RESUMEN
All forms of Kaposi's sarcoma (KS) are characterized by spindle cell proliferation, angiogenesis, inflammatory cell infiltration, and edema. We have previously reported that spindle cells of primary KS lesions and KS-derived spindle cell cultures express high levels of basic fibroblast growth factor (bFGF), which is promoted by the inflammatory cytokines identified in these lesions. These cytokines, namely, tumor necrosis factor, interleukin-1, and interferon-gamma, induce production and release of bFGF, which stimulates angiogenesis and spindle cell growth in an autocrine fashion. Here we show that both AIDS-KS and classical KS lesions co-express vascular endothelial growth factor (VEGF) and bFGF. VEGF production by KS cells is promoted synergistically by inflammatory cytokines present in conditioned media from activated T cells and in KS lesions. KS cells show synthesis of VEGF isoforms that are mitogenic to endothelial cells but not to KS spindle cells, suggesting a prevailing paracrine effect of this cytokine. This may be due to the level of expression of the flt-1-VEGF receptor that is down-regulated in KS cells as compared with endothelial cells. KS-derived bFGF and VEGF synergize in inducing endothelial cell growth as shown by studies using both neutralizing antibodies and antisense oligodeoxynucleotides directed against these cytokines. In addition, VEGF and bFGF synergize to induce angiogenic KS-like lesions in nude mice and vascular permeability and edema in guinea pigs. These results indicate that inflammatory cytokines present in KS lesions stimulate the production of bFGF and VEGF, which, in turn, cooperate to induce angiogenesis, edema, and KS lesion formation.
Asunto(s)
Permeabilidad Capilar/fisiología , Factores de Crecimiento Endotelial/metabolismo , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Linfocinas/metabolismo , Sarcoma de Kaposi/fisiopatología , Animales , Extractos Celulares , Medios de Cultivo Condicionados/metabolismo , Citocinas/farmacología , Sinergismo Farmacológico , Edema/fisiopatología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiología , Matriz Extracelular/metabolismo , Cobayas , Humanos , Inmunohistoquímica , Ratones , Ratones Desnudos , Neovascularización Patológica/fisiopatología , Oligonucleótidos Antisentido/farmacología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores de Factores de Crecimiento/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular , Sarcoma de Kaposi/metabolismo , Células Tumorales Cultivadas , Factor A de Crecimiento Endotelial Vascular , Receptor 1 de Factores de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
Kaposi's sarcoma (KS) is an angioproliferative disease associated with infection by the human herpesvirus-8 (HHV-8). HHV-8 possesses genes including homologs of interleukin-8 (IL-8) receptor, Bcl-2, and cyclin D, which can potentially transform the host cell. However, the expression of these genes in KS tissues is very low or undetectable and HHV-8 does not seem to transform human cells in vitro. In addition, KS may not be a true cancer at least in the early stage. This indicated that besides its transforming potential, HHV-8 may act in KS pathogenesis also through indirect mechanisms. Evidence suggests that KS may start as an inflammatory-angiogenic lesion mediated by cytokines. However, little is known on the nature of the inflammatory cell infiltration present in KS, on the type of cytokines produced and on their role in KS, and whether this correlates with the presence of HHV-8. Here we show that both acquired immunodeficiency syndrome (AIDS)-KS and classical KS (C-KS) lesions are infiltrated by CD8+ T cells and CD14+/CD68+ monocytes-macrophages producing high levels of gamma-interferon (gamma IFN) which, in turn, promotes the formation of KS spindle cells with angiogenic phenotype. gamma IFN, in fact, induces endothelial cells to acquire the same features of KS cells, including the spindle morphology and the pattern of cell marker expression. In addition, endothelial cells activated by gamma IFN induce angiogenic lesions in nude mice closely resembling early KS. These KS-like lesions are accompanied by production of basic fibroblast growth factor, an angiogenic factor highly expressed in primary lesions that mediates angiogenesis and spindle cell growth. The formation of KS-like lesions is upregulated by the human immunodeficiency virus Tat protein demonstrating its role as a progression factor in AIDS-KS. Finally, gamma IFN and HLA-DR expression correlate with the presence of HHV-8 in lesional and uninvolved tissues from the same patients. As HHV-8 infects both mononuclear cells infiltrating KS lesions and KS spindle cells, these results suggest that HHV-8 may elicit or participate in a local immune response characterized by infiltration of CD8+ T cells and intense production of gamma IFN which, in turn, plays a key role in KS development.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Productos del Gen tat/farmacología , Herpesvirus Humano 8/inmunología , Interferón gamma/biosíntesis , Neovascularización Patológica/patología , Sarcoma de Kaposi/virología , Animales , Linfocitos T CD8-positivos/patología , Sinergismo Farmacológico , Endotelio Vascular/patología , VIH-1 , Antígenos HLA-DR/análisis , Infecciones por Herpesviridae/inmunología , Humanos , Interferón gamma/farmacología , Macrófagos/patología , Ratones , Ratones Desnudos , Monocitos/patología , Fenotipo , Sarcoma de Kaposi/inmunología , Sarcoma de Kaposi/patología , Productos del Gen tat del Virus de la Inmunodeficiencia HumanaRESUMEN
AIDS: In an interview with Treatment Issues, Dr. Joseph Sonnabend indicates that use of protease inhibitors may contribute to the development of heart disease. Protease inhibitors appear to abnormally increase triglycerides and cholesterol levels, without a corresponding increase in HDL. The addition of androgenic and anabolic steroids in the HIV treatment mix adds to cardiovascular risk. Preventive measures for patients on steroids include monitoring hematocrit levels, and possibly testosterone levels, to make sure they are not too high. Standard preventive measures for heart disease, such as diet, exercise, and the use of certain drugs, are recommended, although an aggressive approach may be required. Drugs such as Lipitor and Zocor can be used to help reduce lipid abnormalities.^ieng
Asunto(s)
Anabolizantes/efectos adversos , Enfermedades Cardiovasculares/etiología , Infecciones por VIH/complicaciones , Inhibidores de la Proteasa del VIH/efectos adversos , Lípidos/sangre , Enfermedades Cardiovasculares/sangre , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Hematócrito , Humanos , Metabolismo de los Lípidos , Factores de RiesgoAsunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Hipersensibilidad a las Drogas , Pentamidina/administración & dosificación , Neumonía por Pneumocystis/prevención & control , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Adulto , Aerosoles , Relación Dosis-Respuesta a Droga , Hipersensibilidad a las Drogas/fisiopatología , Humanos , Masculino , Pentamidina/inmunología , Pentamidina/uso terapéutico , Factores de TiempoRESUMEN
The effect of AZT on serum HIV p24 antigen and endogenous serum alpha interferon levels was studied in AIDS and ARC patients. Following administration of AZT there was a rapid decline in the serum levels of both HIV p24 antigen and alpha interferon. When AZT treatment was interrupted, the levels of both HIV p24 antigen and of interferon rapidly increased. These findings suggest that HIV or some other AZT sensitive microorganism is the inducer of interferon which is characteristically found in the serum of AIDS and symptomatic HIV infected patients. They also suggest that the rapid decline in interferon levels may underlie some of the symptomatic benefit that follows administration of AZT.
Asunto(s)
Seropositividad para VIH/tratamiento farmacológico , Interferón-alfa/sangre , Zidovudina/uso terapéutico , Antígenos VIH/sangre , Antígenos VIH/efectos de los fármacos , Seropositividad para VIH/sangre , Humanos , Activación de Linfocitos/efectos de los fármacosRESUMEN
A sensitive assay for neutralizing antibodies (NA) against AIDS-related viruses (HTLV-III and LAV) was developed, using human T-cell lymphotropic virus type-I (HTLV-I)-bearing and HTLV-III-susceptible MT-4 cells. NA to HTLV-III in 21 patients with acquired immune deficiency syndrome (AIDS), 10 individuals with AIDS-related complex (ARC), 20 healthy male homosexuals, and 10 healthy male controls were titrated. Antibodies to HTLV-III were also detected by indirect immunofluorescence (IF). The assay was sensitive up to a dilution of 1:10 000. Sera from patients with AIDS showed a geometric mean titer (GMT) of NA of 1:475, whereas much higher GMTs (1:1318 and 1:1009) were observed in patients with ARC and healthy male homosexuals, respectively. Moreover, titers of NA significantly correlated with the levels of anti-HTLV-III antibodies detected by IF.
Asunto(s)
Anticuerpos Antivirales/análisis , Antígenos Virales/inmunología , VIH/inmunología , Reacciones Antígeno-Anticuerpo , Línea Celular , Humanos , Masculino , Métodos , Pruebas de NeutralizaciónRESUMEN
Circulating immune complexes (CICs) are common in patients with the acquired immunodeficiency syndrome (AIDS) as in anemia. In our previous reports, we observed that the deposition of CICs on erythrocytes via C3b receptors (CR1) resulted in a defective CIC clearing system of erythrocytes and in high membrane osmotic fragility of such erythrocytes. We investigated the functional activity of erythrocyte CR1 in 89 patients with AIDS, 41 with AIDS related complex (ARC), 102 healthy homosexual volunteers, and 37 heterosexual males, in relation to the presence of CICs, antibody to lymphadenopathy associated virus/human T lymphotropic virus-III (LAV/HTLV-III), anemia, and the direct and indirect Coombs' tests. CICs were frequently found in all groups except heterosexual males. Absence of CR1 activity was observed in 85% of patients with AIDS, and in 59% with ARC. Impaired CR1 activity also occurred in the homosexual volunteer group. Positive direct Coombs' test and the presence of CICs correlated inversely with CR1 activity while a lowered hematocrit and the presence of antibody to LAV/HTLV-III correlated directly. Neither the sera nor the eluates from erythrocytes with a positive IgG Coombs' test contained IgG antibody against erythrocytes. This suggests decremental loss of CR1 activity progressing from asymptomatic LAV/HTLV-III antibody positive homosexual volunteers to the prodromal spectrum of ARC and finally progressing to a total disappearance in overt AIDS. Of 8 homosexuals volunteers demonstrating the composite of impaired CR1 activity, positive antibody to LAV/HTLV-III, and polyvalent positive direct Coombs' test (with gamma, mu, and C3b), all developed ARC or overt AIDS within 2 years of these observations.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/sangre , Eritrocitos/análisis , Receptores de Complemento/fisiología , Complejo Relacionado con el SIDA/sangre , Complejo Relacionado con el SIDA/inmunología , Síndrome de Inmunodeficiencia Adquirida/inmunología , Anticuerpos Antivirales/análisis , Prueba de Coombs , Anticuerpos Anti-VIH , Hematócrito , Homosexualidad , Humanos , Masculino , Receptores de Complemento 3bRESUMEN
Karyotypes of peripheral lymphocytes of 19 male homosexuals showed increased hypodiploidy. Chromosomes #19 and #20 were most frequently lost. Also, structural chromosome aberrations frequently occurred consisting chiefly of translocations and simple chromosome breaks. Terminal deletions, inversions, and isochromosomes occurred less commonly. In three of the cases, 100% of the cells were involved in a pericentric inversion of a chromosome #9. Chromosomes #3 in p21.1 and 1 in p32.3 were repeatedly affected. Structural aberrations were seen less frequently in men with acquired immunodeficiency syndrome(AIDS) and AIDS-related complex than in asymptomatic homosexuals. The hypodiploidy with preferential loss of chromosomes was constantly present. The marker chromosomes and simple breaks at repeated sites are another manifestation of damage to the immune system in these male homosexuals from Greenwich Village in New York City. The chromosomal damage was potentially the result of exposure to amyl and butyl nitrites, viral infections, or immunologic reactions to sperm, which crossreact with lymphocytes.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/genética , Aberraciones Cromosómicas , Homosexualidad , Adulto , Marcadores Genéticos , Humanos , Cariotipificación , Linfocitos/ultraestructura , Masculino , Persona de Mediana Edad , Ploidias , Translocación GenéticaRESUMEN
A method is described for measuring antibody-dependent cellular cytotoxicity (ADCC) of mononuclear cells from human peripheral blood using an established murine cell line and commercially prepared antisera. The test utilizes a standard 51Cr release technique. The ADCC activity of mononuclear cells obtained from 10 healthy human volunteers was measured at 4 different effector: target cell ratios. A linear relationship between %51Cr release (ADCC) and the number of effector cells was observed.
Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos , Pruebas Inmunológicas de Citotoxicidad/métodos , Monocitos/inmunología , Animales , Citotoxicidad Inmunológica , Femenino , Humanos , Inmunidad Celular , Leucemia L1210 , Masculino , RatonesRESUMEN
We have reviewed the biologic characteristics, immune responses, and diverse array of diseases occurring from Epstein-Barr virus infections in immune deficient patients. We have summarized possible roles of the virus in the risk groups for AIDS. Data is convincing that EBV is responsible for some of the cases of lymphadenomegaly and Burkitt-like, non-Hodgkin's lymphomas in patients with pre-AIDS and AIDS. A hypothesis has been proposed wherein EBV and other stimulants of B and T cells allow productive infection by the retrovirus and spread of HTLV-III throughout the helper T cell populations.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/microbiología , Deltaretrovirus , Herpesvirus Humano 4 , Infecciones Tumorales por Virus/inmunología , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Animales , Homosexualidad , Humanos , Inmunoglobulinas/análisis , Linfoma/complicaciones , Trastornos Linfoproliferativos/inmunología , Masculino , Riesgo , Infecciones Tumorales por Virus/complicacionesRESUMEN
Blood samples from a series of 12 patients with Kaposi's sarcoma or infectious complications of the acquired immunodeficiency syndrome (AIDS) and from 18 homosexual contacts of AIDS patients were screened for interferon-related tubuloreticular inclusions (TRI) in circulating leukocytes. In the AIDS patients, TRI were detected by transmission electron microscopy in 1.5 to 10% of mononuclear cell sections. They were most frequent in patients with a decreased fraction of T helper cells and T4/T8 ratios less than 0.2. Only rare TRI-positive sections were found in 3/12 homosexual contacts with lymphadenopathy and 1/6 asymptomatic contacts. Serum interferon was found to be elevated in each AIDS case tested, but was not a sufficient condition for detection of TRI in homosexual contacts. Active DNA virus infections, including cytomegalovirus, were common to the AIDS cases and possibly contributed to the TRI pathogenesis. Localization of TRI in T suppressor/cytotoxic cells was demonstrated with monoclonal anti-Leu 2a antibodies. The pathophysiologic significance of interferon stimulation with formation of TRI in immunocompetent cells requires further investigation.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/sangre , Cuerpos de Inclusión/efectos de los fármacos , Interferones/farmacología , Linfocitos T/ultraestructura , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Anticuerpos Monoclonales/inmunología , Femenino , Hemofilia A/complicaciones , Homosexualidad , Humanos , Linfadenitis/sangre , Linfocitos/clasificación , Masculino , Microscopía Electrónica , Sarcoma de Kaposi/sangreRESUMEN
PIP: The authors present a multifactorial model for the development of acquired immunodeficiency syndrome (AIDS) in homosexual men. It is posited that there is no specific AIDS agent; rather, AIDS is conceptualized as the result of an interaction of the known or likely effects of repeated exposures to specific environmental factors. It is suggested that different pathways may lead to similar disorders of immune regulation in other groups affected by AIDS. The salient environmental factors include: repeated exposures to multiple allogenic semen, repeated infection with cytomegalovirus, and infection with other sexually transmitted pathogens. It is proposed that AIDS develops in 2 stages: a reversible stage of disease acquisition followed by a self-sustaining stage of disease progression. Promiscuity is critical to the 1st stage, since it is associated with an accumulation of effects that eventually lead to the 2nd stage. The frequency with which an individual is reexposed to cytomegalovirus is a function of the number of different sexual partners, the prevalence of cytomegalovirus carriage in the population with whose members the person interacts, and the specific nature of sexual practice (e.g., passive anal intercourse). Epstein-Barr virus plays an important role in contributing to disordered immune regulation. The central defect in the self-sustaining stage of AIDS development is an inability of cytotoxic lymphocytes to clear cells infected by cytomegalovirus as a result of both humoral factors and cellular factors. If cytotoxic function becomes further inhibited, expansion of the total cytomegalovirus antigenic load will result in further immunosuppression. Such a multifactorial model is believed to facilitate epidemiologic analysis.^ieng