Glutathione-S-transferase P1 may predispose children to a decline in pulmonary function after stem cell transplant

RATIONALE: Pulmonary complications after hematopoietic stem cell transplant (SCT) are associated with increased mortality. Genetic markers for those at risk for pulmonary impairment post-SCT have not been widely investigated. METHODS: Forty-nine patients were retrospectively selected from a single institution's biorepository with linked clinical data. All subjects performed pre-SCT PFTs. Genotyping was conducted using the Infinium Exome-24 BeadChip. Four single nucleotide polymorphisms (SNPs) were selected (rs1800871, rs1695, rs1800629, rs12477314) and evaluated for association with PFT parameters as change over time from baseline. Associations between SNPs and PFT parameters were assessed and adjusted for the following confounding variables: age, gender, and race. RESULTS: Using the recessive genetic model, patients with one or two minor alleles for the glutathione S-transferase P1 (GSTP1) SNP rs1695 had a lower decline in FEV1 and FEF25-75 at 1-year post-SCT compared to patients who were homozygous for the ancestral allele (adjusted P-values <0.01 and 0.02, respectively). No other SNPs were significantly associated with other PFT parameters. CONCLUSIONS: Our findings suggest that GSTP1 genotype may be associated with lung function during the first year post-SCT. Identifying and investigating genes that predispose patients to pulmonary complications after SCT may allow for more personalized patient management based on pre-emptive genetic testing. The glutathione S-transferase gene merits further investigation

Erythromycin treatment hinders the induction of oral tolerance to fed ovalbumin

The mucosal immune system is constantly exposed to antigen, whether it be food antigen, commensal bacteria, or harmful antigen. It is essential that the mucosal immune system can distinguish between harmful and non-harmful antigens, and initiate an active immune response to clear the harmful antigens, while initiating a suppressive immune response (tolerance) to non-harmful antigens. Oral tolerance is an immunologic hyporesponsiveness to an orally administered antigen and is important in preventing unnecessary gastrointestinal (GI) tract inflammation, which can result in a number of autoimmune and hypersensitivity diseases. Probiotics (beneficial intestinal bacteria), T regulatory cells (Tregs), and dendritic cells (DCs) are all essential for generating tolerance. Antibiotics are commonly prescribed to fight infections and often necessary for maintaining health, but they can disrupt the normal intestinal probiotic populations. There is increasing epidemiologic evidence that suggests that antibiotic usage correlates with the development of atopic or irritable bowel disorders, which often result due to a breakdown in immune tolerance. This study investigated the effect of the antibiotic erythromycin on oral tolerance induction to ovalbumin (OVA). The results demonstrated that antibiotic treatment prior to exposure to fed antigen prevents tolerance to that antigen, which may be associated with a reduction in intestinal Lactobacillus populations. Furthermore, antibiotic treatment resulted in a significant decrease in the tolerogenic CD11c+/CD11b+/CD8α- MLN DCs independent of tolerizing treatment. These results provide evidence that antibiotic treatment, potentially through its effects on tolerogenic DCs and intestinal microflora, may contribute to autoimmune and atopic disorders via a breakdown in tolerance and support prior epidemiologic studies correlating increased antibiotic usage with the development of these disorders