T-cell receptor gene therapy for cancer: the progress to date and future objectives

In the last decade research has begun into the use of T-cell receptor (TCR) gene therapy as a means to control and eradicate malignancies. There is now a large body of evidence to demonstrate that through the use of this technology one can redirect T-cell antigen specificity to produce both cytotoxic and helper T cells, which are functionally competent both in vitro and in vivo and show promising antitumour effects in humans. This review focuses on the means by which TCR gene transfer is achieved and the recent advances to modify the TCRs and vector delivery systems which aim to enhance the efficiency and safety of TCR gene transfer protocols.     

Haemophilus influenzae induces neutrophil necrosis: a role in chronic obstructive pulmonary disease?

Noncapsulate Haemophilus influenzae is commonly found in the airways of patients with chronic obstructive pulmonary disease (COPD), both during stable disease and during exacerbations. Neutrophils are also found in large numbers in sputum from patients with COPD, which also contains released neutrophil products such as elastase. Why H. influenzae colonizes the lungs of patients with COPD in the presence of such large numbers of infiltrating neutrophils is not known. We set out to determine if abnormal interactions between H. influenzae and neutrophils could impact on COPD pathology. Noncapsulate H. influenzae clinical isolates were incubated in vitro with neutrophils from healthy volunteers, and respiratory burst activity, cytokine and chemokine production, phagocytosis and killing of bacteria, and neutrophil apoptosis and necrosis were measured. Neutrophil morphology was determined in sputum samples. H. influenzae were phagocytosed by neutrophils, thereby activating a respiratory burst and the secretion of the neutrophil chemoattractant IL-8. However, rather than kill the bacteria, the neutrophils themselves were killed (largely via necrosis) and released their granule contents into the extracellular environment. Neutrophil-derived IL-8, generated after the interaction of H. influenzae with neutrophils, may result in the further infiltration of neutrophils into the lungs, thereby amplifying the inflammatory response. However, the infiltrating neutrophils fail to kill the bacteria and instead release tissue-damaging products into the lung as they undergo necrosis. These results may help to explain the clinical picture in COPD.     

Decreased blood dendritic cell counts in type 1 diabetic children

In this study DC numbers, phenotype and DC responses to the Toll-like receptor (TLR)-3 ligand, poly I:C, were examined in new-onset Type 1 diabetes (T1D) patients (ND) and in established T1D patients (ED). Absolute blood myeloid DC (MDC) and plasmacytoid DC (PDC) numbers were decreased in ND and ED patients compared to age-matched controls. The decrease in MDC and PDC counts was less evident in patients with a combination of T1D and coeliac disease (CD) or CD alone. The age-dependent decline in blood DC numbers, found in control children, was not evident in ND patients, such that 2-10 years old ND children had similar MDC and PDC numbers to 15-17 years old controls. In ED patients the t-score of MDC and PDC numbers related to the age of diagnosis but not to disease duration. Blood DC in T1D patients were not distinguished from those of controls by the levels of HLA-DR, CD40 and CD86 expression or the percentage of DC expressing cytokines, IL-12, IL-10, IL-6 and TNF-alpha, in responses to poly I:C. If low DC numbers are shown to contribute to the autoimmunity in T1D, interventions aimed to increase DC numbers may mitigate against beta-cell loss.     

Detection of human bocavirus in Canadian children in a 1-year study

Human bocavirus was detected by PCR in 65 (5.1%) of 1,265 respiratory specimens collected in 2002 and 2003 from the Stollery Children's Hospital from children <17 years of age. The spectrum of illness included upper respiratory infection, croup, bronchiolitis, and pneumonia with a prominence of cough and fever.     

Quantitative MRI-pathology correlations of brain white matter lesions developing in a non-human primate model of multiple sclerosis

Experimental autoimmune encephalomyelitis (EAE) induced with recombinant human myelin/oligodendrocyte glycoprotein in the common marmoset is a useful preclinical model of multiple sclerosis in which white matter lesions can be well visualized with MRI. In this study we characterized lesion progression with quantitative in vivo MRI (4.7 T; T(1) relaxation time +/- Gd-DTPA; T(2) relaxation time; magnetization transfer ratio, MTR, imaging) and correlated end stage MRI presentation with quantitative ex vivo MRI (formaldehyde fixed brains; T(1) and T(2) relaxation times; MTR) and histology. The histopathological characterization included axonal density measurements and the numeric quantification of infiltrated macrophages expressing markers for early active [luxol fast blue (LFB) or migration inhibition factor-related protein-14 positive] or late active/inactive [periodic acid Schiff (PAS) positive] demyelinating lesion. MRI experiments were done every two weeks until the monkeys were sacrificed with severe EAE-related motor deficits. Compared with the normal appearing white matter, lesions showed an initial increase in T(1) relaxation times, leakage of Gd-DTPA and decrease in MTR values. The progressive enlargement of lesions was associated with stabilized T(1) values, while T(2) initially increased and stabilized thereafter and MTR remained decreased. Gd-DTPA leakage was highly variable throughout the experiment. MRI characteristics of the cortex and (normal appearing) white matter did not change during the experiment. We observed that in vivo MTR values correlated positively with the number of early active (LFB+) and negatively with late active (PAS+) macrophages. Ex vivo MTR and relaxation times correlated positively with the number of PAS-positive macrophages. None of the investigated MRI parameters correlated with axonal density.     

Dronabinol and marijuana in HIV-positive marijuana smokers. Caloric intake, mood, and sleep

OBJECTIVES: Individuals with HIV constitute the largest group using cannabinoids for medicinal reasons; yet, no studies have directly compared the tolerability and efficacy of smoked marijuana and oral dronabinol maintenance in HIV-positive marijuana smokers. This placebo-controlled within-subjects study evaluated marijuana and dronabinol across a range of behaviors: eating topography, mood, cognitive performance, physiologic measures, and sleep. METHODS: HIV-positive marijuana smokers (n = 10) completed 2 16-day inpatient phases. Each dronabinol (5 and 10 mg) and marijuana (2.0% and 3.9% Delta9-tetrahydrocannabinol [THC]) dose was administered 4 times daily for 4 days, but only 1 drug was active per day, thereby maintaining double-blind dosing. Four days of placebo washout separated each active cannabinoid condition. RESULTS: As compared with placebo, marijuana and dronabinol dose dependently increased daily caloric intake and body weight in HIV-positive marijuana smokers. All cannabinoid conditions produced significant intoxication, except for low-dose dronabinol (5 mg); the intoxication was rated positively (eg, "good drug effect") with little evidence of discomfort and no impairment of cognitive performance. Effects of marijuana and dronabinol were comparable, except that only marijuana (3.9% THC) improved ratings of sleep. CONCLUSIONS: These data suggest that for HIV-positive marijuana smokers, both dronabinol (at doses 8 times current recommendations) and marijuana were well tolerated and produced substantial and comparable increases in food intake.