progesterone induced Blocking Factor differentially regulates trophoblast and tumor invasion by altering matrix metalloproteinase activity

Invasiveness is a common feature of trophoblast and tumors; however, while tumor invasion is uncontrolled, trophoblast invasion is strictly regulated. Both trophoblast and tumor cells express high levels of the immunomodulatory progesterone-induced Blocking Factor (PIBF), therefore, we aimed to test the possibility that PIBF might be involved in invasion. To this aim, we used PIBF-silenced or PIBF-treated trophoblast (HTR8/Svneo, and primary trophoblast) and tumor (HT-1080, A549, HCT116, PC3) cell lines. Silencing of PIBF increased invasiveness as well as MMP-2,-9 secretion of HTR8/SVneo, and decreased those of HT-1080 cells. PIBF induced immediate STAT6 activation in both cell lines. Silencing of IL-4Rα abrogated all the above effects of PIBF, suggesting that invasion-related signaling by PIBF is initiated through the IL-4Rα/PIBF-receptor complex. In HTR-8/SVneo, PIBF induced fast, but transient Akt and ERK phosphorylation, whereas in tumor cells, PIBF triggered sustained Akt, ERK, and late STAT3 activation. The late signaling events might be due to indirect action of PIBF. PIBF induced the expression of EGF and HB-EGF in HT-1080 cells. The STAT3-activating effect of PIBF was reduced in HB-EGF-deficient HT-1080 cells, suggesting that PIBF-induced HB-EGF contributes to late STAT3 activation. PIBF binds to the promoters of IL-6, EGF, and HB-EGF; however, the protein profile of the protein/DNA complex is different in the two cell lines. We conclude that in tumor cells, PIBF induces proteins, which activate invasion signaling, while—based on our previous data—PIBF might control trophoblast invasion by suppressing proinvasive genes.

dydrogesterone supplementation in women with threatened preterm delivery the impact on cytokine profile hormone profile and progesterone induced Blocking Factor

Abstract Progesterone is indispensable in creating a suitable endometrial environment for implantation, and also for the maintenance of pregnancy. Successful pregnancy depends on an appropriate maternal immune response to the fetus. A protein called progesterone-induced Blocking Factor (PIBF) acts by inducing Th2-dominant cytokine production to mediate the immunological effects of progesterone. The aim of this prospective study was to compare serum concentrations of progesterone (P), estradiol (E2), anti-inflammatory (IL-10) and pro-inflammatory (IL-6, TNFα, IFNγ) cytokines, and serum PIBF concentrations in women with threatened preterm delivery who were given progesterone supplementation (study group) with those of women with threatened preterm delivery who were not given progesterone supplementation (control group). After dydrogesterone treatment of patients in the study group, serum PIBF as well as progesterone concentrations significantly increased. Women in this group had significantly higher serum levels of IL-10 than controls. The length of gestation was significantly higher in the group of women who were given progesterone supplementation. Our data suggest that dydrogesterone treatment of women at risk of preterm delivery results in increased PIBF production and IL-10 concentrations, and lower concentrations of IFNγ.

endometrial expression of progesterone induced Blocking Factor and galectins 1 3 9 and 3 binding protein in the luteal phase and early pregnancy in cattle

Progesterone-induced Blocking Factor (PIBF) and galectins modulate the maternal immune response during pregnancy. We hypothesized that the relative transcript abundance of the above genes would be …

functional rather than immunoreactive levels of igg4 correlate closely with clinical response to grass pollen immunotherapy

To cite this article: Shamji MH, Ljorring C, Francis JN, Calderon MA, Larche M, Kimber I, Frew AJ, Ipsen H, Lund K, Wurtzen PA, Durham SR. Functional rather than immunoreactive levels of IgG4 correlate closely with clinical response to grass pollen immunotherapy. Allergy 2012; 67: 217–226.

Abstract

Background:  Induction of allergen-specific IgG4 antibodies is the most consistent immunological finding in immunotherapy trials. However, quantitative assessments of IgG4 antibodies have not proven beneficial in evaluating clinical changes during or after immunotherapy. In the current study, we investigated the relationship between clinical outcome and allergen-specific IgG4 titres or functional antibody responses following immunotherapy. We hypothesized that functional assays of serum IgG–associated inhibitory activity such as inhibition of IgE–allergen interactions (IgE-Blocking Factor) and inhibition of CD23-dependent IgE-facilitated allergen binding (IgE-FAB) correlate more closely with clinical outcome and may be biomarkers of clinical response.

Methods:  In an 8-month dose–response randomized double-blind placebo-controlled study, 221 polysensitized subjects with severe seasonal rhinitis received Alutard SQ, Phleum pratense 100 000 SQ-U, 10 000 SQ-U or placebo injections. Serum specimens were collected before treatment, after up-dosing, during the peak season and at the end of the study. Allergen-specific IgG4 titres and IgG-associated inhibitory activity were evaluated.

Results:  A time- and dose-dependent increase in serum inhibitory activity for both the IgE-Blocking Factor and IgE-FAB was observed, which paralleled increases in grass pollen–specific IgG4 antibodies. A modest but significant inverse relationship was demonstrated between postimmunotherapy serum inhibitory activity and combined symptom–rescue medication scores (IgE-FAB: r = −0.25, P = 0.0002; IgE-Blocking Factor: r = −0.28, P < 0.0001), whereas this was not observed for immunoreactive IgG4 levels (r = −0.11, P = 0.12). Conclusions:  Functional assays of inhibitory IgG4 and IgE-Blocking Factor may be more useful surrogates of clinical response than IgG4. Whether these antibody effects may serve as predictive biomarkers of clinical efficacy in individual patients requires further investigation.

Functional rather than immunoreactive levels of IgG4correlate closely with clinical response to grass pollen immunotherapy

Induction of allergen-specific IgG(4) antibodies is the most consistent immunological finding in immunotherapy trials. However, quantitative assessments of IgG(4) antibodies have not proven beneficial in evaluating clinical changes during or after immunotherapy. In the current study, we investigated the relationship between clinical outcome and allergen-specific IgG(4) titres or functional antibody responses following immunotherapy. We hypothesized that functional assays of serum IgG-associated inhibitory activity such as inhibition of IgE-allergen interactions (IgE-Blocking Factor) and inhibition of CD23-dependent IgE-facilitated allergen binding (IgE-FAB) correlate more closely with clinical outcome and may be biomarkers of clinical response.

functional rather than immunoreactive levels of igg4 correlate closely with clinical response to grass pollen immunotherapy

To cite this article: Shamji MH, Ljorring C, Francis JN, Calderon MA, Larche M, Kimber I, Frew AJ, Ipsen H, Lund K, Wurtzen PA, Durham SR. Functional rather than immunoreactive levels of IgG4 correlate closely with clinical response to grass pollen immunotherapy. Allergy 2012; 67: 217–226.

Abstract

Background:  Induction of allergen-specific IgG4 antibodies is the most consistent immunological finding in immunotherapy trials. However, quantitative assessments of IgG4 antibodies have not proven beneficial in evaluating clinical changes during or after immunotherapy. In the current study, we investigated the relationship between clinical outcome and allergen-specific IgG4 titres or functional antibody responses following immunotherapy. We hypothesized that functional assays of serum IgG–associated inhibitory activity such as inhibition of IgE–allergen interactions (IgE-Blocking Factor) and inhibition of CD23-dependent IgE-facilitated allergen binding (IgE-FAB) correlate more closely with clinical outcome and may be biomarkers of clinical response.

Methods:  In an 8-month dose–response randomized double-blind placebo-controlled study, 221 polysensitized subjects with severe seasonal rhinitis received Alutard SQ, Phleum pratense 100 000 SQ-U, 10 000 SQ-U or placebo injections. Serum specimens were collected before treatment, after up-dosing, during the peak season and at the end of the study. Allergen-specific IgG4 titres and IgG-associated inhibitory activity were evaluated.

Results:  A time- and dose-dependent increase in serum inhibitory activity for both the IgE-Blocking Factor and IgE-FAB was observed, which paralleled increases in grass pollen–specific IgG4 antibodies. A modest but significant inverse relationship was demonstrated between postimmunotherapy serum inhibitory activity and combined symptom–rescue medication scores (IgE-FAB: r = −0.25, P = 0.0002; IgE-Blocking Factor: r = −0.28, P < 0.0001), whereas this was not observed for immunoreactive IgG4 levels (r = −0.11, P = 0.12). Conclusions:  Functional assays of inhibitory IgG4 and IgE-Blocking Factor may be more useful surrogates of clinical response than IgG4. Whether these antibody effects may serve as predictive biomarkers of clinical efficacy in individual patients requires further investigation.

Functional rather than immunoreactive levels of IgG4correlate closely with clinical response to grass pollen immunotherapy

Induction of allergen-specific IgG(4) antibodies is the most consistent immunological finding in immunotherapy trials. However, quantitative assessments of IgG(4) antibodies have not proven beneficial in evaluating clinical changes during or after immunotherapy. In the current study, we investigated the relationship between clinical outcome and allergen-specific IgG(4) titres or functional antibody responses following immunotherapy. We hypothesized that functional assays of serum IgG-associated inhibitory activity such as inhibition of IgE-allergen interactions (IgE-Blocking Factor) and inhibition of CD23-dependent IgE-facilitated allergen binding (IgE-FAB) correlate more closely with clinical outcome and may be biomarkers of clinical response.