Altered Immunogenicity of Donor Lungs via Removal of Passenger Leukocytes Using Ex Vivo Lung Perfusion.

Passenger leukocyte transfer from the donor lung to the recipient is intrinsically involved in acute rejection. Direct presentation of alloantigen expressed on donor leukocytes is recognized by recipient T cells, promoting acute cellular rejection. We utilized ex vivo lung perfusion (EVLP) to study passenger leukocyte migration from donor lungs into the recipient and to evaluate the effects of donor leukocyte depletion prior to transplantation. For this purpose, female pigs received male left lungs either following 3 h of EVLP or retrieved using standard protocols. Recipients were monitored for 24 h and sequential samples were collected. EVLP-reduced donor leukocyte transfer into the recipient and migration to recipient lymph nodes was markedly reduced. Recipient T cell infiltration of the donor lung was significantly diminished via EVLP. Donor leukocyte removal during EVLP reduces direct allorecognition and T cell priming, diminishing recipient T cell infiltration, the hallmark of acute rejection.

National Healthcare Delivery Systems Influence Lung Transplant Outcomes for Cystic Fibrosis.

Successful lung transplantation (LTx) depends on multiple components of healthcare delivery and performance. Therefore, we conducted an international registry analysis to compare post-LTx outcomes for cystic fibrosis (CF) patients using the UNOS registry in the United States and the National Health Service (NHS) Transplant Registry in the United Kingdom. Patients with CF who underwent lung or heart-lung transplantation in the United States or United Kingdom between January 1, 2000 and December 31, 2011 were included. The primary outcome was all-cause mortality. Kaplan-Meier analysis and Cox proportional hazards regression evaluated the effect of healthcare system and insurance on mortality after LTx. 2,307 US LTx recipients and 451 individuals in the United Kingdom were included. 894 (38.8%) US LTx recipients had publically funded Medicare/Medicaid insurance. US private insurance and UK patients had improved median predicted survival compared with US Medicare/Medicaid recipients (p < 0.001). In multivariable Cox regression, US Medicare/Medicaid insurance was associated with worse survival after LTx (US private: HR0.78,0.68-0.90,p = 0.001 and UK: HR0.63,0.41-0.97, p = 0.03). This study in CF patients is the largest comparison of LTx in two unique health systems. Both the United States and United Kingdom have similar early survival outcomes, suggesting important dissemination of best practices internationally. However, the performance of US public insurance is significantly worse and may put patients at risk.

Second line options for hyperlipidemia management after cardiac transplantation.

Despite widespread statin therapy, 91% of cardiac transplant patients have hyperlipidemia within 5 years from cardiac transplantation. The implications of this are profound, particularly given that coronary allograft vasculopathy is a leading cause of death. Unfortunately the solution is not easy, with problems of toleration at higher statin doses and a lack of good quality evidence for second line agents. We review the literature and discuss some of the key issues transplant physicians are faced with when considering alternatives to statin therapy.

Isolation of Aspergillus species from the airway of lung transplant recipients is associated with excess mortality.

BACKGROUND: Aspergillus spp. are the leading cause of invasive fungal infection in lung transplant recipients. We investigated the relationship between the isolation of Aspergillus spp. from the respiratory tract of lung transplant recipients and their risk of mortality. METHODS: A retrospective, observational cohort study of all patients who received lung allografts between January 1999 and May 2011 at a single UK centre was performed. The time from transplantation to death was analysed using Cox regression models. Isolation of Aspergillus spp. from the respiratory tract was included as a covariate in the Cox regression model. RESULTS: Two hundred-thirteen patients were included. The median follow-up time was 5 years during which 102 patients (47.9%) died. Aspergillus was isolated from 74 (34.7%) patients. Twenty patients (27%) had Aspergillus isolated in the first 60 days post-transplant. Forty-one patients (55.4%) in the Aspergillus group and 61 patients (43.9%) in the non-Aspergillus group died during follow-up. A hazard ratio of 2.2 (95% CI 1.5-3.3; P < 0.001) for death following a positive Aspergillus sample was observed. CONCLUSION: Isolation of Aspergillus spp. from patients following lung transplantation is associated with a significant increase in mortality. Novel preventative strategies are required to minimise the impact of Aspergillus in lung transplant recipients.

Persistent medical management of chylopericardium following orthotopic heart transplant.

We describe a case of chylopericardium post orthotopic heart transplant, having had previous cardiac surgeries. This was managed conservatively for a prolonged period after which the patient recovered. We emphasise the fact that medical management works although the recovery time may be prolonged.

Potential immunologic effects of statins in cancer following transplantation.

3-hydroxy-3-methyglutaryl CoA reductase inhibitors (statins) are frequently used following organ transplantation and have well reported pleiotropic effects, including immunomodulation, which may be of benefit in preventing graft rejection. However, the immunomodulatory effects of statins on cell transformation and malignancy, combined with the immunologic processes and administration of immunosuppression are almost completely unknown. The administration of immunosuppression is well recognised as the main cause of cancer following transplantation, so the addition of an immunomodulatory agent should be associated with an increased incidence of cancer, as immune surveillance and response may be suppressed, allowing cellular transformation and proliferation combined with lack of recognition to occur. This hypothetical review attempts to delineate the mode of action of statins in terms of pro/anti-carcinogenic mechanisms, while considering graft rejection and the presence of immunosuppression.

BNP directly immunoregulates the innate immune system of cardiac transplant recipients in vitro.

BACKGROUND: The innate immune system plays an important role in cardiac allograft rejection. BNP has frequently been reported to elevate during acute cardiac rejection, yet the explanation behind this phenomenon is unclear. We hypothesized that BNP might interact with the innate immune system in cardiac transplant recipients and devised a series of in vitro culture experiments to explore this phenomena. METHODS: PBMCs were isolated from whole blood of (total n = 40) cardiac transplant recipients. Short (24h, n = 20) and long term (72h, n = 20) co-cultures of innate cells in the presence or absence of BNP were performed. BNP was added at two specific concentrations and compared to placebo control. Innate cells were immunophenotyped using flow cytometry. RESULTS: BNP dose dependently reduced the total number of monocytes, B cells and NK cells. Furthermore, BNP co-culture impaired NK cell cytotoxicity and adhesion of non-classical monocytes (via down-regulation of CD11c). DISCUSSION: BNP has an additional physiological role of moderating components of the innate immune system. Although speculative, this could be beneficial to cardiac transplant recipients as the innate immune system is involved in allograft rejection. Further investigation is required to elucidate the mechanism behind how BNP affects immune cells and whether the same effects are consistent with the adaptive immune system.

CMV infection is associated with the depletion but lack of activation of peripheral blood natural killer cells in a lung transplant cohort.

INTRODUCTION: Following lung transplantation, cytomegalovirus (CMV) has both direct and indirect adverse effects on the allograft. Natural killer cells mediate immune responses to CMV. This can be both dependent and independent of MHC class I expression. However, their role during CMV infection following lung transplantation is unknown. In this study, the immunophenotypic characteristics of NK cells were correlated with CMV infection following lung transplantation. METHODS: Seventy lung transplant recipients were included in the study. NK cells were characterised via flow cytometric analysis of CD3, CD16, CD56, CD107a, CD107b, and CD161. CMV infection was determined using an established quantitative PCR technique on peripheral blood. RESULTS: The number of peripheral blood NK cells with CD16, CD56 and CD161 phenotypes decreased in patients with CMV infection. However, there were no correlations between CMV infection and NK cell activation determined via LAMP expression. CONCLUSIONS: This study reports comparative differences in the peripheral blood NK cell repertoire in lung transplant recipients with CMV infection versus those without. However, NK cell activity did not alter with CMV infection, suggesting that CMV infection alone does not induce an NK cell response.

HMG-CoA reductase inhibitors deplete circulating classical and non-classical monocytes following human heart transplantation.

BACKGROUND: Monocytes mediate immune responses following solid organ transplantation via cytokine secretion and differentiation to macrophage/dendritic cell lineages. To date, the pleiotropic immunomodulatory effect of statins on human monocytes following human heart transplantation has yet to be elucidated. This study was designed to assess the effects of statin administration on the monocyte repertoire. METHODS: 108 patients were recruited into the study. Clinical data were collected from patients' notes. Peripheral blood immunophenotype was determined via flow cytometry (using CD11c, CD14, CD16, CD49d, CD64, CD80 and CD195). RESULTS: There were fewer circulating classical (p=0.0001) and non-classical (p=0.0013) monocytes in patients treated with a statin. CD64 expression was down-regulated (p=0.011 and p=0.049) whereas CD49d expression was up-regulated (p=0.004 and p=0.022) on classical and non-classical monocytes in this group. Patients receiving Atorvastatin had fewer circulating classical monocytes (p=0.001) compared to patients administered Pravastatin. Patients receiving Pravastatin had fewer circulating non-classical monocytes (p=0.029) compared to patients administered Atorvastatin. DISCUSSION: Statin administration alters the circulating monocyte repertoire following heart transplantation, including population size, FcgammaRI and VLA-4 adhesion molecule expression. Furthermore, different statin treatments are associated with a selective depletion of macrophage or DC (re)generating monocytes.

Natural killer cells and lung transplantation, roles in rejection, infection, and tolerance.

Despite improvements in surgical technique, organ preservation, immunosuppression, and management of infection, the long term survival following lung transplantation remains low, mainly due to immune mediated complications such as acute and chronic rejection. Almost all immunosuppressive agents used in the prophylaxis and treatment of rejection following lung transplantation are targets of T cell maturation, function or proliferation, which in theory should cause sufficient disruption of the adaptive immune system to prevent graft rejection. However the five year survival rate of only 50% suggests this is not the case. More recent evidence suggests that NK cells may play a significant role in immune processes following lung transplantation. This article reviews the literature on the potential function of NK cells in rejection, infection, malignancy and tolerance following lung transplantation.