Immunomodulation in the treatment of haematological malignancies

Despite the continuous advances in immunology and cancer biology, haematological malignancies are often incurable. Conventional chemotherapy and radiation are efficacious for some lymphoma and leukaemia, however relapse and progressive disease often occurs. The evidence that the immune system can play an essential role in controlling cancer progression provide a basis for the development of active therapies, such as immunization, aimed to evoke or amplify a tumour-specific immune response. However, the inability of the patient’s own immune system to mount effective responses against tumour antigens is a major limit of vaccination approaches. The adoptive transfer of effectors of the adaptive immune system is an attractive strategy to circumvent the limitations of autologous immune responses. Donor lymphocyte infusion and the transfer of monoclonal antibodies (MoAbs) have been the first forms of adoptive therapy approved for clinical use and are still fundamental components of immunotherapy of haematological malignancies. Due to the continuous characterization of tumour-specific antigen, the development of tumour-tailored therapies that exploit the specificity of antibodies and T cell receptors (TCRs) is progressing rapidly. This review highlights the current advances in the field of adoptive immunotherapy of haematological malignancies, starting by elucidating the ongoing progress in passive transfer of MoAbs. We will also discuss recent advances in the adoptive transfer with tumour-specific high avidity T cells, which can be generated ex vivo by the transfer of gene constructs encoding single chain antibodies or TCRs, thus redirecting T cell specificity to selected tumour antigens. The ability to produce gene-modified T cells of desired specificity and defined functional activity may improve in the future T cell based immunotherapy of cancer.     

Clinical variables related to antidepressant-induced mania in bipolar disorder

BACKGROUND: The development of mania or hypomania during antidepressant treatment is a serious complication of the clinical management of bipolar disorder (BP). The primary aim of this study was to evaluate the clinical variables related to antidepressant-induced mania or hypomania (AIM) in patients with BP. METHODS: DSM-IV BP-I or BP-II patients who had had at least one depressive episode treated with antidepressants were considered. Patients were subdivided into two groups according to the presence (n = 30) or absence (n = 106) of manic or hypomanic episodes occurring during antidepressant treatment. Possible predictive clinical variables of AIM were considered: gender, diagnostic subtype, age at onset, duration of illness, duration of untreated illness, type of antidepressant administered, number of previous spontaneous hypomanic or manic episodes, number of previous depressive episodes, presence of lifetime suicide attempts, presence of mood stabilizer treatments, presence of psychotic symptoms during spontaneous episodes, family history for psychiatric disorders in first degree relatives. Data were compared between the two groups, with (AIM+) and without (AIM-) antidepressant-induced mania, using Student's t tests and chi-square tests. RESULTS: The lack of mood stabilizer treatments during antidepressant therapy (chi-square = 37.602, df = 1, p < 0.001) and the exposure to tricyclic antidepressants (chi-square = 4.901, df = 1, p < 0.05) resulted significantly associated to the development of AIM. LIMITATIONS: This study was not done under controlled conditions and the relatively small sample studied warrants further replications. CONCLUSIONS: These results point out the risk of mania induction associated to the use of tricyclic antidepressants in BP patients, mainly in absence of adequate mood stabilizers.     

Nucleofection is an efficient nonviral transfection technique for human bone marrow-derived mesenchymal stem cells

Viral-based techniques are the most efficient systems to deliver DNA into stem cells because they show high gene transduction and transgene expression in many cellular models. However, the use of viral vectors has several disadvantages mainly involving safety risks. Conversely, nonviral methods are rather inefficient for most primary cells. The Nucleofector technology, a new nonviral electroporation-based gene transfer technique, has proved to be an efficient tool for transfecting hard-to-transfect cell lines and primary cells. However, little is known about the capacity of this technique to transfect adult stem cells. In this study, we applied the Nucleofector technology to engineer human bone marrow- derived mesenchymal stem cells (hMSCs). Using a green fluorescent protein reporter vector, we demonstrated a high transgene expression level using U-23 and C-17 pulsing programs: 73.7%+/-2.9% and 42.5%+/-3.4%, respectively. Cell recoveries and viabilities were 38.7%+/-2.9%, 44.5%+/-3.9% and 91.4%+/-1.3%, 94.31%+/-0.9% for U-23 and C-17, respectively. Overall, the transfection efficiencies were 27.4%+/-2.9% (U-23) and 16.6%+/-1.4% (C-17) compared with 3.6%+/-2.4% and 5.4%+/-3.4% of other nonviral transfection systems, such as FUGENE6 and DOTAP, respectively (p<.005 for all comparisons). Nucleofection did not affect the immunophenotype of hM-SCs, their normal differentiation potential, or ability to inhibit T-cell alloreactivity. Moreover, the interleukin-12 gene could be successfully transfected into hMSCs, and the immunomodulatory cytokine was produced in great amount for at least 3 weeks without impairment of its biological activity. In conclusion, nucleofection is an efficient nonviral transfection technique for hMSCs, which then may be used as cellular vehicles for the delivery of biological agents.     

EEG correlates (event-related desynchronization) of emotional face elaboration: a temporal analysis

An EEG frequency band analysis was conducted, in order to explore the significance of brain oscillations (delta, theta, alpha and beta) for emotional face comprehension during different post-stimulus time intervals (50-150; 150-250; 250-350; and 350-450 ms). The study was conducted on twenty adults who looked at emotional (happy, sad, angry, fearful) or neutral faces. The results showed that motivational significance of the stimulus can modulate the power synchronization (event-related desynchronization (ERD) decrease) within the frequency band of delta and theta. We propose that delta and theta respond to variations in processing stage of emotional face: whereas, delta reflects updating of the stimulus, theta responds to the emotional significance of face. The findings revealed that emotional discrimination by theta is observable mainly within 150-250 time interval and that it is more distributed on anterior regions, whereas delta is maximally synchronized within 250-350 interval and more posteriorly distributed for all the stimulus type. Finally, a right-hemisphere dominance was found for theta during emotional face comprehension.     

Endothelial nitric oxide synthase (Glu298Asp) polymorphism is an independent risk factor for migraine with aura

OBJECTIVE: The aim of the present study was to evaluate whether the functional endothelial nitric oxide synthase (eNOS) Glu298Asp polymorphism, which has been demonstrated to decrease the endothelial NOS activity, might be a risk factor for migraine. BACKGROUND: It has widely demonstrated that nitric oxide (NO) is involved in migraine pathogenesis. Several genetic risk factors have been associated with migraine, but no study has unraveled a possible relationship between migraine and eNOS Glu298Asp. Methods.-One hundred fifty-six migraine patients and 125 healthy nonheadache volunteers entered the study. Demographic and clinical characteristics were carefully recorded, and a neurological workup was performed. RESULTS: eNOS AspAsp homozygous patients had a 3-fold time risk for migraine with aura (MA) when compared to migraine without aura (MO) patients (OR-3.02, 95% CI-1.21 to 7.51), and more than 2-fold time increased risk when compared to control subjects (OR-2.21, 95% CI-1.00 to 5.04). In migraine patients, no difference in age at onset, mean attack's intensity, family history for any of the studied comorbidities, or the presence of comorbidities was found in eNOS AspAsp homozygous compared to eNOS GluGlu or eNOS GluAs carriers. CONCLUSIONS: Homozygous Asp298, a common variant of the eNOS gene, is an independent risk factor for MA in this study population.     

Endocrine function is altered in chronic migraine patients with medication-overuse

OBJECTIVE: To evaluate the effects of analgesic overuse on endocrine function in patients with chronic migraine and medication-overuse headache (CM-MOH). BACKGROUND: Chronic migraine is frequently associated with an overuse of symptomatic medications. Drugs currently used in acute migraine attacks are associated with several endocrine effects. At present, the endocrine effects of medication overuse in chronic migraine patients are unknown. METHODS: Eighteen patients with CM-MOH, diagnosed according to the ICHD-II criteria, and 18 healthy controls received an intravenous administration of GHRH, hCRH, and TRH. Plasma concentrations of GH, TSH, ACTH, and cortisol were measured for a 90-minute period after administration of the specific releasing hormones. RESULTS: Hormonal basal concentrations were similar in both groups. GH response to GHRH was significantly reduced in patients with CM-MOH in comparison with controls. TRH induced a reduction of TSH concentrations only at the end of the test. After hCRH administration, ACTH and cortisol concentrations were significantly higher in cases than in controls. A significant correlation between duration of the disease and altered hormonal response was found. CONCLUSIONS: Our study shows that both corticotropic and somatotropic functions are significantly impaired in CM-MOH patients and suggests a role for hormones in the development of chronic migraine.     

Regulation of peripheral T cell activation by calreticulin

Regulated expression of positive and negative regulatory factors controls the extent and duration of T cell adaptive immune response preserving the organism's integrity. Calreticulin (CRT) is a major Ca2+ buffering chaperone in the lumen of the endoplasmic reticulum. Here we investigated the impact of CRT deficiency on T cell function in immunodeficient mice reconstituted with fetal liver crt-/- hemopoietic progenitors. These chimeric mice displayed severe immunopathological traits, which correlated with a lower threshold of T cell receptor (TCR) activation and exaggerated peripheral T cell response to antigen with enhanced secretion of inflammatory cytokines. In crt-/- T cells TCR stimulation induced pulsatile cytosolic elevations of Ca2+ concentration and protracted accumulation of nuclear factor of activated T cells in the nucleus as well as sustained activation of the mitogen-activated protein kinase pathways. These observations support the hypothesis that CRT-dependent shaping of Ca2+ signaling critically contributes to the modulation of the T cell adaptive immune response.     

Lack of startle blink potentiation to mutilation pictures irrespective of fearfulness

Previous research has shown that in healthy individuals blood-related stimuli elicit a distinctive autonomic response pattern and heightened processing as compared with other unpleasant and arousing visual stimuli. In addition, growing evidence suggests that information processing of disorder-related stimuli is also different in blood phobia as compared with other specific phobias. In the present study, the magnitude of the startle eyeblink reflex elicited during the viewing of mutilation, human attack, erotica and neutral pictures was recorded in 22 blood phobics and 25 healthy controls. Startle eyeblink responses were measured at 300, 1500, 3500 and 4500-ms time intervals after picture onset in order to assess the attentional/affective modulation and its temporal course. Reliable startle inhibition to erotic pictures and startle potentiation to human attack scenes were found relative to neutral pictures. However, while both groups rated mutilations as the most unpleasant and arousing content, no blink facilitation relative to neutral contents was found at either early or late probe times. Crucially, such effect occurred independently of fear levels, as no difference between phobics and controls was found in the size of the startle blinks elicited throughout the viewing of blood pictures.