RESUMEN
T-cell activation is dependent on signals delivered through the antigen-specific T-cell receptor and accessory receptors on T-cells. Integration of signals through this family of costimulatory and inhibitory receptors and their ligands regulates the balance between T-cell activation, tolerance, and immunopathology. Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, deliver inhibitory signals and exert a vital and diverse range of immunoregulatory roles in T-cell activation, tolerance, and immune-mediated tissue damage. In this review, we revisit current understanding of the immunoregulatory functions of PD-1 and its ligands and their involvement in immune-mediated diseases.
Asunto(s)
Antígeno B7-H1/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/metabolismo , Antígeno B7-H1/metabolismo , Infecciones por VIH/inmunología , Infecciones por VIH/metabolismo , Humanos , Tolerancia Inmunológica/fisiología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Receptor de Muerte Celular Programada 1/metabolismoRESUMEN
Artemisinin derivatives, the current cornerstone of malaria treatment, possess also anti-angiogenic and anti-tumor activity. Hypoxia plays a crucial role both in severe malaria (as a consequence of the cytoadherence of infected erythrocytes to the microvasculature) and in cancer (due to the restricted blood supply in the growing tumor mass). However, the consequences of hypoxia onto the effects of artemisinins is under-researched. This study aimed at assessing how the inhibition of microvascular endothelial cell (HMEC-1) growth induced by dihydroartemisinin (DHA, an antimalarial drug and the active metabolite of currently in-use artemisinins) is affected by oxygen tension. Low doses of DHA (achieved in the patients' plasma when treating malaria) were more inhibitory in hypoxia, whereas high doses (required for anti-angiogenic or anti-tumor activity) were more effective in normoxia. The peroxide bridge is essential for cellular toxicity (deoxyDHA was inactive). High doses of DHA caused HMEC-1 apoptosis and G2 cell cycle arrest. Effects were mediated by the generation of oxidative stress as demonstrated by DCF-DA fluorescence and membrane lipid peroxidation analysis. Overall, these results suggest that DHA inhibition of endothelial cell growth is related to the level of tissue oxygenation and drug concentration. This should be considered when studying both the effects of artemisinin derivatives as antimalarials and the potential therapeutic applications of these drugs as anti-tumor agents.
Asunto(s)
Antimaláricos/farmacología , Artemisininas/farmacología , Hipoxia de la Célula , Células Endoteliales/efectos de los fármacos , Apoptosis/efectos de los fármacos , Ácido Ascórbico/farmacología , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Células Endoteliales/metabolismo , Humanos , Peroxidación de Lípido/efectos de los fármacos , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Human endogenous retroviruses are suggested to play a pathogenic role in multiple sclerosis (MS); one of such retroviruses, the MS-associated retroviral agent (MSRV) has repeatedly been isolated in MS patients. OBJECTIVE AND METHODS: We analyzed cytokine profiles in MSRV envelope protein (MSRV ENV-SU)-stimulated peripheral blood mononuclear cells of 30 relapsing-remitting MS patients with either acute (AMS) (n = 13) or stable (SMS) (n = 17) disease. Results suggest that MSRV ENV-SU induces the production of inflammatory cytokines, including tumor necrosis factor-alpha (P < 0.05) and interferon-gamma (P < 0.004) in AMS patients and of interleukin-10 (P < 0.05), an inflammation-dampening cytokine, in SMS individuals. CONCLUSIONS: These data strengthen the hypothesis indicating that MSRV could be involved in the pathogenesis of MS.
Asunto(s)
Citocinas/metabolismo , Retrovirus Endógenos/inmunología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple Recurrente-Remitente/virología , Linfocitos T/inmunología , Linfocitos T/virología , Enfermedad Aguda , Adulto , Complejo CD3/metabolismo , Femenino , Humanos , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Receptores de Lipopolisacáridos/metabolismo , Masculino , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Linfocitos T/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Adulto JovenAsunto(s)
Anticuerpos Monoclonales/efectos adversos , Macroglobulinemia de Waldenström/tratamiento farmacológico , Anticuerpos Monoclonales de Origen Murino , Antígenos CD/sangre , Antígenos CD4/sangre , Antígenos CD8/sangre , Progresión de la Enfermedad , Femenino , Humanos , Factores Inmunológicos/efectos adversos , Receptores de Lipopolisacáridos/sangre , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/complicaciones , Enfermedades del Sistema Nervioso/inmunología , Rituximab , Macroglobulinemia de Waldenström/complicacionesAsunto(s)
Enfermedades Desmielinizantes/virología , Retrovirus Endógenos/inmunología , Productos del Gen env/inmunología , Esclerosis Múltiple/virología , Proteínas Gestacionales/inmunología , Animales , Enfermedades Desmielinizantes/inmunología , Humanos , Esclerosis Múltiple/inmunología , Superantígenos/inmunologíaRESUMEN
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.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/inmunología , Inmunidad Celular/inmunología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Adyuvantes Inmunológicos/uso terapéutico , Adulto , Anticuerpos Monoclonales/farmacología , Antígenos CD28/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Citocinas/biosíntesis , Enterotoxinas/farmacología , Femenino , Humanos , Técnicas In Vitro , Interferón beta/uso terapéutico , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Interleucina-1/biosíntesis , Interleucina-1/inmunología , Interleucina-12/biosíntesis , Interleucina-12/inmunología , Interleucina-2/biosíntesis , Interleucina-2/inmunología , Interleucina-6/biosíntesis , Interleucina-6/inmunología , Receptores de Lipopolisacáridos/análisis , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Proteína Básica de Mielina/farmacología , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Immune activation has been observed in HIV-infected and uninfected Africans, among whom it is thought to modify interaction between the immune system and HIV. To characterize this phenomenon accurately, in-depth immunologic analyses were performed in a rural African population. Freshly drawn peripheral blood mononuclear cells (PBMCs) of HIV-infected African (from Gulu, Uganda) and Italian antiviral-naive patients and those of uninfected Ugandan and Italian study subjects were analyzed. Individuals were matched for age and sex and determined to be free from parasitic infections. Intracellular cytokines were measured in mitogen (M)- and gp160 peptides + staphylococcal enterotoxin B and alpha CD28 (env)-stimulated T lymphocytes. Interferon (IFN)-gamma-producing CD8(+) T cells were quantified in an enzyme-linked immunosorbent assay. Results showed that M-stimulated production of interleukin (IL)-10 and tumor necrosis factor (TNF)-alpha increases in CD4(+) and CD8(+) cells of African infected patients and uninfected study subject; and that env-stimulated IL-10 and TNF-alpha production is increased in CD8(+) T lymphocytes of African HIV-infected patients. M- and env-stimulated IFN-gamma-producing CD8(+) T cells were reduced in African participants and not increased by preincubation with alpha IL-10 monoclonal antibody. This is the first set of data that has reported immune activation in rural Africa by single-cell analysis of cytokine production. These results help in defining the immunologic background to be considered in the design of therapeutic and vaccine-based approaches to HIV infection in an African setting.
Asunto(s)
Población Negra , Citocinas/análisis , Infecciones por VIH/inmunología , Leucocitos Mononucleares/inmunología , Antígenos CD28/farmacología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Enterotoxinas/farmacología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Proteínas gp160 de Envoltorio del VIH/farmacología , Infecciones por VIH/sangre , Infecciones por VIH/etnología , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Mitógenos/farmacología , Subgrupos de Linfocitos T/inmunología , Uganda/etnologíaRESUMEN
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)
Asunto(s)
Diferenciación Celular/inmunología , Infecciones por VIH/transmisión , Linfocitos T/patología , Adulto , Factores de Edad , Antígenos de Superficie/sangre , Antígenos CD4/sangre , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Niño , Preescolar , Estudios de Cohortes , Femenino , Proteínas gp160 de Envoltorio del VIH/farmacología , Infecciones por VIH/inmunología , Seropositividad para VIH , Humanos , Inmunidad Celular/inmunología , Recién Nacido , Transmisión Vertical de Enfermedad Infecciosa , Interferón gamma/metabolismo , Interleucina-7/sangre , Activación de Linfocitos/efectos de los fármacos , Masculino , Mitógenos/farmacología , MadresRESUMEN
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.
Asunto(s)
Infecciones por VIH/inmunología , VIH-1 , Receptores CCR5/análisis , África , Anticuerpos Anti-VIH/sangre , Infecciones por VIH/etnología , Infecciones por VIH/virología , Seronegatividad para VIH/inmunología , Seropositividad para VIH/inmunología , Seropositividad para VIH/virología , Humanos , Italia , Pruebas de Neutralización , Reacción en Cadena de la Polimerasa , ARN Mensajero/análisis , Receptores CCR5/genética , Receptores CXCR4/análisis , Receptores CXCR4/genéticaAsunto(s)
Antígenos CD , Antígenos de Diferenciación/sangre , Antígenos CD8/sangre , Infecciones por VIH/tratamiento farmacológico , Complejos Multienzimáticos/sangre , NAD+ Nucleosidasa/sangre , Linfocitos T/química , ADP-Ribosil Ciclasa , ADP-Ribosil Ciclasa 1 , Fármacos Anti-VIH/uso terapéutico , Biomarcadores , Infecciones por VIH/inmunología , Humanos , Glicoproteínas de Membrana , PronósticoRESUMEN
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.
Asunto(s)
Esclerosis Múltiple Crónica Progresiva/genética , Esclerosis Múltiple Recurrente-Remitente/genética , Proteína Básica de Mielina/genética , Polimorfismo Genético , Secuencias Repetitivas de Ácidos Nucleicos , Alelos , Secuencia de Aminoácidos , Análisis Mutacional de ADN , Femenino , Eliminación de Gen , Predisposición Genética a la Enfermedad , Humanos , Italia , Masculino , Datos de Secuencia MolecularRESUMEN
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.
Asunto(s)
Citocinas/inmunología , Retrovirus Endógenos/inmunología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple Recurrente-Remitente/virología , Enfermedad Aguda , Adulto , Antígenos Virales/inmunología , Enfermedad Crónica , Femenino , Humanos , Interferón gamma/inmunología , Interleucina-10/inmunología , Interleucina-12/inmunología , Interleucina-2/inmunología , Masculino , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
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.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Anticuerpos Antinucleares/sangre , Interferón beta/administración & dosificación , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/inmunología , Adulto , Anticuerpos Anticardiolipina/sangre , Autoanticuerpos/inmunología , ADN/inmunología , Femenino , Humanos , Interferón beta-1a , Interferon beta-1b , Masculino , Persona de Mediana Edad , Mitocondrias/inmunología , Músculo Liso/inmunologíaRESUMEN
To verify the possible role of human herpesviruses as triggering or aggravating factors in relapsing-remitting multiple sclerosis (RRMS) clinical acute attack, we studied the prevalence of some herpesviruses in the peripheral blood mononuclear cells (PBMCs) collected from 22 MS patients during an MS relapse and in a stable phase and from 18 healthy controls (HC). DNA belonging to Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), Human cytomegalovirus (HCMV), Epstein-Barr virus (EBV) and Human Herpes virus 6 (HHV-6) has been searched by specific nested polymerase chain reaction (n-PCR). EBV and HHV6 DNA has been detected with high frequency in acute and stable MS and in healthy controls without significant differences. HCMV DNA was observed both in acute and stable MS but not in HC, and, more interestingly, HSV-1 DNA was only found in 13% of acute MS, while both stable MS and healthy controls were negative. On the basis of these results we focused on HSV-1, and to confirm them and to demonstrate that HSV-1 is actively replicating in MS patients during clinical relapse, we searched both messenger RNA (mRNA) and DNA of HSV-1 in the PBMCs of 15 acute MS patients and 15 healthy controls. We found HSV-1 mRNA and DNA in a significant number of acute MS patients but not in the control group. On the whole these data indicate that HSV-1 reactivate in the peripheral blood of MS patients during clinical acute attack and probably play a role in the triggering of MS relapses.
Asunto(s)
Herpes Simple/inmunología , Herpesvirus Humano 1/genética , Esclerosis Múltiple Recurrente-Remitente/virología , Enfermedad Aguda , Adulto , ADN Viral/análisis , Femenino , Herpes Simple/epidemiología , Herpesvirus Humano 1/inmunología , Herpesvirus Humano 2/genética , Herpesvirus Humano 2/inmunología , Humanos , Leucocitos Mononucleares/virología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/epidemiología , Esclerosis Múltiple Recurrente-Remitente/inmunología , ARN Mensajero/análisis , ARN Viral/análisis , Estudios SeroepidemiológicosRESUMEN
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.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Timo/patología , Fármacos Anti-VIH/administración & dosificación , Recuento de Linfocito CD4 , Niño , Estudios de Cohortes , Didanosina/administración & dosificación , Didanosina/uso terapéutico , Quimioterapia Combinada , Infecciones por VIH/inmunología , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Indinavir/administración & dosificación , Indinavir/uso terapéutico , Lamivudine/administración & dosificación , Lamivudine/uso terapéutico , Tamaño de los Órganos , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Estavudina/administración & dosificación , Estavudina/uso terapéutico , Carga Viral , Zidovudina/administración & dosificación , Zidovudina/uso terapéuticoRESUMEN
Clinical, virologic, and immunologic outcomes were analyzed in children with vertically transmitted human immunodeficiency virus (HIV) infection (n = 25) and clinical symptoms and evidence of immunosuppression to establish the efficacy of 18 months' treatment with stavudine, lamivudine, and indinavir. Children were naive for treatment with protease inhibitors and lamivudine and had minimal exposure to stavudine. At 1, 6, 12, and 18 months, the proportions of patients with HIV-RNA <400 copies/mL were 79%, 100%, 94%, 87% in Centers for Disease Control and Prevention (CDC) immunologic class 2 and 50%, 67%, 67%, 72% in CDC immunologic class 3. At 12 months, the median CD4(+) count and percent increased significantly in both CDC immunologic class groups, but to a greater extent in the class 3 group. In the 12- to 18-month period, there were no significant changes within the groups. In both groups there was a steady increase in the proportion and number of children with positive skin test responses. Children in class 2 were more likely to have a positive delayed-type hypersensitivity response and a greater number of positive responses. Lymphocyte proliferative response to recall antigens improved significantly in all patients. The rate of increase in positive test results was faster in children in class 2 than in those in class 3. Only minor clinical events occurred during 18 months of therapy. Potent antiretroviral therapy achieves a sustained benefit in HIV-infected children, but immune reconstitution is more likely achieved in children with less advanced disease.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Indinavir/uso terapéutico , Lamivudine/uso terapéutico , Estavudina/uso terapéutico , Adolescente , Recuento de Linfocito CD4 , División Celular , Niño , Quimioterapia Combinada , Infecciones por VIH/inmunología , Humanos , Hipersensibilidad Tardía , Transmisión Vertical de Enfermedad Infecciosa , Pruebas Cutáneas , Linfocitos T/inmunología , Resultado del TratamientoRESUMEN
BACKGROUND: The thymus is the organ responsible for the maturation and selection of T lymphocytes and is thus pivotal in allowing the development of a functional immune system. Because in HIV infection cell-mediated immune responses are severely impaired, we studied the role of thymus in the control of the progression of HIV infection to AIDS. METHODS: Thymic volume was analysed by magnetic resonance imaging in 31 vertically HIV-infected children. Plasma HIV viral load and phenotypic and functional cellular immunity-defining parameters were examined in the same patients. RESULTS: Thymic volume was not correlated with age or nutritional status; thymic volume was nevertheless correlated with CD4 T-lymphocyte counts and with the percentage and absolute number of CD45RA+CD62L+ (naive) T lymphocytes. In addition, the ability of peripheral blood mononuclear cells to proliferate upon tetanus stimulation was directly proportional to thymic volume. Finally, a negative correlation was detected between thymic volume and HIV viral load. CONCLUSION: Because low HIV plasma viraemia and preserved immune function are favourable prognostic indices in HIV disease, these data indicate that an immunological, thymic-dependent control of the progression of HIV infection might be possible, at least in vertically transmitted HIV infection.
Asunto(s)
Infecciones por VIH/inmunología , Timo/inmunología , Linfocitos T CD4-Positivos/inmunología , Niño , Progresión de la Enfermedad , Infecciones por VIH/transmisión , Infecciones por VIH/virología , Humanos , Transmisión Vertical de Enfermedad Infecciosa , Selectina L/inmunología , Antígenos Comunes de Leucocito/inmunología , Imagen por Resonancia Magnética , Radiografía , Linfocitos T Colaboradores-Inductores/inmunología , Timo/citología , Timo/diagnóstico por imagen , ViremiaAsunto(s)
Antígenos CD/análisis , Antígenos de Diferenciación/análisis , Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1 , Indinavir/administración & dosificación , Lamivudine/administración & dosificación , NAD+ Nucleosidasa/análisis , Estavudina/administración & dosificación , Viremia/virología , ADP-Ribosil Ciclasa , ADP-Ribosil Ciclasa 1 , Niño , Quimioterapia Combinada , Humanos , Glicoproteínas de MembranaRESUMEN
The effects of synthetic malaria pigment (beta-haematin, BH) on the expression of the intercellular adhesion molecule 1 (ICAM-1) and platelet endothelial cell adhesion molecule 1 (PECAM-1) and the production of interleukin-6 (IL-6) by human microvascular endothelial cells were measured using flow cytometry analysis and immunoenzymatic assay. BH alone did not affect basal levels of ICAM-1, PECAM-1 or IL-6. When added to cell cultures before or with, but not after, lipopolysaccharide or tumour necrosis factor alpha, BH at 1-100 micrograms/mL induced a dose-dependent inhibition of ICAM-1 and PECAM-1 expression and IL-6 production. Cell viability and human leucocyte antigen A,B,C expression remained unaffected. Similar, though more variable, results were obtained using human umbilical vein endothelial cells. These results suggested that accumulation of pigment within endothelial cells following repeated malaria infection reduces local inflammation and parasite sequestration through inhibition of either cytokine production or parasitized erythrocyte receptors on endothelial cells.
Asunto(s)
Endotelio Vascular/efectos de los fármacos , Hemina/farmacología , Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-6/metabolismo , Plasmodium falciparum/química , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Animales , Endotelio Vascular/metabolismo , Humanos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Peripheral blood (PB) lymphocyte subpopulations, IgG, IgM, IgA and IgE serum immunoglobulins and C3 and C4 complement fractions were evaluated in 29 schizophrenic patients, 31 of their relatives and 20 healthy subjects. The patients fulfilled DSM-III criteria for schizophrenia, and were unmedicated for 3 months prior to the PB sample collection. When compared to healthy controls and their own relatives, the schizophrenic patients showed a lower level of CD4+ cells, while the CD4+ 45RA+ (naive) subset was significantly higher. Conversely, the number of CD4+ 45RA- (memory) lymphocytes was significantly lower in schizophrenic patients in comparison to their relatives and controls, while the CD8+ supressor/cytotoxic T-cell percentage was significantly higher. No significant differences were observed for the IgG, IgM, IgA, IgE and C3 and C4 complement fraction levels among the three groups. The present data confirm the presence of immunological abnormalities in schizophrenic patients and suggest a possible role of environmental factors in the triggering of an autoimmune pathogenic mechanism.