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Infecciones por VIH/virología , VIH-1/genética , Receptores CCR5/genética , Genotipo , HumanosAsunto(s)
Anticuerpos Monoclonales/biosíntesis , Biotecnología/normas , Técnicas de Cultivo/normas , Citocinas/normas , Proteínas Recombinantes/normas , United States Food and Drug Administration , Vacunas Sintéticas/biosíntesis , Biotecnología/métodos , Técnicas de Cultivo/métodos , Citocinas/biosíntesis , Humanos , Modelos Teóricos , Proteínas Recombinantes/biosíntesis , Estados UnidosRESUMEN
The Center for Biologics Evaluation and Research, whose regulatory authority includes monoclonal antibodies, cytokines, vaccines, toxins and somatic cellular therapies, communicates to sponsors issues for consideration in the development of biological products through the publication of "Points to Consider" and "Guideline" documents. This paper summarizes the available "Points to Consider" and "Guideline" documents and outlines recommendations from these documents for characterizing the cells used to produce biological products.
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Productos Biológicos/biosíntesis , Biotecnología/legislación & jurisprudencia , Animales , Línea Celular , Humanos , Muridae , Retroviridae/aislamiento & purificación , Estados UnidosRESUMEN
Stem cell activity in murine lupus was investigated by analyzing endogenous splenic colony-forming units in sublethally irradiated inbred, congenic, and consomic mice as well as F1 crosses. Splenic colony-forming units (CFU-s) were elevated (greater than 100) in young NZB mice as compared with nonautoimmune-prone mice (less than 10). In lpr/lpr and gld/gld mice, elevated levels of CFU-s were in association with disease manifestations. F1 crosses of inbred lpr/lpr mice often showed an excess of CFU-s in females when compared with male littermates. The autoimmunity accelerating factor on the Y chromosome of BXSB mice led to high numbers of CFU-s relative to female littermates. The xid gene, which does not alter stem cell activity but, instead, interferes with terminal lymphocyte maturation, had no effect on CFU-s in congenic mice. These studies demonstrate that there is a strong association between increased numbers of CFU-s and the development of generalized autoimmunity; increased stem cell division may be important for the development of murine lupus.
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Enfermedades Autoinmunes/patología , Bazo/citología , Células Madre/citología , Animales , Autoanticuerpos/genética , Ensayo de Unidades Formadoras de Colonias , Femenino , Genes MHC Clase II , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NZB , Ratones EndogámicosRESUMEN
A linkage map of distal mouse chromosome 1 was generated using restriction fragment length polymorphism (RFLP) analysis of DNA prepared from 95 [C3H-gld/gld X Mus spretus)F1 X C3H-gld/gld] backcross mice. The gene order was: (centromere) C4bp, Ren-1,2, Ly-5, [At-3/gld], Apoa-2/Ly-17, Spna-1 (telomere). All mice expressing the phenotype of gld homozygotes were homozygous for the At-3 RFLP characteristic of C3H mice and none of the mice heterozygous for At-3 RFLPs had characteristics of gld homozygotes, demonstrating close linkage between these genes. The identification of an RFLP closely linked to the gld gene provides a starting point for the identification of a genetic defect that results in abnormal T cells and autoimmune disease.
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Enfermedades Autoinmunes/genética , Ligamiento Genético , Trastornos Linfoproliferativos/genética , Mutación , Polimorfismo Genético , Polimorfismo de Longitud del Fragmento de Restricción , Animales , Mapeo Cromosómico , Cruzamientos Genéticos , Enzimas de Restricción del ADN , Femenino , Genes Recesivos , Masculino , Ratones , Ratones Endogámicos C3H , Fenotipo , Recombinación GenéticaRESUMEN
The xid gene was introduced into C3H-gld/gld mice to determine its effects on the development of autoimmune disease. C3H-gld/gld.xid mice were compared with C3H-gld/gld mice for the development of lymphadenopathy, surface phenotype of lymph node (LN) cells, c-myb oncogene RNA production, serum immunoglobulin (Ig) levels, and autoantibody production. In addition, C3H-gld/gld and C3H-lpr/lpr mice were examined for serum Ig and autoantibody levels. The results showed that the xid gene had no effect on either the development of the severe lymphadenopathy characteristic of C3H-gld/gld mice or the phenotype of the Ly-2-, L3T4-, Ly-5(B220)+ T-cell subset that is expanded in the LN and spleens of these mice. Similarly, xid did not affect the high levels of c-myb oncogene RNA expression by C3H-gld/gld LN and spleen cells. By contrast, the xid gene caused a significant reduction in serum IgM but not IgA levels and almost completely ablated the generation of both IgM and IgG anti-ssDNA antibodies and anti-dsDNA antibodies. These data suggest that the xid gene can dramatically decrease the B-cell manifestations of autoimmunity in gld homozygotes without affecting their abnormal T-cell expansion. Comparisons of age-matched C3H-gld/gld and C3H-lpr/lpr mice showed that they had similarly elevated serum IgM and IgA levels and anti-ssDNA and anti-dsDNA antibody levels providing further evidence that gld and lpr produce parallel defects in C3H mice.
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Enfermedades Autoinmunes/inmunología , Síndromes de Inmunodeficiencia/inmunología , Trastornos Linfoproliferativos/inmunología , Ratones Mutantes/inmunología , Animales , Autoanticuerpos/metabolismo , Enfermedades Autoinmunes/genética , ADN/inmunología , Regulación de la Expresión Génica , Inmunoglobulinas/metabolismo , Síndromes de Inmunodeficiencia/genética , Trastornos Linfoproliferativos/genética , Ratones , Proteínas Proto-Oncogénicas/genética , ARN Mensajero/genética , Linfocitos T/inmunologíaRESUMEN
Mice and humans with systemic lupus erythematosus (SLE) have been studied with regard to cellular, genetic and molecular genetic abnormalities. B cell hyperactivity and autoantibody production are the hallmarks of this illness. In humans with SLE, there is increased stem cell, B cell precursor and B cell proliferation. The same is true of NZB mice. In lpr/lpr and gld/gld mice, marked expansion of a subpopulation of T cells allows extrathymic terminal T cell maturation and secondary B cell hyperactivity. Androgens suppress these processes and polyclonal immune activators accelerate them. Three types of genes are identified: inducing genes, accelerating genes and background genes. These give rise to abnormal expression of various cellular oncogenes, T cell receptor genes and immunoglobulin genes. The data suggest that abnormal immune regulation plays a critical role in the development of SLE, with polyclonal B cell activation being common to both mice and humans with SLE. Different genetic and cellular abnormalities underlie the ultimate syndrome, the common denominator, generalized autoimmunity, that we call SLE.
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Regulación de la Expresión Génica , Lupus Eritematoso Sistémico/genética , Animales , Linfocitos B/inmunología , Genes Recesivos , Humanos , Lupus Eritematoso Sistémico/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos , Oncogenes , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T/inmunologíaRESUMEN
The murine "motheaten" (me) mutation has been bred onto the NFS background and combined with the X-linked immunodeficiency (xid) mutation to investigate the effect of the xid-induced B cell maturational block on the widespread immune dysfunction, high levels of autoantibodies, and early mortality found in the motheaten mice. The xid markedly reduced spontaneous IgM secretion by spleen cells, serum IgM, anti-ssDNA antibodies, anti-bromelain-treated-erythrocyte antibodies, and T cell binding (but not thymocytotoxic) antibodies; however, neither phenotype nor mortality was affected, suggesting that other factors are responsible for early death. Marked expansion of the Ly-1+ B cell pool was prevented by xid in the motheaten mouse leaving only a very small population of sIgM-positive B cells. This failure of non-Ly-1+ B cell development in me/me X xid mice suggests that me/me leads to inhibition of non-Ly-1+ B cells and preferential expansion of Ly-1+ B cells in motheaten mice, perhaps as a result of their high levels of maturation and activation factors.
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Enfermedades Autoinmunes/genética , Síndromes de Inmunodeficiencia/genética , Ratones Mutantes/fisiología , Animales , Formación de Anticuerpos , Antígenos de Diferenciación de Linfocitos T , Antígenos Ly/análisis , Antígenos de Superficie/análisis , Autoanticuerpos/metabolismo , Linfocitos B/clasificación , Linfocitos B/inmunología , ADN de Cadena Simple/inmunología , Inmunoglobulinas/metabolismo , Activación de Linfocitos , Ratones , Fenotipo , Receptores de Antígenos de Linfocitos B/análisis , Bazo/inmunología , Linfocitos T/clasificación , Linfocitos T/inmunología , Antígenos Thy-1RESUMEN
A prospective serological study was undertaken in hospital personnel who care for Lassa fever (LF) patients in an endemic region of Sierra Leone, West Africa. Among personnel from three hospitals where barrier nursing is practised, antibody prevalence and seroconversion by age and sex were consistently equal to or lower than those of persons in nearby village populations. No group among hospital personnel evaluated by age, sex, contact, or occupational exposure was at higher risk than another. Hospital staff in Sierra Leone who care for LF patients using simple barrier nursing methods have no higher risk of infection than the local population. These findings support the proposal that patients with LF in non-endemic countries need not be confined to isolators.
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Infección Hospitalaria/epidemiología , Fiebre de Lassa/epidemiología , Enfermedades Profesionales/epidemiología , Personal de Hospital , Adolescente , Adulto , Anciano , Anticuerpos Antivirales/análisis , Infección Hospitalaria/inmunología , Infección Hospitalaria/mortalidad , Femenino , Humanos , Fiebre de Lassa/inmunología , Fiebre de Lassa/mortalidad , Virus Lassa/inmunología , Masculino , Persona de Mediana Edad , Enfermedades Profesionales/inmunología , Enfermedades Profesionales/mortalidad , Población Rural , Sierra LeonaRESUMEN
In a study of Lassa fever in Sierra Leone, West Africa, we identified two variables associated with a high risk of death, and we evaluated the efficacy of ribavirin and Lassa virus-convalescent plasma for the treatment of Lassa fever. A serum aspartate aminotransferase level greater than or equal to 150 IU per liter at the time of hospital admission was associated with a case-fatality rate of 55 percent (33 of 60). Patients with the same risk factor who were treated for 10 days with intravenous ribavirin, begun within the first 6 days after the onset of fever, had a case-fatality rate of 5 percent (1 of 20) (P = 0.0002 by Fisher's exact test). Patients whose treatment began seven or more days after the onset of fever had a case-fatality rate of 26 percent (11 of 43) (P = 0.01). Viremia with levels greater than or equal to 10(3.6) TCID50 per milliliter on admission was associated with a case-fatality rate of 76 percent (35 of 46). Patients with this risk factor who were treated with intravenous ribavirin within the first six days after onset of fever had a case-fatality rate of 9 percent (1 of 11) (P = 0.006), whereas those treated after seven days or more of illness had a fatality rate of 47 percent (9 of 19) (P = 0.035). Oral ribavirin was also effective in patients at high risk of death. Lassa-convalescent plasma did not significantly reduce mortality in any of the high-risk groups. We conclude that ribavirin is effective in the treatment of Lassa fever and that it should be used at any point in the illness, as well as for postexposure prophylaxis.
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Fiebre de Lassa/tratamiento farmacológico , Ribavirina/uso terapéutico , Ribonucleósidos/uso terapéutico , Administración Oral , Adulto , Anticuerpos Antivirales/análisis , Aspartato Aminotransferasas/sangre , Evaluación de Medicamentos , Humanos , Inmunización Pasiva , Inyecciones Intravenosas , Fiebre de Lassa/prevención & control , Virus Lassa/inmunología , Virus Lassa/aislamiento & purificación , Distribución Aleatoria , Ribavirina/administración & dosificación , Factores de Tiempo , Viremia/microbiologíaRESUMEN
A case-control study was conducted to investigate the findings of antibody to Ebola virus in the serum of a guinea pig from Tandala, Zaire. Case households, defined by the possession of one or more guinea pigs, were compared to neighboring households without guinea pigs. Seven (5.1%) of 138 samples of human sera and 36 (26%) of 138 samples of guinea pig sera had antibody to Ebola virus. There was no clustering of seropositivity among humans or guinea pigs within households, nor was there any association between the ownership of guinea pigs and seropositivity among household members. These data suggest sporadic subclinical infection of guinea pigs and humans without a dominant role for person-to-person or guinea pig-to-guinea pig transmission.