Biomedical subjects
Publications and source records attributed to A Franco.
Presentation of one case of intrasinusale located renal angiomyolipoma. Given the location, the ECO as well as the IVU, arteriography and CAT presented diagnostic doubts. We believe this unusual presentation should be added to those circumstances where uncertainty of tumor diagnosis due to size, behaviour or clinical signs and symptoms, elicits a more aggressive attitude.
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Previously, six T cell clones, which are specific for an encephalitogenic determinant of myelin proteolipid protein (PLP) peptide residues 139 to 151 (HSLGKWLGHPDKF), were derived from SJL mice and shown to use diverse TCR genes. To design TCR antagonist peptides that could interfere with the activation of these clones in vitro and inhibit experimental allergic encephalomyelitis (EAE) in vivo, we first determined the TCR and MHC contact residues of the encephalitogenic peptide. The analysis indicated that residues 144 (tryptophan) and 147 (histidine) were the TCR binding sites and that residues 145 (leucine) and 148 (proline) were important for MHC class II (IAs) binding. On the basis of this information, a peptide analogue (leucine 144/arginine 147), in which both of the major TCR contact residues were substituted, was synthesized. This analogue acts as a TCR antagonist for the panel of PLP 139-151-specific T cell clones, does not cause EAE by itself, blocks the induction of disease by the native 139-151 peptide, and prevents clinical disease progression if administered at the first signs of disease. Thus, although multiple TCR genes are used by PLP 139-151-specific clones, a single peptide analogue can interfere with the disease process. This approach should be feasible for designing peptide analogues that can be tested for therapeutic efficacy in human autoimmune diseases in which the pathogenic Ags are known and TCR use is diverse.
Highly purified CD4+ T cells isolated from liver biopsies of patients with hepatitis B virus-induced CAH had a strong cytotoxic activity and were comprised of a substantial number of cells (25%-40%) expressing CD56 surface marker. These cells were absent in CD4+ T cells from the peripheral blood of CAH patients or normal controls and these suspensions did not have cytotoxic activity. CD4+CD56+ T cells were further characterized by studies at the clonal level. A total of 71 hepatitis B envelope antigen-specific CD4+ T cell clones was investigated (23 from liver biopsies, 48 from peripheral blood of patients or normal vaccinated individuals). A total of 16 out of 23 (69.5%) of the clones from liver biopsies, but only 4.1% (2 out of 48) of those from PBLs, expressed CD56. A clone was defined as CD56+ when 40% or more of the cells expressed the marker. Production of TNF-alpha, IL-4, IL-5, IL-2, and IFN-gamma was investigated in 15 CD4+CD56+ and in 18 CD4+CD56- T cell clones, which shared the same HLA restriction element (DR2w15) and the same fine specificity (peptide 193-207 of the S region). All of the clones from the two groups released TNF-alpha and IL-2. However, all of the CD4+CD56+ T cell clones produced IFN-gamma but not IL-4 and IL-5 (Th1-like cell clones). Fourteen of the CD4+CD56- clones released IFN-gamma, IL-4, and IL-5 (Th0-like cell clones); three produced IL-4 and IL-5 but not IFN-gamma (Th2-like cell clones); and only one had a Th1 cytokine secretion profile. Cell fractionating studies within single CD4+CD56+ T cell clones showed that cells expressing high density CD56 had a stronger cytotoxic activity and produced higher levels of IFN-gamma than cells with low density CD56, thus further supporting a correlation between CD56 expression and cell functions. The results indicate that: 1) in CAH patients, cytotoxic CD4+ T cells with a Th1 cytokine secretion profile are compartmentalized in the liver, 2) these cells may be identified by the expression of CD56, 3) the expansion of these cells may be facilitated by antigenic stimulation within the inflammatory environment of the liver, and 4) CD4+CD56+ cells may play a pathogenetic role in hepatitis B virus infection.
The feasibility of using T cell receptor (TcR) antagonist peptides to inhibit autoimmune disease has been examined. First, the fine antigenic structure of the I-As-restricted encephalitogenic determinant proteolipid protein (PLP) 139-151 has been analyzed. It was found that residues 145 and 148 were I-As anchor residues, and residue 144 appeared to be especially critical in T cell activation. Residues 142, 143, 146, and 147 were found to be crucial for activation of some, but not all, of the T cells studied. Next, good I-As-binding nonantigenic analogs were tested for TcR antagonism. Accordingly, several single substitution analogs were identified which could act as TcR antagonists. Moreover, when two such analogs were combined, the resulting TcR antagonist pool inhibited most of the PLP 139-151-specific T cell clones in vitro. When the efficacy of this TcR antagonist pool in inhibiting EAE induction in vivo was examined, it was found that the analog pool was a remarkably potent inhibitor of disease induction. The TcR antagonist pool was approximately 10-fold more potent than our best major histocompatibility complex blocker and was still capable of significant inhibition when injected in equimolar amounts with the encephalitogenic PLP 139-151 determinant.
Celiac disease (CD) is a small intestinal disorder characterized by the malabsorption of most nutrients. Disease pathogenesis appears to be associated with immune-mediated pathology. Susceptibility is associated with genes coding for DQw2 class II molecules. In the present report we investigated T cell responses to A-gliadin (AGL), a major alpha-gliadin component known to activate disease. Gliadin-specific lines were generated from a CD patient and a normal donor. Three major points were revealed by the analysis of these T cells: (1) On the basis of mapping experiments using Epstein-Barr virus (EBV) lines and DR-transfected fibroblasts and DR-, DP-, and DQ-specific monoclonal antibodies (mAb), all responses appeared to be DR-restricted. Thus, in contrast to the strong association of disease susceptibility with DQ molecules, no DQ-restricted, gliadin-specific response was detectable. (2) Fine specificity analysis, using a panel of synthetic peptides spanning the entire alpha-gliadin component molecule, revealed that the clones derived from the normal donor were DR53-restricted and AGL 21-40-specific, while clones derived from the CD patient were DR7-restricted and peptide 1-20-specific. (3) Both whole AGL and AGL 1-20 were presented to the patient-derived clones with much higher efficiency by DDR-transfected fibroblasts than by EBV lines. These data suggested that fibroblasts processed this determinant efficiently, while EBV lines were unable to do so. Indeed, analysis of a panel of truncated AGL 1-20 analogs revealed that peptide AGL 1-8, which contained the minimal T cell epitope, was presented with equal efficiency by fixed or irradiated EBV and irradiated DR7-transfected fibroblasts.
Histamine (HA) acts as a neurotransmitter and/or neuromodulator in mammalian brain. Central HA has been found to be involved in the regulation of behavioral, cognitive, neurovegetative, neuroendocrine and neuroimmune functions. In this study we have evaluated psychomotor activity (PMA) and passive avoidance behavior (PAB) in rats with bilateral neurotoxic lesions in the posterior hypothalamic region (PHR) (L), where histaminergic neurons are located, and in sham-operated rats (S), two weeks after neurosurgery. In an open-field paradigm, lesioned rats showed higher PMA scores than sham-operated animals. However, L rats exhibited a significant decrease in PMA on consecutive days (motor habituation) similar to that found in S rats. In a maze paradigm, in which the animals had to learn to stay on a neutral platform in order to avoid a 1.5 mA electric footshock during 10 trails, no significant differences were observed between L and S rats on the task performance. According to the present results, it seems that bilateral neurotoxic lesions in the PHR induced hyperactivity with no apparent effects on PAB, suggesting that neuronal HA might be involved, directly and/or by influencing arousal/alertness-mediated mechanisms, in the regulation of PMA processes.
Histamine (HA) is a biogenic amine involved in the regulation of neurovegetative, cognitive, neuroendocrine and neuroimmune functions in the central nervous system (CNS). A bidirectional interaction between the CNS and the neuroimmune system has been demonstrated in recent years. However, data concerning brain HA-cytokine interactions are scarce. In this study we have evaluated tumor necrosis factor-alpha (TNF-alpha) levels in the posterior hypothalamic region (PHR) and hippocampus (HP) of rats with: (a) bilateral ibotenic acid neurotoxic lesions in histaminergic neurons located in the PHR (I); (b) saline injections in the PHR (S); and (c) sham operation (C), two weeks after neurosurgery. The bilateral disruption of PHR HA neurons with ibotenic acid decreased TNF-alpha levels in the PHR with respect to sham-operated (C), but not saline-injected (S), rats. In contrast, hippocampal TNF-alpha concentrations were higher in lesioned rats (I) than in C and S animals. Our results indicate that the neurotoxic destruction of HA neurons decreases TNF-alpha synthesis in the hypothalamus while enhancing TNF-alpha production in the hippocampus, suggesting that neuronal HA might be involved in the regulation of the brain TNF-alpha system.
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Recent studies demonstrated that antigen analogs can act as powerful and specific inhibitors of T cell activation, leading to the formulation of the concept that antigen analog/MHC complexes may act as antagonists of the T cell receptor (TCR). TCR antagonism appears to be associated with engagement of the TCR below a crucial affinity threshold necessary for full T cell activation. Studies addressing the molecular mechanism of this effect suggest that TCR antagonists could act by interfering with membrane-related events (such as proper receptor clustering) that might precede intracellular signaling. Discovery of the TCR antagonism phenomenon also suggested a possible rational approach to antigen-specific immunointervention in allergies and autoimmune diseases. The feasibility of such an approach is now being actively investigated. Finally, TCR antagonist peptides may provide a useful tool to probe TCR-peptide/MHC interactions involved in the process of thymic education.
BACKGROUND: Factor VII is essential for coagulation activation by the extrinsic pathway. Hemorrhages of the central nervous system in patients with congenital factor VII deficiency seem to have a higher incidence compared with other congenital coagulopathies. The purpose of this paper is to report two rare cases of subarachnoid hemorrhage and factor VII deficiency. CASE DESCRIPTION: Two cases of women affected by a congenital deficiency of factor VII and subarachnoid hemorrhage are reported. Diagnosis was obtained by cerebral computer tomography; cerebral pan-angiography was normal. Complete coagulation studies were performed showing prothrombin time prolongation and factor VII deficiency. In one patient, family studies revealed the existence of a similar coagulation disorder. CONCLUSIONS: We suggest routine coagulation studies in all patients with subarachnoid hemorrhage. Determination of factor VII activity might be performed in patients with normal activated partial thromboplastin time and prolonged prothrombin time.
Fibrin and fibrinogen degradation products in the cerebrospinal fluid (CSF-FDP) were first studied in a group of 29 patients observed during the first and the second week after subarachnoid hemorrhage (SAH), then in a second group of 26 patients for a total of 55 patients. In the latter group only the first FDP value obtained as soon as possible after SAH was taken in consideration. In the whole series of 55 patients several noteworthy factors were found: 1) FDP determination should be performed as soon as possible after SAH; 2) CSF-FDP at or above 40, 80 micrograms/ml was found both in the patients with severe neurological deficits and in those with cerebral ischemia (statistically significant); 3) the significance of CSF-FDP in patients who rebled was also evaluated. In conclusion CSF-FDP could be considered useful in predicting cerebral ischemia.
CDP-choline (cytidine-5-diphosphate-choline) is an acetylcholine precursor frequently used in cerebrovascular disorders and psychoorganic syndromes. Furthermore, several authors have demonstrated the positive effects of CDP-choline on cognitive disorders and memory deficits. In the present study, the effects of CDP-choline (1000 mg/day, p.o. for 1 month) on cognition, evaluated by the Mini-Mental State Examination (MMSE) of Folstein et al., and on blood flow velocities, measured by transcranial Doppler ultrasonography (TCD), were investigated in patients with Alzheimer's disease: (AD, n = 20, age: 66.75 +/- 6.73 years, range: 57-78 yr). Cognitive function was measured by means of the MMSE in basal conditions (A) and after 1 month of treatment with CDP-choline (C). TCD measures were taken through the temporal window for right (MCA-R) and left (MCA-L) middle cerebral arteries with a 2 MHz pulsed transducer using a TC-2000S in basal conditions (A), 1 h after the administration of CDP-choline (B) and after 1 month of treatment with CDP-choline (C). MMSE scores were significantly increased (p < 0.005) in patients with early-onset Alzheimer's disease (EOAD) after CDP-choline treatment. Moreover, the orientation subtest significantly increased in the global group of AD patients (p < 0.01) and in EOAD patients (p < 0.02). Significant differences (p < 0.05) were also found in MCA-Land MCA-R measures between recordings. These results suggest that CDP-choline influences cognitive and cerebrovascular function in Alzheimer's disease, probably through a mechanism linked to an immunogenic and/or neurotrophic effect at the microvascular niche.(ABSTRACT TRUNCATED AT 250 WORDS)
Malignant transformation of human hepatocytes is often accompanied by an increased expression of major histocompatibility complex (MHC) molecules, but whether this phenomenon is related to an enhanced immunogenicity remains unknown. In this study, we tested the capacity of a series of human hepatoma cell lines to induce proliferation of allogeneic T cells in primary mixed lymphocyte tumour cultures (MLTC). These cell lines were positive for class I molecules, whereas class II molecule expression was either constitutive or inducible by treatment with interferon-gamma (IFN-gamma). We found that HA22T/VGH cells expressing class II molecules constitutively stimulated high proliferative responses of purified CD4+ T lymphocytes, whereas class II-negative Li7A cells stimulated CD4+ T-cell responses only when induced by treatment with IFN-gamma. HA22T/VGH and Li7A cells also exerted a significant stimulatory activity for purified CD8+ T cells whereas HepG2 cells, in which MHC class II molecules are neither constitutive IFN-gamma-inducible, were unable to induce CD4+ and CD8+ T-cell proliferative responses. Phenotypical analysis revealed that HA22T/VGH and Li7A expressed high levels of intracellular adhesion molecule-1 (ICAM-1) and experiments with blocking monoclonal antibodies (mAb) demonstrated that this molecule played a key role in mediating the co-stimulatory function of hepatoma cells. In addition, HA22T/VGH cells were found to produce mRNA for interleukin-1 (IL-1) beta and IL-6, while Li7a only produced IL-1 beta, yet both these cytokines were found to play a small part, if any, in T-cell co-activation. On the whole, these results show tht hepatoma cells expression MHC antigens and ICAM-1 are able to deliver signals necessary for activation of resting CD4+ and CD8+ T cells and suggest that they may actively participate in the anti-tumour immune response.
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The nutcracker phenomenon consists in the compression of the left renal vein by the aortomesenteric clamp. This is an infrequent cause of haematuria. The present paper presents one case of nutcracker phenomenon showing haematuria after mild accidental lumbar bruising, with arteriographic diagnosis. CAT assessment showed a mark in the lumbar ureter as well as peripyelic and periureteral varices.
Recent investigations indicate that a neuroimmune reaction, associated with inflammatory mechanisms, can contribute in Alzheimer's disease (AD) to cell damage and neurodegeneration. Activation of microglial cells, expression of immunohistochemical markers of brain immune function, the presence of complement proteins in brain tissue and changes in cytokine production have been reported in AD. We have studied the concentration of interleukin-1 beta (IL-1 beta) in different regions of the central nervous system (CNS) in post-mortem samples from patients with AD or vascular dementia (VD) and in age-matched control subjects (CS). IL-1 beta levels were significantly higher in AD than in VD or CS in the frontal cortex, parietal cortex, temporal cortex, hypothalamus, thalamus and hippocampus. The highest increases in IL-1 beta levels were observed in the frontal cortex (CS = 0.75 +/- 0.045; AD = 2.47 +/- 0.12, p < 0.001; VD = 1.52 +/- 0.078 pg/mg, p < 0.001) and hippocampus (CS = 0.71 +/- 0.042; AD = 2.63 +/- 0.19, p < 0.001; VD = 1.21 +/- 0.23 pg/mg, p < 0.01). No significant changes were detected in the occipital cortex and cerebellum in either AD or VD. These results clearly demonstrate that demented patients show a generalized increment of IL-1 beta production in the CNS, with maximum response in those brain regions where AD neuropathology is most prominent. This overall increase in cytokine production might represent an early event in the activation of a neuroimmune cascade leading to cell death and neurodegeneration in brain regions where a primary cause (e.g., genetic, toxic, vascular) facilitates the induction of resting microglia for firing brain immune function.
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