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Background Studies have demonstrated an association between anti-TNF/immunomodulator agents used in inflammatory bowel disease (IBD) and impaired hepatitis B virus (HBV) vaccine immunogenicity, but little data exist on whether specific medication types affect protective HBsAb titers. Our aim was to analyze this association. Methods This is a retrospective cohort study. Inclusion criteria: age ≥18, diagnosis of Crohn's disease (CD) or ulcerative colitis (UC), previous HBV vaccination series and/or ≥1 positive HBsAb, and record of IBD therapy in 6 months before titer level. Patients were stratified based upon medication exposures: anti-TNF, immunomodulator, combination anti-TNF and immunomodulatory, and a reference arm. Titer levels following vaccination and specific medication types given in the 6 months before titer were recorded. Seroprotection was defined as HBsAb ≥10 IU/l and ≥100 IU/l. Results The study cohort (N = 391) was 70.8% white, 51.4% female and 64.2% had CD and 35.8% had UC. The mean age was 45.8 years. A significantly lower percentage of patients exposed to anti-TNF, immunomodulator or dual therapy had titers ≥10 (P < 0.01). Regarding specific medications, only patients exposed to infliximab (P < 0.01) were less likely to have titer levels ≥10, after controlling for other medication exposures, age at titer level, and interval time between vaccination/titer level. This was not found for patients exposed to adalimumab, methotrexate, 6-mercaptopurine, or azathioprine. Conclusions Patients exposed to infliximab were significantly less likely to have protective HBsAb titer levels following vaccination, a trend not seen in patients on adalimumab. Efforts to vaccinate IBD patients against HBV before use of immunomodulators and anti-TNFs, infliximab specifically, and screen periodically thereafter must be reinforced.

The development of asthmatic inflammation involves a complex array of cytokines that promote the recruitment and activation of a number of different immune cells. While factors involved in initiating and establishing inflammation are well characterized, the process by which this pro-inflammatory cascade is regulated is less well understood. The identification and characterization of immunomodulatory cytokines in asthma has been a difficult proposition. Many of the putative regulatory factors have pleiotropic bioactivities and have been characterized as pro-inflammatory in association with certain pathologic conditions. This chapter addresses the potential role of several endogenous factors which appear to attenuate asthmatic inflammation. Understanding the integration of these factors into the regulation of the inflammatory process will likely result in novel therapeutic approaches.

Epithelial cells from individuals with asthma or from allergen-sensitized mice contain intracellular interleukin (IL)-16 protein, not present in epithelial cells from individuals without asthma or unsensitized mice. IL-16 is only present in the bronchoalveolar lavage (BAL) fluid following airway challenge with either allergen or vasoactive amine. This suggests that the initial response to allergen (sensitization) results in synthesis but not secretion of IL-16. In this study, we investigated what factors produced during the sensitization phase are responsible for epithelial cell priming for IL-16 production. We determined that ovalbumin (OVA)-sensitized mice have an increase in systemic tumor necrosis factor-alpha levels, and that serum or BAL fluid stimulation of bronchial epithelial cells results in production of IL-16 that is subsequently secreted only following serotonin stimulation. The mechanism for IL-16 production was shown to be caspase-3-dependent, and serotonin-induced secretion of IL-16 required binding of the serotonin type 2 receptor. The relevance of the priming effect associated with sensitization for IL-16 production and storage was confirmed in vivo by serotonin airway challenge of OVA-sensitized mice, resulting in rapid secretion of IL-16 into BAL fluid. As IL-16 has been shown to regulate CD4+ cell recruitment and activation, and is detected early following airway challenge of individuals with asthma, this two-step process for IL-16 production by epithelial cells may represent a rapid response mechanism in the orchestration of allergic airway inflammation.

Interleukin (IL)-9 is a T helper 2 cytokine implicated as a candidate gene and contributor to human asthma. We hypothesized that the inflammatory potential of bronchial epithelium is affected by its local environment and explored this hypothesis with respect to the effect of IL-9 on bronchial epithelium. We investigated the response of primary and immortalized human bronchial epithelial cells to IL-9 stimulation with respect to the release of T-cell chemoattractant factors. In response to IL-9, the HBE4-E6/E7 cell line, but not BEAS-2B cells, released the T-cell chemoattractants IL-16 and regulated on activation, normal T cells expressed and secreted (RANTES) in a dose-dependent fashion. We found a similar dose response to IL-9 in primary cells from bronchial brushings of healthy subjects and that nearly all of the T-cell chemoattraction was attributable to IL-16 and RANTES. Reverse transcriptase/polymerase chain reaction of BEAS-2B, HBE4-E6/E7, and primary cells from two subjects revealed messenger RNA for IL-9 receptor (IL-9R) alpha but not in BEAS-2B cells. Fluorescence-activated cell sorter analysis of HBE4-E6/E7 and primary cells confirmed surface expression of the IL-9 receptor. Costimulation of both cell types with IL-9 and antibody to either gamma-common chain or IL-9Ralpha completely blocked the release of T-cell chemoattractant activity, confirming the primary role of a functioning IL-9 receptor for IL-9 signaling in HBE4-E6/E7 and primary bronchial epithelial cells. We conclude that IL-9 is a stimulus for airway epithelial cell release of T-cell chemoattractant factors, which in turn may modulate the immune response in allergic airway inflammation.