas J DJ Ruano Rodrigo R Markovic Svetomir N SN Dong Haidong H Dronca Roxana S RS

American journal of reproductive immunology (New York, N.Y. : 1989) 20171204 2

<h4>Problem</h4>Pregnancy requires balance between tolerance to the haploidentical fetus and the mother's ability to mount immune responses. There are parallels to this phenomenon that occur in metastatic cancer. We assessed soluble program death ligand-1 soluble PD-L1 (sPD-L1) and galectin-9 in the blood of pregnant women during gestation as these molecules are highly involved in immune suppression during cancer.<h4>Method of study</h4>Maternal blood was collected from 30 primigravida women at ...[more]

PMID: 29205636

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Project description:ContextDue to recent advantages in cancer therapy, immune checkpoint inhibitors (ICIs) are new classes of drugs targeting programmed cell death protein 1 (PD-1) or its ligand programmed cell death protein 1-ligand 1 (PD-L1) used in many cancer therapies. Acute interstitial nephritis (AIN) is a potential and deleterious immune-related adverse events (irAE) in the kidney observed in patients receiving ICIs and the most common biopsy-proven diagnosis in patients who develop acute kidney injury (AKI). Based on previous reports, AIN in patients receiving ICIs is associated with tubular positivity for PD-L1, implicating that PD-L1 positivity reflects susceptibility to develop renal complications with these agents. It remains unclear if PD-L1 positivity is acquired specifically during ICI therapy or expressed independently in the kidney.MethodsPD-L1 was analyzed in experimental mouse models of ischemia-reperfusion injury (IRI), folic acid-induced nephropathy (FAN), unilateral ureteral obstruction (UUO), and nephrotoxic serum nephritis (NTN) by immunostaining, SDS-PAGE, and subsequent immunoblotting. In addition, we included a total number of 87 human kidney samples (six renal biopsies with AIN related to ICI therapy, 13 nephrectomy control kidneys, and 68 ICI-naïve renal biopsies with various underlying kidney diseases to describe PD-L1 expression.ResultsWe here report distinct PD-L1 expression in renal compartments in multiple murine models of kidney injury and human cases with various underlying kidney diseases, including ICI-related AIN and renal pathologies independent of ICI therapy. PD-L1 is frequently expressed in various renal pathologies independent of ICI therapy and could potentially be a pre-requisit for susceptibility to develop AKI and deleterious immune-related AIN. In addition, we provide evidence that tubular PD-L1 positivity in the kidney is associated with detection of urinary PD-L1+ tubular epithelial cells.ConclusionOur study implicates that PD-L1 is frequently expressed in various renal pathologies independent of ICI therapy and could potentially be a pre-requisit for susceptibility to develop AKI and deleterious immune-related AIN. Because non-invasive detection of PD-L1+ cells in corresponding urine samples correlates with intrarenal PD-L1 positivity, it is attractive to speculate that further non-invasive detection of PD-L1+ cells may identify patients at risk for ICI-related AIN.

Dataset Information

Immune checkpoint molecules soluble program death ligand 1 and galectin-9 are increased in pregnancy.

Publications

Immune checkpoint molecules soluble program death ligand 1 and galectin-9 are increased in pregnancy.

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