The MDR1/ABCB1 gene, a high-impact risk factor for cardiac transplant rejection.

BACKGROUND: Variations in the expression and activity levels of the multidrug-resistance MDR1/ABCB1 encoded P- glycoprotein (P-gp) have an impact on the therapeutic efficacy of many drugs. C3435T and G2677 polymorphisms of the MDR1/ABCB1 gene correlate with cellular expression levels of P-gp, a membrane-bound efflux pump which removes a multitude of drugs, including chemotherapy drugs and immunosuppressants, from cells. We aimed to investigate whether the phenomenon of drug resistance, mediated by the MDR1/ABCB1 gene and seen in tumor cells to chemotherapeutic agents, is important in the field of transplantation, predisposing some patients to resistance to immunosuppressants. METHODS: G2677 and C3435T polymorphisms of the ABCB1 gene were determined by PCR in 170 heart transplant recipients. We examined the relationship between MDR1/ABCB1 polymorphisms and endomyocardial biopsy-proven rejection (EBPR) determined by biopsy performed at set intervals according to a standard protocol. RESULTS: A significant relationship was found between a patient's C3435T genotype and freedom from first grade > or =3A rejection episode. 3435-CC recipients were 1.8 times (1.05-3.09; P = 0.03) more likely to undergo a > or =3A rejection episode in the first 12 months. Haplotypes derived from the G2677 and C3435T polymorphisms (GG/CC, GT/CT and TT/TT) amplified this phenomenon further (log rank, P = 0.03; HR 2.18; 1.21-4.26; P = 0.02). CONCLUSIONS: ABCB1 polymorphisms correlate with freedom from grade > or =3A EBPR and we believe that this may be attributed to MDR1/ABCB1 encoded P-gp mediating the efflux of immunosuppressants out of leukocytes, with depleted immunosuppressant levels in leukocytes manifesting as increased cellular rejection.

Changes in induced sputum in the presence of bronchiolitis obliterans syndrome and correlation with spirometry in single and bilateral lung transplant recipients.

Bronchiolitis obliterans syndrome is a clinical diagnosis based on lung function parameters. Using induced sputum, taken from lung transplant recipients, this paper reports on the correlation between the neutrophil count and the percentage change from postoperative baseline for FEV(1), FEF(50), and FEF(25-75). In double lung transplant recipients the correlations were significant for FEV(1) (r = -0.68, p = 0.002), FEF(50) (r = -0.65, p = 0.016), and FEF(25-75) (r = -0.56, p = 0.016). In single lung transplant recipients, no significant correlations were seen.

PG490-88, a derivative of triptolide, attenuates obliterative airway disease in a mouse heterotopic tracheal allograft model.

The current treatment of obliterative bronchiolitis in lung transplant recipients is sub-optimal. Triptolide is a novel immunosuppressant that has a mechanism of action distinct from currently available immunosuppressants, including induction of T-cell apoptosis, blockade of fibroblast proliferation/maturation and inhibition of transforming growth factor-beta (TGF-beta) mRNA production. We hypothesized that triptolide may be helpful in blocking obliterative airway disease in lung transplant recipients. We investigated the effect of PG490-88, a water-soluble derivative of triptolide, in a mouse heterotopic tracheal allograft model of obliterative airway disease. We show that PG490-88 attenuates airway obliteration in this model and inhibits accumulation of inflammatory cells, and therefore may have preventive or therapeutic benefits for patients with obliterative airway disease (OAD) following lung transplantation.

Natural killer cells in peripheral blood and lung tissue are associated with chronic rejection after lung transplantation.

BACKGROUND: Natural killer (NK) cells have the capacity to recognize and respond to alloantigen, yet their role in lung transplant rejection is not well defined. The aim of this study was to correlate NK cell numbers and immunophenotype in peripheral blood and tissue with graft function after lung transplantation. METHODS: NK cell subsets were immunophenotyped in peripheral blood (n = 41). Lung tissue was stained for NK cells via CD16 and morphologic assessment (n = 30). RESULTS: Peripheral blood NK cells were activated in patients with chronic rejection, but the overall number of cells was lower in these patients when compared with stable patients. Furthermore, there was significantly more CD16(+) NK cells in the lung compartment of patients with bronchiolitis obliterans syndrome compared with stable patients (p = 0.001). CONCLUSIONS: In patients with chronic rejection, peripheral blood NK cells are activated but their numbers decrease, while the number of NK cells in the lungs increases. This suggests NK cells systemically activate and migrate to the lung during the progression of chronic rejection after lung transplantation.

Extracorporeal membrane oxygenator as a bridge to successful surgical repair of bronchopleural fistula following bilateral sequential lung transplantation: a case report and review of literature.

BACKGROUND: Lung transplantation (LTx) is widely accepted as a therapeutic option for end-stage respiratory failure in cystic fibrosis. However, airway complications remain a major cause of morbidity and mortality in these patients, serious airway complications like bronchopleural fistula (BPF) are rare, and their management is very difficult. CASE PRESENTATION: A 47-year-old man with end-stage respiratory failure due to cystic fibrosis underwent bilateral sequential lung transplantation. Severe post-operative bleeding occurred due to dense intrapleural adhesions of the native lungs. He was re-explored and packed leading to satisfactory haemostasis. He developed a bronchopleural fistula on the 14th post-operative day. The fistula was successfully repaired using pericardial and intercostal vascular flaps with veno-venous extracorporeal membrane oxygenator (VV-ECMO) support. Subsequently his recovery was uneventful. CONCLUSION: The combination of pedicled intercostal and pericardial flaps provide adequate vascular tissue for sealing a large BPF following LTx. Veno-venous ECMO allows a feasible bridge to recovery.