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Biomedical subjects

P Ferrante

Publications and source records attributed to P Ferrante.

At least 19 recordsLinked to original sources
PubMed2002

Expression of JC virus T-antigen in a patient with MS and glioblastoma multiforme.

OBJECTIVE: To investigate the presence of human polyomavirus JC virus genome and the expression of the viral oncoprotein T-antigen in neoplastic cells of a patient with MS and a glioblastoma multiforme. BACKGROUND: The postmortem examination of an immunocompetent patient with a neurologic disorder revealed the concurrence of MS plaques in the white matter of the brain and a glioblastoma multiforme in the region of the thalamus. METHODS AND RESULTS: PCR analysis of DNA from demyelinated plaques and the tumor area using primers derived from specific regions of the JC virus genome revealed the presence of viral DNA corresponding to the viral early and late genes. Further examination of the samples for the JC virus regulatory region identified the presence of sequences identical to JC virus Mad-4 and JC virus W1 viral isolates in the tumor and the demyelinated regions. Results from immunohistochemistry showed the detection of the viral early protein, T-antigen, and the cellular tumor suppressor protein, p53, in the nuclei of neoplastic cells. Interestingly, expression of T-antigen, but not p53, was observed in neurofilament-positive cells with neuronal morphology and in glial fibrillary acidic protein-positive astrocytes in the cortex juxtaposed to the MS plaques. Examination of viral late gene expression by immunohistochemistry showed no evidence for viral capsid proteins, thus ruling out productive replication of JC virus in the tumor and MS demyelinated plaques. CONCLUSIONS: These observations provide molecular and clinical evidence of the association of JC virus in the brain of a patient with concurrent glioblastoma multiforme and MS.

Aged↗
PubMed2001

HLA-DRB1*1501 and response to copolymer-1 therapy in relapsing-remitting multiple sclerosis.

BACKGROUND: Copolymer 1 (Cop-1) is a random synthetic amino acid copolymer, effective in the treatment of the relapsing-remitting form of MS (RRMS). In vitro and in vivo studies suggest that the mechanism of Cop-1 involves its binding to major histocompatibility complex class II molecules as an initial step. OBJECTIVE: To assess a possible relationship between human leukocyte antigen (HLA) alleles and response to Cop-1 therapy. METHODS: Eighty-three patients with RRMS, 44 treated with Cop-1 and 39 with interferon beta-1a (IFNbeta-1a) for 2 years, were typed by molecular methods for HLA class II genes and subgrouped according to clinical outcome. RESULTS: Data have shown a possible positive correlation between presence of DRB1*1501 and response to Cop-1 therapy (p = 0.008). No relationship between HLA alleles and therapy has been found in IFNbeta-1a treated patients. CONCLUSIONS: Results suggest that DRB1*1501 might be relevant for the clinical outcome in Cop-1 treated patients and, if confirmed in larger studies, it could be helpful in the selection of RRMS patients for different therapeutic options.

Adult↗
PubMed2001

Single-cell analysis of cytokine production shows different immune profiles in multiple sclerosis patients with active or quiescent disease.

Peripheral blood mononuclear cells of multiple sclerosis (MS) patients were stimulated with myelin basic protein (MBP) together with anti-CD28 monoclonal antibody and staphylococcal enterotoxin B to optimize cytokine production by antigen-specific cells. Type 1 (IL-2, IL-12, IFNgamma) and pro-inflammatory (TNFalpha, IL-1beta, IL-6) cytokines were augmented in CD4+, CD8+, and CD14+ cells of acute MS patients and of patients undergoing disease reactivation. These cytokines were reduced in IFNbeta-treated and in stable MS patients; type 2 cytokines (IL-4, IL-10) were increased in these patients. Similar immune profiles are seen in MS patients in whom remission is naturally or pharmacologically (IFNbeta) achieved. Cytokine alterations are particularly evident in CD14+ cells, underlying their critical role in the modulation of the immune response.

Adjuvants, Immunologic↗
PubMed2001

Multiple sclerosis: infectious hypothesis.

In the search for the etiology of multiple sclerosis (MS), consideration has been given in turn to infectious agents, to genetic markers, and more recently to a combination of genetic and environmental factors, but after over a century of research, a definite conclusion has not been reached. The hypothesis that an infectious agent is responsible for triggering MS is perhaps one of neurology's most enduring notions. Interest in an infectious etiology has waxed and waned over the last two centuries since Pierre Marie first proposed that MS often starts as an infectious process. The possible role of infectious agents has been suggested by: the different geographic gradients in frequency among Caucasians; changes in prevalence due to migration, and the effect of age at migration; the suggestion of epidemics and clusters of cases in some small communities; and the remarkably low degree of concordance in monozygotic twins. The infectious hypothesis is strongly supported by the different temporal patterns of the disease in different geographic areas. Incidence rates have remained stable in some areas, but have changed over time in other regions. On the other hand, the hypothesis is hampered by the lack of evidence for a specific agent, and the weakness of the results of analytical studies that have tested the association between MS and previous infections. Despite these drawbacks, recent studies of a few select pathogens suggest that viral or bacterial infections or reactivations may trigger clinical exacerbations in relapsing-remitting MS.

Adult↗
PubMed2001

High-dose chemotherapy for ovarian carcinoma: long-term results from the Solid Tumour Registry of the European Group for Blood and Marrow Transplantation (EBMT).

PURPOSE: to determine the outcome of epithelial ovarian cancer in patients registered with the European Group for Blood and Marrow Transplantation (EBMT). PATIENTS AND METHODS: A retrospective analysis was performed on 254 patients with advanced or recurrent disease, median age 46 years (14-63) from 39 centres treated between 1982 and 1996. Only 25% of patients were known to have no or microscopic disease after initial surgery; in approximately 20% the disease status was unknown, the remainder had macroscopic disease. RESULTS: One hundred five patients received high-dose chemotherapy in complete or very good partial remission, twenty-seven in second remission and the remainder in the presence of residual disease. Most received melphalan or carboplatin, or a combination (86%) supported by autologous bone marrow or peripheral blood stem cells. The survival of patients treated in remission was significantly better than in other groups (median 33 vs. 14 months; P = 0.0001). The durability of remission was longer after transplantation in first remission than in second remission (median disease-free survival 18 vs. 9 months; P = 0.005). With a median follow-up of 76 months from diagnosis the median disease-free and overall survival in stage III disease transplanted in remission is 42 and 59 months and for stage IV disease 26 and 40 months. CONCLUSIONS: High-dose chemotherapy has a potential benefit for patients in remission. The results support the conduct of randomised studies to determine whether there is a real value from this treatment.

Adolescent↗
PubMed2001

Increased frequency of JC virus type 2 and of dual infection with JC virus type 1 and 2 in Italian progressive multifocal leukoencephalopathy patients.

To verify the possibility of different role of JC virus genotypes in the etiology of progressive multifocal leukoencephalopathy, we analysed several JC virus isolates amplified from AIDS patients with and without progressive multifocal leukoencephalopathy and healthy controls by nucleotide sequencing. Cerebrospinal fluid (CSF), peripheral blood mononuclear cells (PBMCs) and urine from 52 AIDS patients suffering from various neurological diseases including 21 cases of progressive multifocal leukoencephalopathy, and PBMCs and urine from healthy subjects were evaluated by nested polymerase chain reaction (PCR) for the presence of DNA belonging to the highly conserved large T antigen (LT) of JC virus. The different JC virus subtypes were identified by nucleotide sequence analysis of the virion protein (VP1) genomic region. JC virus DNA was detected in all the CSF samples from the progressive multifocal leukoencephalopathy patients, but not in the CSF from non-progressive multifocal leukoencephalopathy cases, while the frequency of JC virus DNA detection in the PBMCs and urine did not differ among the three groups studied. JC virus type 2 was detected only in progressive multifocal leukoencephalopathy patients, and in particular in 52.4% of their CSF samples. Moreover, in the CSF of 19.0% of the progressive multifocal leukoencephalopathy cases, dual infection with both JC virus types 1 and 2 was found. The data obtained in this study indicate that the unexpected involvement of JC virus type 2, a strain not common in Italy, and the high frequency of dual infection with both JC virus types 1 and 2 in progressive multifocal leukoencephalopathy CSF, can be indications of risk factors for progressive multifocal leukoencephalopathy development.

Acquired Immunodeficiency Syndrome↗
PubMed2000

T-lymphocyte maturation abnormalities in uninfected newborns and children with vertical exposure to HIV.

Cell-mediated immunity and T-lymphocyte maturation are impaired in HIV-infected children. These abnormalities would be detected in HIV-uninfected offspring of HIV women (seroreverters [SR]) if HIV or its soluble proteins could cross the placental barrier. Immunophenotypic analyses were performed in 20 healthy HIV-uninfected newborns of HIV-infected mothers (SR), and in 14 healthy newborns of HIV-negative women (UC). The same analyses were performed in 3 groups of older children: SR (n = 41); UC (n = 15); and HIV-infected children (n = 25). Antigen-specific cells were evaluated with ELISpot and fluorimetric analyses; IL-7 serum concentration was measured by enzyme-linked immunosorbent assay (ELISA). Results showed that in SR newborns: (1) the CD4/CD8 ratio was reduced, (2) CD4(+) and CD8(+) naive T-cell percentages were decreased, (3) percentage of activated CD8(+) T cells was increased, and (4) percentages of CD3(+)/4(-)/8(-) (DN) and DN/25(-)/44(+) were augmented. These abnormalities were partially retained in older SR children. CD4(+) and CD8(+) HIV-specific cells were detected in a portion of newborn SRs but not in older SRs. Serum IL-7 was augmented both in newborn and older SRs. Cell-mediated immunity and T-cell maturation are altered even in HIV-uninfected newborns of HIV-infected mothers; these abnormalities persist over time. The biologic significance of these observations and potential subsequent clinical events should be investigated in larger cohorts of seroreverters. (Blood. 2000;96:3866-3871)

Adult↗
PubMed2000

Mucosal and systemic immune activation is present in human immunodeficiency virus-exposed seronegative women.

Immune parameters were analyzed in peripheral blood mononuclear cells (PBMC) and cervical mucosa biopsy specimens of human immunodeficiency virus (HIV)-seronegative women sexually exposed to HIV (exposed seronegative [ESN]), HIV-infected women, and healthy women without HIV exposure. HIV was not detected in PBMC or cervical mucosa biopsy specimens of ESN women. However, interleukin (IL)-6, IL-10, IL-12, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha and -beta mRNA were elevated in PBMC and cervical mucosa biopsy specimens of ESN and HIV-infected women; CCR5 and CXCR4 mRNA were augmented in cervical mucosa biopsy specimens, but not in PBMC, of ESN and HIV-infected women; HIV-specific IFN-gamma-secreting cells were detected in vaginal washes of ESN and HIV-infected women; and phenotypic alterations were present in PBMC of ESN women. These results suggest that active HIV infection is not required for T cell activation; immune alterations occur in women in whom HIV infection cannot be detected virologically or clinically.

Cytokines↗
PubMed2000

Immune activation in africa is environmentally-driven and is associated with upregulation of CCR5. Italian-Ugandan AIDS Project.

BACKGROUND: HIV infection in Africa is associated with immune activation and a cytokine profile that stimulates CCR5 expression. We investigated whether this immune activation is environmentally driven; if a dominant expression of CCR5 could indeed be detected in African individuals; and if R5 HIV strains would be prevalent in this population. METHODS: Freshly drawn peripheral blood mononuclear cells from HIV-uninfected African and Italian individuals living in rural Africa, from HIV-uninfected Africans and Italians living in Italy, and from HIV-infected African and Italian patients were analysed. Determinations of HIV coreceptor-specific mRNAs and immunophenotype analyses were performed in all samples. Virological analyses included virus isolation and characterization of plasma neutralizing activity. FINDINGS: Results showed that: immune activation is detected both in Italian and African HIV-uninfected individuals living in Africa but not in African subjects living in Italy; CCR5-specific mRNA is augmented and the surface expression of CCR5 is increased in African compared with Italian residents (CXCR4-specific mRNA is comparable); R5-HIV strains are isolated prevalently from lymphocytes of African HIV-infected patients; and plasma neutralizing activity in HIV-infected African patients is mostly specific for R5 strains. CONCLUSIONS: Immune activation in African residents is environmentally driven and not genetically predetermined. This immune activation results in a skewing of the CCR5 : CXCR4 ratio which is associated with a prevalent isolation of R5 viruses. These data suggest that the selection of the predominant virus strain within the population could be influenced by an immunologically driven pattern of HIV co receptor expression.

Africa↗
PubMed2000

Early immune reconstitution after potent antiretroviral therapy in HIV-infected children correlates with the increase in thymus volume.

DESIGN: Despite significant rises in total CD4 T cells, the process of immune reconstitution in adults with HIV infection treated with potent antiretroviral treatment results in a rather slow increase in phenotypically naive lymphocytes. In children more than in adults, thymic function may be at least partly restored when disease-induced immunosuppression is attenuated by pharmacological means. METHODS: Twenty-five vertically infected and antiretroviral-experienced [zidovudine (ZDV)/ZDV plus didanosine (ddl)] children were prospectively followed during 12 months of treatment with lamivudine (3TC), stavudine (d4T) and indinavir (IDV). The plasma HIV viral load and phenotypic and functional cellular immunity-defining parameters were examined. The relationship between the degree of immune reconstitution and thymus volume assessed by nuclear magnetic resonance was also examined. RESULTS: An early and steep increase in CD45RA+62L+ T cells was observed in parallel with a sustained decrease in plasma HIV RNA levels and a significant rise in total CD4 T cells. This increase was significantly greater than that observed in CD4+CD45RO+ T cells. Analysis of the CD4 T cell receptor (TCR) beta repertoire and T helper function showed the ability to reconstitute families almost completely absent at baseline, and a substantial improvement of antigen-specific responses by peripheral blood lymphocytes. The rise in CD4 cells and in CD4+CD45RA+62L+ T cells was statistically associated with changes in thymus size observed over time. CONCLUSION: These data suggest a relevant contribution of the thymus to reconstitution of the peripheral pool of T cells in vertically HIV-infected children treated with potent antiretroviral regimens.

Anti-HIV Agents↗
PubMed2000

JC virus in human glial-derived tumors.

To investigate the presence and the role of polyomaviruses JC (JCV), BK (BKV), and the simian polyomavirus (SV40) in human brain tumors, samples from 25 glial-derived tumors (10 astrocytomas, 5 ependymomas, 5 oligodendrogliomas, and 5 glioblastomas) were examined by means of molecular biology and immunohistochemistry. Nested PCR of the large T (LT) region and its sequence analysis showed JCV in 6 cases (4 astrocytomas, 1 oligodendroglioma, and 1 ependymoma), while the transcriptional control region (TCR) was amplified only in 1 astrocytoma, the oligodendroglioma, and the ependymoma, one of which (astrocytoma) also stained positively by immunohistochemistry (JCV LT). TCR sequence analysis of the oligodendroglioma showed a JCV rearranged structure not related to a known viral strain, while the astrocytoma and the ependymoma disclosed a JCV Mad-4 strain that is known to induce brain tumors in animals. We suggest that JCV could have played a role in the pathogenesis of these brain tumors.

Adolescent↗
PubMed2000

A polymorphism in the repetitive (TGGA)n sequence 5' to the human myelin basic protein gene in Italian multiple sclerosis patients.

Human myelin basic protein (hMBP) gene is one of the candidate genes in the complex mosaic of multiple sclerosis (MS) susceptibility. In this study we verified the distribution of the polymorphism of the region 5' flanking the first exon of the hMBP gene, in 97 relapsing remitting, 74 primary progressive Italian MS patients, and in 236 healthy controls, using polymerase chain reaction (PCR) and gel electrophoresis analysis in this region from 1116 - 1540 nt. Three different band patterns were observed: one homozygote with a 354 bp long fragment, one homozygote with 424 bp long fragment and one heterozygote with both bands present. The short fragment was statistically more frequent in RRMS patients than in HC (P<0.05). The long fragment was more present in HC. Similarly the short homozygous pattern (354 bp/354 bp) was significantly higher in the RRMS patients versus the healthy controls (P<0.01). The sequence analysis of the hMBP alleles showed that while the long fragments matched the prototype sequence completely, all the short fragments showed a deletion of 70 bp from nt 1177 to nt 1247, which explains the short 354 bp allele detected by PCR. Moreover two single mismatches in positions 1386 (T-->C) and 1431 (G-->A), were present only in the short hMBP fragment.

Alleles↗
PubMed2000

Augmented type 1 cytokines and human endogenous retroviruses specific immune responses in patients with acute multiple sclerosis.

In vitro antigen- and mitogen-stimulated cytokine production were analysed in multiple sclerosis (MS) patients with either acute (AMS) or stable (SMS) disease and in healthy controls (HC). We also investigated whether immune responses to human endogenous retroviruses (HERV) could be detected in MS and whether these immune responses would be correlated with disease status by analysing cytokine production after stimulation of PBMC with HERV peptides. Results showed that mitogen-stimulated IL-2 and IFN-gamma was augmented and IL-10 was decreased in AMS compared to both SMS and healthy controls. Whereas the production of the metabolically active IL-12 (p70 heterodimer), was comparable in SMS, AMS and HC, production of the total IL-12 (p70 heterodimer and the p40 chain) were augmented in SMS compared to both AMS and HC. HERV-peptides IL-2 and IFN-gamma production was more frequent and more potent in AMS compared to both SMS patients and HC. HERV-specific type 2 cytokine production was more frequent and potent in SMS compared to AMS and HC. Thus a prevalent type 1 cytokine profile was seen in AMS patients, while IL-10 production predominated in SMS individuals.

Acute Disease↗
PubMed2000

Presence of autoantibodies against complement regulatory proteins in relapsing-remitting multiple sclerosis.

Complement was proposed to play an important role in the onset of Multiple Sclerosis (MS) lesions by inducing physical damage to myelin-producing cells. Every somatic cell is however endowed with a repertoire of membrane-bound molecules which normally down-regulate the complement activation cascade (Regulators of Complement Activation, RCA) and therefore protect cells from complement-dependent lysis. We show here that antibodies against two complement regulatory molecules expressed in the membrane of human cells (CD46 and CD59) are present in sera from relapsing-remitting MS patients in the acute phase, that they are directed against the active site of the RCA molecules and that they inactivate their regulatory function, thus providing a mechanism by which cells of the nervous system might be damaged in a complement-dependent fashion during the acute MS phase. Moreover, we found that most of these sera also contain antibodies reacting with an epitope of the transmembrane glycoprotein of HIV which is conserved in most retroviruses; this may support the hypothesis that self-reacting antibodies might have arisen in these patients as an immune response after retroviral infection or expression of endogenous retroviral proteins.

Acute-Phase Reaction↗
PubMed2000

Serum auto antibodies presence in multiple sclerosis patients treated with beta-interferon 1a and 1b.

To verify the possible effect of IFN-beta treatment on auto antibodies development in multiple sclerosis (MS) we studied 69 MS patients before and during the treatment with IFN-beta 1b (n=35) and IFN-beta 1a (n=20) for 27 and 12 months respectively, and, as controls, 14 untreated MS patients. The serum, collected every 3 months from all the patients, was investigated for the presence of antinuclear (ANA), anti-smooth muscle (ASMA), anti-mitochondrial (AMA), anti-native DNA (nDNA) anti-cardiolipin (aCL), anti-parietal cells (APCA), anti-microsomal (AMC) and anti-tireoglobulin (ATG) antibodies. Among the IFN-beta 1b-treated MS patients an increase of the frequency and of the level of ANA, AMC and ATG was observed. ASMA and ANA antibodies were already present in about 45% of the MS patients before the treatment and fluctuated over the time. In one patient the treatment was interrupted after 6 months because of the occurrence of high ASMA level and of an autoimmune hepatitis. The data obtained in the smaller number of MS patients treated with IFN-beta 1a were very similar. No increase in aCL level was observed during both the IFN treatments. Our results indicate that the treatment with IFN-beta induces an increase of AMC and ATG antibodies in MS patients and confirm that, although rare, autoimmune diseases could be observed. The possible effect of these auto antibodies on the treatment efficacy and on MS clinical course need to be further investigated.

Adjuvants, Immunologic↗