Mucociliary clearance (MCC) and submucosal glands are major components of airway innate immunity that have impaired function in cystic fibrosis (CF). Although both of these defense systems develop postnatally in the ferret, the lungs of newborn ferrets remain sterile in the presence of a functioning cystic fibrosis transmembrane conductance regulator gene. We evaluated several components of airway innate immunity and inflammation in the early CF ferret lung. At birth, the rates of MCC did not differ between CF and non-CF animals, but the height of the airway surface liquid was significantly reduced in CF newborn ferrets. CF ferrets had impaired MCC after 7 days of age, despite normal rates of ciliogenesis. Only non-CF ferrets eradicated Pseudomonas directly introduced into the lung after birth, whereas both genotypes could eradicate Staphylococcus. CF bronchoalveolar lavage fluid (BALF) had significantly lower antimicrobial activity selectively against Pseudomonas than non-CF BALF, which was insensitive to changes in pH and bicarbonate. Liquid chromatography-tandem mass spectrometry and cytokine analysis of BALF from sterile Caesarean-sectioned and nonsterile naturally born animals demonstrated CF-associated disturbances in IL-8, TNF-α, and IL-β, and pathways that control immunity and inflammation, including the complement system, macrophage functions, mammalian target of rapamycin signaling, and eukaryotic initiation factor 2 signaling. Interestingly, during the birth transition, IL-8 was selectively induced in CF BALF, despite no genotypic difference in bacterial load shortly after birth. These results suggest that newborn CF ferrets have defects in both innate immunity and inflammatory signaling that may be important in the early onset and progression of lung disease in these animals.
Posttransplant lymphoproliferative disorders (PTLDs) represent life-threatening complications of bone marrow and solid organ transplantation (SOTx). These are B-cell malignancies triggered by Epstein-Barr Virus (EBV) infection in chronically immunosuppressedRestoration of protective anti-Epstein-Barr Virus (anti-EBV) T-cell immunity by adoptive transfer of ex vivo expanded EBV-specific cytotoxic T lymphocytes (CTLs) has been shown to be a safe and effective approach to prevent or treat posttransplant lymphoproliferative disorders (PTLDs) in bone marrow transplant recipients (1-3). Standard published protocols emphasize the effectiveness of using autologous lymphoblastoid cell lines (LCLs) as stimulator cells in boosting memory immune responses to EBV in vitro (2,3). However this same approach has not proven effective in priming naïve anti-EBV T cells in vitro (4,5). As EBV − SOTx recipients are at high risk of developing PTLD, we have been interested in establishing protocols to generate EBV-specific CTLs from these individuals. Studies performed by other groups, and in our laboratory, have recently established the key role of using dendritic cells (DCs) as antigen-presenting cells in activating naïve T cells against EBV epitopes (6,7). In the current study we wanted to assess and compare the ability of DCs loaded with necrotic/apoptotic LCLs in cross-priming autologous naïve EBV-reactive T cells vs. boosting memory T cells, and to further characterize the quality of the resulting immune responses.The CTL lines were evaluated by flow cytometry analyses with MHC Class I/peptide tetramers and mAbs to detect memory/activation markers, ELISPOT analysis for IFN-c production, and in cytotoxicity tests. Results indicate that in our system, in vitro cross-priming promotes both activated poly-epitope viral-specific CD8+ CTLs and Th1-type CD4+ T-cell responses in EBV − donors. The polarized Type 1 pattern of cytokine expression induced by DCs fed with apoptotic/necrotic LCLs correlated with the ability of T cells to mediate cytotoxicity against autologous LCLs, which was further enhanced by addition of rhIL-12 in the first round of in vitro stimulation. These results support the prospective development of DC-based cellular immunotherapy for EBV − SOTx patients at high risk of developing PTLD or patients with refractory PTLD. Materials and Methods Human subjectsSeven immunocompetent adult volunteers were recruited in this study following informed consent under IRB-approved protocol. Peripheral blood mononuclear cells (PBMCs) were isolated from heparinized blood (8), while sera served as material for determination of EBV status. 1369
Background: Galactose-a-1,3-galactose (alpha-gal) is a carbohydrate that is ubiquitously expressed in all mammals except for primates and humans. Patients can become sensitized to this antigen and develop alpha-gal syndrome (AGS), or a red meat allergy. Symptoms range from generalized gastroenteritis and malaise to anaphylaxis, and in endemic areas, the prevalence can be as high as 20%. Although AGS patients commonly avoid alpha-gal by avoiding meat, patients have also developed symptoms due to animal-derived medical products and devices. With the rise in transcatheter aortic valve replacement, we investigate the immunogenicity of common cardiac materials and valves.Objective: To assess the in vitro immunoglobulin E response toward common medical products, including cardiac patch materials and bioprosthetic valves in patients with AGS.Methods: Immunoblot and immunohistochemistry techniques were applied to assess immunoglobulin E reactivity to various mammalian derived tissues and medical products for patients with AGS.Results: AGS serum showed strong reactivity to all of the commercially available, nonhuman products tested, including various decellularized cardiac patch materials and bioprosthetic aortic valves. AGS serum did not react to tissues prepared using alpha-gal knockout pigs.Conclusions: Despite commercial decellularization processes, alpha-gal continues to be present in animal-derived medical products, including bioprosthetic valves. Serum from patients with AGS demonstrates a strong affinity for these products in vitro. This may have serious potential implications for sensitized patients undergoing cardiac surgery, including early valve failure and accelerated coronary artery disease.
Supravalvar pulmonary stenosis after the arterial switch operation for dextrotransposition of the great arteries is common and more than one reintervention are required in a subset of patients. The benefit of balloon angioplasty of the main pulmonary artery and left pulmonary artery was shown to be temporary. Attempting balloon angioplasties at these locations remain reasonable, although families should be counseled about the increased incidence of, and decreased time to, subsequent reintervention that is associated with this treatment option.
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