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.

Donor CCR5 Delta32 polymorphism and outcome following cardiac transplantation.

BACKGROUND: Chemokines regulate the recruitment and trafficking of leukocytes during an immune response. Animal models have shown correlations between chemokine production and leukocyte infiltration during allograft rejection. Also, antagonism of chemokine receptors in transplant models has produced prolonged graft survival. Individuals homozygous for a 32 base pair deletion in the CC chemokine receptor 5 (CCR5) gene have an inactive receptor. Renal transplant recipients homozygous for the deletion have been shown to survive significantly longer than those heterozygous or homozygous for the wild type allele. CCR5 ligands are upregulated during allograft rejection aiding infiltration of leukocytes. We investigated the influence of CCR5Delta32 polymorphism on outcome following human cardiac transplantation. METHODS: Recipients and corresponding donors were genotyped for CCR5Delta32 polymorphism using polymerase chain reactions. RESULTS: We found no correlation between recipient genotype and outcome following transplantation. However, there was a significant correlation between donor genotype and mortality in patients transplanted for a nonischemic condition (DD = n/a, ID = 4%, II = 25%, P = .0014). CONCLUSIONS: The induction of CCR5 expression in endomyocardial biopsy tissue is known to correlate with leukocyte graft infiltration. We suggest that donor CCR5 may be more important for leukocyte trafficking during rejection than recipient CCR5 expression. The CCR5 gene is highly conserved, and due to the small population available for this study, more work is required from other centers.

CD4-veCD8-ve CD30+ve T cells are detectable in human lung transplant patients and their proportion of the lymphocyte population after in vitro stimulation with donor spleen cells correlates with preservation of lung physiology.

INTRODUCTION: Survival following lung transplantation is less than 50% at 5 years, mainly due to immune-mediated chronic rejection. Recently a novel subset of T cells, CD4-veCD8-ve CD30+ve, so-called double negative (DN) CD30+ve T cells, has been described and shown to be responsible for tolerance in an animal model of skin transplantation. METHODS: We investigated 18 lung transplant recipients for the presence of DN CD30+ve T cells in resting peripheral blood and also following in vitro stimulation of recipient peripheral blood mononuclear cells (PBMCs) with donor spleen cells. RESULTS: Small percentages (0.2% to 6%) of DN T cells are detectable in resting PBMCs of human transplant patients (n = 18), but these did not correlate with allograft function, acute rejection episodes, HLA mismatch, or CMV status. On repeated stimulation of recipient PBMCs (two exposures) in vitro by donor spleen cells (2:1 ratio stimulators to responders) the percentage of DN CD30+ve T cells within the lymphocyte pool correlated with preservation of allograft lung function (both for FEV(1), P = .009, and FEF(25-75), P = .036) and was inversely correlated with grade of chronic rejection. On repeated exposure of recipient PBMCs to donor spleen cells with a 1:1 ratio the percentage of DN CD30+ve T cells correlated with the number of acute rejection episodes of grade 2 or greater. The total number of HLA mismatches correlated with the percentage DN CD30+ve T cells present after primary stimulation of recipient PBMCs with donor spleen cells (1:1 ratio). The number of mismatches at the B locus inversely correlated with the percentage of DN CD30+ve T cells after primary stimulation of recipient PBMCs with donor spleen cells (1:1 ratio; P = .031, n = 18). CONCLUSION: Percentages of DN CD30+ve T cells present following repeated stimulation of recipient PBMCs by donor spleen cells correlated with preservation of graft function following lung transplantation.

Angiotensin converting enzyme insertion/deletion polymorphism does not influence postcardiac transplantation hypertension onset or progression.

BACKGROUND: The angiotensin converting enzyme insertion deletion polymorphism (ACE I/D) has been associated with much cardiovascular pathology, including posttransplantation hypertension. Hypertension is a significant cause of morbidity and mortality after cardiac transplantation. We investigated the influence of the ACE I/D polymorphism on posttransplantation hypertension. METHODS: A total of 211 heart transplant recipients and 154 corresponding donors were genotyped for the ACE I/D polymorphism by polymerase chain reaction. ACE enzymatic activity was measured by spectrophotometric kinetic analysis. Sitting systolic and diastolic blood pressures were recorded at 3 consecutive visits, and the mean was calculated. Clinical data, including demographics and medication, were collected for all recipients. Results were analyzed by the chi-square test and analysis of variance, taking a p value of <0.05 to be significant. RESULTS: A total of 41.7% of the subjects were hypertensive (diastolic blood pressure >90 mm Hg) at the time of the study, with 79.6% taking at least one antihypertensive agent. We found no difference between the number of antihypertensive agents, cyclosporin dose and level, renal function, or systolic blood pressure for the different recipient or donor genotypes. We also found no significant correlation between ACE enzymatic activity and systolic or diastolic blood pressure. CONCLUSIONS: Our study of 211 recipients and 154 corresponding donors is the largest investigation of this polymorphism in a cardiac transplantation population. We found no apparent relationship between the ACE genotype (of either donor or recipient) and systemic hypertension (absolute measurements and the number or dose of antihypertensive agents used).

The effects of ACE inhibition on serum angiotensin II concentration following cardiac transplantation.

AIMS: ANGII mediates vascular neointimal formation through smooth muscle cell stimulation and enhanced production of growth factors leading to increased arterial medial layer thickness, which is a characteristic of transplant arteriosclerosis. ACE inhibition is known to be of benefit to patients with cardiovascular risk factors. We aimed to determine the effect of ACE inhibitor therapy on ACE enzymatic activity and serum ANGII levels following cardiac transplantation. METHODS: A total of 43 serum samples from eight transplant recipients were used for analysis. Samples were taken monthly from the date of transplant for the initial 6 months. ANGII was measured using sandwich ELISA. ACE enzymatic activity was measured using spectrophotometric kinetic analysis. RESULTS: There was a significant reduction in ACE enzymatic activity among individuals treated with ACE inhibitor therapy (18.0 +/- 16.6 vs 31.8 +/- 23.4, P = .008). We found significantly higher ANGII serum levels in patients receiving ACE inhibitor therapy compared to those not (2.4 +/- 2.1 vs 8.0 +/- 7.4, P = .002). There was also a significant positive correlation between ACE enzymatic activity and ANGII serum level (coefficient 0.332, P = .03). CONCLUSIONS: Our results suggest an effective ACE independent pathway for ANGII conversion. Chymase can convert ANGI with higher affinity than ACE. Also, chymase is stored in mast cells, which infiltrate the myocardium following transplantation. This data indicate that pharmacological chymase inhibition may be a possible therapeutic strategy following transplantation.

The influence of donor age on transplant coronary artery disease and survival post heart transplantation: is it safe to extend donor age?

BACKGROUND: Due to the increasing demand for suitable cardiac donor organs, acceptance criteria need to be re-evaluated. We retrospectively analyzed the effect of donor age on survival following cardiac transplantation. METHOD: Three hundred thirty-five cardiac transplant recipients and corresponding donor data were reviewed using SPSS. RESULTS: Seventy-two recipients had early posttransplant angiography or postmortem data available. The mean donor age of recipients with evidence of graft coronary artery disease (32.5 +/- 11.7 years) was significantly higher than that of recipients free of transplant coronary artery disease (TCAD) (24.8 +/- 9.4 years; P=.003). Recipient of organs from donors aged less than 50 years were less likely to develop TCAD than those of donors aged over 50 years (odds ratio 0.333; 95% CI 0.239-0.465; P=.044). TCAD also occurred much earlier posttransplantation in recipients of organ from donors over 50 years (mean time 6.5 years; median 5.0 years) than those of donors under 50 years (mean time 12.7 years; median 14.0 years). CONCLUSION: We observed no increase in mortality associated with cardiac donors over 50 years. However, increased donor age was associated with an increased incidence of TCAD.

Assessing the spastic condition of individuals with upper motoneuron involvement: validity of the myotonometer.

OBJECTIVES: To examine the validity of a newly developed tissue compliance device to measure muscle tone and to quantify the level of severity of the spastic condition. DESIGN: Validity study. SETTING: Research laboratory. PARTICIPANTS: Twenty subjects, 10 with upper motoneuron (UMN) disorders (spastic-type cerebral palsy or adult-onset cerebrovascular accident) who comprised the experimental group; and 10 nondisabled, age-equivalent subjects, who served as controls. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Muscle tone of the biceps brachii muscle was assessed with the Myotonometer and Modified Ashworth Scale (MAS). The Myotonometer was used to quantify the muscle's resistance to stretch in a relaxed state and during maximal voluntary isometric contractions. Analyses of variance determined differences among subjects. Correlations between Myotonometer measurements and MAS scores were calculated. RESULTS: Significant differences (p < .05) were observed between experimental and control groups and between the involved and uninvolved extremities of the experimental group with Myotonometer measurements. Correlations between MAS scores and Myotonometer measurements ranged from .64 to .81. CONCLUSION: The Myotonometer effectively identified differences in the spastic condition of the biceps brachii muscle in subjects with UMN involvement. Correlations with the MAS were moderate to high.

Inducible nitric oxide synthase transcription in human lung transplantation.

BACKGROUND: Recent animal data suggest that inducible nitric oxide synthase (iNOS) mRNA expression in the bronchoalveolar lavage (BAL) may be useful for the diagnosis of lung rejection. The aim of this study was to evaluate iNOS mRNA transcription in the BAL fluid of human lung allografts. METHODS: iNOS mRNA transcription was quantified by competitive reverse transcription-polymerase chain reaction in 51 BAL cell pellets of lung transplant patients. According to bacteriological and histological results, BAL samples were divided into three groups: normal (n=21), acute rejection (AR, n=15), and infection (INF, n=15). RESULTS: Compared with the control group, iNOS transcription increased significantly with INF (P=0.0005) but only slightly with AR (P>0.05). INF values were significantly higher than AR values (P=0.0029). CONCLUSION: BAL iNOS mRNA transcript determination by competitive reverse transcription-polymerase chain reaction may be useful in differentiating infected from normal and/or acutely rejecting allografts.

Primary non-small-cell lung cancer: determining the suitability of the patient and tumor for resection.

Choosing resective surgery for patients with bronchogenic carcinoma requires assessments of tumor suitability and patient suitability. Tumor suitability is largely dependent on the assessed stage of the tumor complex, based on characteristics of the primary tumor, detection of lymph node metastases, and detection of distant metastases. Imaging tests that assist in the determination of tumor stage include computed tomographic scans and positron emission tomographic (PET) scans. PET scans are more sensitive and specific than computed tomography. PET is also helpful in screening for distant metastases. Mediastinoscopy is required in most cases of mediastinal adenopathy. Patient suitability is assessed by predicting short-term surgical mortality, and the likelihood of crippling long-term respiratory failure. There is no single test that provides such information. Pulmonary function tests can be used to calculate the "predicted postoperative" function, and several algorithmic approaches have been devised to predict surgical risk. Assessments of regional pulmonary function are obtained with quantitative perfusion scintiscans. Cardiac function is also an important factor.

Dendritic cells and macrophages in lung allografts: A role in chronic rejection?

Antigen presentation by lung macrophages/dendritic cells (DC) is thought to be important in obliterative bronchiolitis/bronchiolitis obliterans syndrome (OB/BOS), which severely limits survival post-lung transplantation. However, a recent study found minimal numbers of DC in lung allografts. We looked at numbers and phenotype of macrophages/DC in lung allografts using endobronchial biopsy (EBB) and transbronchial biopsy (TBB) from 22 lung transplant patients. Biopsies were stained with monoclonal markers of DC (CD1a, RFD1, and major histocompatibility complex [MHC] Class II), and "suppressor macrophages" (RFD1 and RFD7). Dendritic cells were also stained for the costimulatory molecules CD80 and CD86. Significantly greater numbers of DC/high-power field (HPF) were seen in biopsies when we defined DC using dendritic morphology and Class II MHC expression instead of CD1a expression. Dendritic cell numbers were significantly higher in eight patients with OB/BOS compared with 14 stable patients. Fifty percent of DC expressed CD86 and 20% expressed CD80. There was no difference in CD80 or CD86 expression between OB/BOS patients and stable patients. There was no correlation between DC numbers and presence or absence of acute rejection (AR), and/or cytomegalovirus (CMV) pneumonitis on current or prior biopsies. There were significantly more MHC Class II DC in EBB compared with TBB. We found minimal staining for lung macrophages capable of suppressing T-cell inflammation. We conclude that studies of lung allografts may underestimate DC numbers if relying on CD1a as the sole marker of DC. DC are increased in patients with OB/BOS compared with stable patients. EBB may be more important than TBB in looking for inflammatory changes of OB. DC expressing costimulatory molecules are present in lung allografts, and costimulatory pathway blockade may be useful in human lung allografts. Also, the absence of "suppressor" macrophages may increase susceptibility of human lung allografts to the rejection process.

Smoking cessation. Techniques and benefits.

Tobacco dependency syndrome is an organic disease caused by chronic use of inhaled tobacco smoke. It is occasionally controlled by willpower alone, but often requires pharmacotherapy in conjunction with various techniques to manage the psychological manifestations. The two effective drugs are bupropion, which is an oral antidepressant, and nicotine, which can be administered by several modalities, including a skin patch, an oral inhalant, a nasal spray, and a chewable oral preparation. Successful therapy may require both drugs, and multiple simultaneous nicotine modalities. High-dose nicotine therapy may achieve an abstinence rate of 80% during therapy, but maintaining drug-free abstinence at such high levels over long periods is less successful, possibly because the tobacco smoke-induced changes in brain structure and function are not easily reversed.

Environmental tobacco smoke and lung cancer incidence.

Tobacco smoking has been irrefutably linked to lung cancer risk. Exposure to environmental tobacco smoke and lung cancer risk has been more controversial. Various sources have claimed confounding factors such as diet and classification bias could account for the reported link. We review the available evidence and some recent papers on this topic and conclude that the evidence linking environmental tobacco smoke and lung cancer is unequivocal and cannot be explained by confounding factors.

Long-latency contributions to reciprocal inhibition during various levels of muscle contraction.

Reciprocal inhibition is a functional term and refers to the proportional decrease in antagonist motoneuron activity that accompanies an agonist contraction. A condition-test (C-T) H-reflex paradigm (conditioned stimulus applied to the common peroneal nerve; test reflex elicited by posterior tibial nerve stimulation) was used during: (1) rest, (2) a tonic isometric tibialis anterior (TA) contraction at 10% of its maximal voluntary contraction (MVC) and, (3) a TA contraction at 25% MVC. The purpose of the study was to assess whether or not long-latency contributions to reciprocal inhibition of soleus H-reflexes changed with increasing levels of TA contraction. C-T intervals ranged from 5 to 150 ms. Subjects (n=14) had long-latency inhibition at rest (x = -35.0 +/- 18.7%). This inhibition was enhanced during 10% (x = -46.1 +/- 17.9%; p = 0.17) and 25% MVCs (x = -56.3 +/- 14.0%; p < 0.01). Findings indicate that long-latency contributions to reciprocal inhibition of the soleus motoneuron pool are enhanced with increasing force of TA muscle contraction up to 25% MVC. These results indicate that long-latency contributions to reciprocal inhibition of soleus H-reflexes are not static but rather are task-specific and change in relation to levels of TA muscle activity.