RESUMEN
The highly selective breeding of Arabian horses results in inbreeding depression and genetic disorders, thereby causing significant economic loss. The Polish population of Arabians has a great impact on many breeding programmes. The aim of the current study was to monitor genetic variants involved in the most common genetic disorders of this breed. A total of 808 elite Arabian horses were screened for cerebellar abiotrophy (CA), severe combined immunodeficiency (SCID) and lavender foal syndrome (LFS) genetic disorders by Sanger sequencing and allelic discrimination methods. The investigated population was clear of LFS. The unfavourable SCID allele was detected in three heterozygous horses (q = 0.00185). Regarding CA, the minor allele frequency was q = 0.04029. This is the first report of SCID carriers in Poland. This investigation demonstrates the value of genetic testing to support breeding decisions and to facilitate genetic disease monitoring.
Asunto(s)
Enfermedades Cerebelosas/veterinaria , Pruebas Genéticas/veterinaria , Enfermedades de los Caballos/genética , Amaurosis Congénita de Leber/veterinaria , Inmunodeficiencia Combinada Grave/veterinaria , Animales , Enfermedades Cerebelosas/genética , Femenino , Predisposición Genética a la Enfermedad , Enfermedades de los Caballos/inmunología , Caballos , Amaurosis Congénita de Leber/genética , Masculino , Linaje , Polonia , Inmunodeficiencia Combinada Grave/genética , SíndromeRESUMEN
Canine oral papillomavirus (CPV1, also known as COPV), the most common cause of non-neoplastic papillomas, has not been shown to cause squamous cell carcinomas (SCC). Furthermore, malignant transformation of benign papillomas to SCC has only been reported in a single group of dogs with severe combined immunodeficiency infected with CPV2. Here, we report a series of 7 dogs with benign CPV1-associated papillomas with histologic evidence of CPV1 causing malignant transformation to carcinoma in situ and ultimately SCC. Expression of p53 and p16 proteins in CPV1-infected cells within the benign papillomas and lesions that progressed into SCC also supported an association between papillomavirus and malignant transformation. Moreover, our retrospective analysis indicated that while there have been increased numbers of viral papillomas with malignant transformation, the number of annually diagnosed canine viral papillomas has remained constant over the past decade in our laboratory. We speculate that either an altered host immunity from increased usage of immunosuppressive drugs or changing environmental factors, e.g. increase exposure to UV radiation, may cause an increased oncogenic potential of this "low-risk" virus. This study aims to raise awareness of the malignant potential of CPV1 and to encourage further investigations into the cause of this suspected change in its oncogenic potential.
Asunto(s)
Carcinoma de Células Escamosas/veterinaria , Enfermedades de los Perros/patología , Lambdapapillomavirus/aislamiento & purificación , Neoplasias de la Boca/veterinaria , Papiloma/veterinaria , Infecciones por Papillomavirus/veterinaria , Animales , Biomarcadores de Tumor/análisis , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Enfermedades de los Perros/virología , Perros , Histocitoquímica , Inmunohistoquímica , Microscopía , Neoplasias de la Boca/patología , Neoplasias de la Boca/virología , Papiloma/complicaciones , Papiloma/virología , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/virología , Estudios Retrospectivos , Inmunodeficiencia Combinada Grave/complicaciones , Inmunodeficiencia Combinada Grave/veterinariaRESUMEN
Understanding the dynamics of acute viral infection is crucial for developing strategies to prevent and control infection. In this study, lentiviral dynamics in a host without adaptive immunity were examined in order to determine kinetic parameters of infection and quantify the effect of neutralizing antibodies in preventing infection, using mathematical modeling of data from equine infectious anemia virus (EIAV) infection of horses with severe combined immunodeficiency (SCID). Estimated parameters were used to calculate the basic reproductive number and virus doubling time and found that the rate that antibodies neutralized virus was ~18 times greater than the virus clearance rate. These results establish EIAV replication kinetics in SCID horses and the minimal efficacy of antibodies that blocked infection. Furthermore, they indicate that EIAV is at most mildly cytopathic. This study advances our understanding of EIAV infection and may have important implications for the control of other viral infections, including HIV.
Asunto(s)
Anemia Infecciosa Equina/prevención & control , Anemia Infecciosa Equina/virología , Virus de la Anemia Infecciosa Equina/inmunología , Virus de la Anemia Infecciosa Equina/aislamiento & purificación , Carga Viral , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Caballos , Modelos Teóricos , Inmunodeficiencia Combinada Grave/complicaciones , Inmunodeficiencia Combinada Grave/veterinariaRESUMEN
BACKGROUND: Pigs with SCID can be a useful model in regenerative medicine, xenotransplantation, and cancer cell transplantation studies. Utilizing genome editing technologies such as CRISPR/Cas9 system allows us to generate genetically engineered pigs at a higher efficiency. In this study, we report generation and phenotypic characterization of IL2RG knockout female pigs produced through combination of CRISPR/Cas9 system and SCNT. As expected, pigs lacking IL2RG presented SCID phenotype. METHODS: First, specific CRISPR/Cas9 systems targeting IL2RG were introduced into developing pig embryos then the embryos were transferred into surrogates. A total of six fetuses were obtained from the embryo transfer and fetal fibroblast cell lines were established. Then IL2RG knockout female cells carrying biallelic genetic modification were used as donor cells for SCNT, followed by embryo transfer. RESULTS: Three live cloned female piglets carrying biallelic mutations in IL2RG were produced. All cloned piglets completely lacked thymus and they had a significantly reduced level of mature T, B and NK cells in their blood and spleen. CONCLUSIONS: Here, we generated IL2RG knockout female pigs showing phenotypic characterization of SCID. This IL2RG knockout female pigs will be a promising model for biomedical and translational research.
Asunto(s)
Subunidad gamma Común de Receptores de Interleucina/genética , Modelos Animales , Inmunodeficiencia Combinada Grave/veterinaria , Enfermedades de los Porcinos/genética , Alelos , Animales , Femenino , Técnicas de Inactivación de Genes , Ingeniería Genética , Subunidad gamma Común de Receptores de Interleucina/fisiología , Inmunodeficiencia Combinada Grave/genética , PorcinosRESUMEN
Pigs with severe combined immunodeficiency (SCID) are versatile animal models for human medical research because of their biological similarities to humans, suitable body size, and longevity for practical research. SCID pigs with defined mutation(s) can be an invaluable tool for research on porcine immunity. In this study, we produced RAG2-knockout pigs via somatic cell nuclear transfer and analyzed their phenotype. The V(D)J recombination processes were confirmed as being inactivated. They consistently lacked mature T and B cells but had substantial numbers of cells considered to be T- or B-cell progenitors as well as NK cells. They also lacked thymic medulla and lymphoid aggregations in the spleen, mesenteric lymph nodes, and ileal Peyer's patches. We showed more severe immunological defects in the RAG2 and IL2RG double-knockout pig through this study. Thus, SCID pigs could be promising animal models not only for translational medical research but also for immunological studies of pigs themselves.
Asunto(s)
Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Técnicas de Inactivación de Genes/veterinaria , Inmunodeficiencia Combinada Grave/veterinaria , Enfermedades de los Porcinos/genética , Enfermedades de los Porcinos/inmunología , Animales , Animales Modificados Genéticamente , Modelos Animales de Enfermedad , Femenino , Técnicas de Inactivación de Genes/métodos , Humanos , Subunidad gamma Común de Receptores de Interleucina/deficiencia , Subunidad gamma Común de Receptores de Interleucina/genética , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Células Progenitoras Linfoides/inmunología , Células Progenitoras Linfoides/patología , Tejido Linfoide/inmunología , Tejido Linfoide/patología , Masculino , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/inmunología , Sus scrofa , Porcinos , Enfermedades de los Porcinos/patologíaRESUMEN
We have identified Severe Combined Immunodeficiency (SCID) in a line of Yorkshire pigs at Iowa State University. These SCID pigs lack B-cells and T-cells, but possess Natural Killer (NK) cells. This SCID phenotype is caused by recessive mutations in the Artemis gene. Interestingly, two human tumor cell lines, PANC-1 and A375-SM, survived after injection into these SCID pigs, but, as we demonstrate here, these cells, as well as K562 tumor cells, can be lysed in vitro by NK cells from SCID and non-SCID pigs. NK cells from both SCID and non-SCID pigs required activation in vitro with either recombinant human IL-2 or the combination of recombinant porcine IL-12 and IL-18 to kill tumor targets. We also showed that SCID NK cells could be activated to produce perforin, and perforin production was greatly enhanced in NK cells from both SCID and non-SCID pigs after IL-2 cytokine treatment. While CD16+, CD172- NK cells constituted an average of only 4% in non-SCID pigs, NK cells averaged 27% of the peripheral blood mononuclear cell population in SCID pigs. We found no significant differences in killing activity per NK cell between SCID and non-SCID pigs. We conclude that survival of human cancer cells in these SCID pigs is not due to an intrinsic defect in NK cell killing ability.
Asunto(s)
Endonucleasas/genética , Inmunodeficiencia Combinada Grave/veterinaria , Sus scrofa/genética , Sus scrofa/inmunología , Enfermedades de los Porcinos/genética , Enfermedades de los Porcinos/inmunología , Animales , Línea Celular Tumoral , Citotoxicidad Inmunológica , Femenino , Genes Recesivos , Humanos , Células K562 , Células Asesinas Naturales/inmunología , Activación de Linfocitos , Masculino , Mutación , Trasplante de Neoplasias , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/inmunología , Porcinos , Trasplante HeterólogoRESUMEN
Severe combined immunodeficiency (SCID) is the result of a set of inherited genetic defects which render components of the immune response nonfunctional. In Arabian horses, Jack Russell terriers, and mice, the disorder is a consequence of the absence of T and B lymphocytes, while natural killer (NK) cell and other leukocyte populations remain intact. Preliminary analysis of a naturally acquired form of inherited SCID in a line of pigs showed several defects in the architecture and composition of secondary lymphoid organs. In this study, a quantitative assessment of lymphocyte populations in affected and normal littermates showed depleted T or B lymphocyte populations in affected pigs; however, NK cells and neutrophils were present in numbers comparable to unaffected littermates. The results indicate that the immune defect in pigs shares the same features as other SCID-affected species.
Asunto(s)
Linfocitos B/inmunología , Tejido Linfoide/inmunología , Inmunodeficiencia Combinada Grave/veterinaria , Enfermedades de los Porcinos/inmunología , Linfocitos T/inmunología , Animales , Histocitoquímica/veterinaria , Recuento de Linfocitos/veterinaria , Inmunodeficiencia Combinada Grave/sangre , Inmunodeficiencia Combinada Grave/inmunología , Porcinos , Enfermedades de los Porcinos/sangreAsunto(s)
Enfermedades de los Caballos/genética , Enfermedades de los Caballos/inmunología , Caballos/anatomía & histología , Caballos/genética , Inmunodeficiencia Combinada Grave/veterinaria , Animales , Cruzamiento/métodos , Genes Recesivos , Modelos Animales , Inmunodeficiencia Combinada Grave/genéticaRESUMEN
REASONS FOR PERFORMING STUDY: The carrier prevalence of severe combined immunodeficiency (SCID), lavender foal syndrome (LFS) and cerebellar abiotrophy (CA) in Arabian foals in South Africa was determined in order to quantify the potential impact of these conditions locally. Furthermore, the carrier prevalence of SCID prior to and following the introduction of a genetic test was compared to evaluate the effect of testing in the population. OBJECTIVES: To estimate the carrier prevalence of SCID, LFS and CA in registered purebred Arabians born in South Africa in the 2004/5 and 2009/10 foaling seasons and compare the changes in prevalence in these disorders between the 2 groups of foals. STUDY DESIGN: Cross-sectional survey. METHODS: Samples were collected from individuals randomly selected from 2 populations of purebred Arabian foals born during the 2004/5 and 2009/10 foaling seasons. Genetic testing for SCID, LFS and CA was performed on DNA extracts using specific polymerase chain reactions, with the products being analysed using fragment analysis on a genetic analyser. RESULTS: The carrier prevalence of LFS and CA for the 2009/10 season was 11.7% (95% confidence interval [CI] 7.6-17.0%) and 5.1% (95% CI 2.5-9.1%), respectively, with no statistically significant change in prevalence between the 2004/5 and 2009/10 foaling seasons. However, the carrier prevalence of SCID was found to have decreased significantly from 6.4% (95% CI 4.8-8.3%) in the 2004/5 foals to 3.4% (95% CI 2.2-5.1%) in the 2009/10 foals (P = 0.009). CONCLUSIONS: The results of this study indicate that genetic screening of Arabian horses for SCID may have played a role in significantly reducing the carrier prevalence within the breeding population and thereby reducing the birth of clinically affected individuals. This study provides an indication of the positive effect of genetic screening for specific conditions in horses.
Asunto(s)
Predisposición Genética a la Enfermedad , Enfermedades de los Caballos/genética , Inmunodeficiencia Combinada Grave/veterinaria , Animales , Heterocigoto , Enfermedades de los Caballos/epidemiología , Caballos , Masculino , Inmunodeficiencia Combinada Grave/epidemiología , Inmunodeficiencia Combinada Grave/genética , Sudáfrica/epidemiologíaRESUMEN
We develop a mathematical model for the interaction between two competing equine infectious anemia virus strains and neutralizing antibodies. We predict that elimination of one or both virus strains depends on the initial antibody levels, the strength of antibody mediated neutralization, and the persistence of antibody over time. We further show that the ability of a subdominant, neutralization resistant virus to dominate the infection transiently or permanently is dependent on the antibody-mediated neutralization effect. Finally, we determine conditions for persistence of both virus strains. We fit our models to virus titers from horses (foals) with severe combined immunodeficiency to estimate virus-host parameters and to validate analytical results.
Asunto(s)
Anemia Infecciosa Equina/virología , Caballos/virología , Interacciones Huésped-Patógeno , Virus de la Anemia Infecciosa Equina/fisiología , Inmunodeficiencia Combinada Grave/veterinaria , Inmunodeficiencia Combinada Grave/virología , Animales , Simulación por Computador , Modelos Biológicos , Mutación/genética , Análisis Numérico Asistido por Computador , ARN Viral/metabolismoRESUMEN
Theileria equi immune plasma was infused into young horses (foals) with severe combined immunodeficiency. Although all foals became infected following intravenous challenge with homologous T. equi merozoite stabilate, delayed time to peak parasitemia occurred. Protective effects were associated with a predominance of passively transferred merozoite-specific IgG3.
Asunto(s)
Anticuerpos Antiprotozoarios/administración & dosificación , Enfermedades de los Caballos/prevención & control , Inmunización Pasiva/métodos , Factores Inmunológicos/administración & dosificación , Inmunodeficiencia Combinada Grave/veterinaria , Theileriosis/prevención & control , Animales , Anticuerpos Antiprotozoarios/inmunología , Enfermedades de los Caballos/terapia , Caballos , Inmunoglobulina G/administración & dosificación , Inmunoglobulina G/inmunología , Factores Inmunológicos/inmunología , Merozoítos/inmunología , Parasitemia/prevención & control , Theileria/inmunología , Factores de TiempoAsunto(s)
Enfermedades de los Caballos/inmunología , Inmunodeficiencia Combinada Grave/veterinaria , Animales , Resultado Fatal , Femenino , Enfermedades de los Caballos/diagnóstico , Enfermedades de los Caballos/tratamiento farmacológico , Caballos , Linfopenia/diagnóstico , Linfopenia/tratamiento farmacológico , Linfopenia/inmunología , Linfopenia/veterinaria , Neumonía/diagnóstico , Neumonía/tratamiento farmacológico , Neumonía/inmunología , Neumonía/veterinaria , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/tratamiento farmacológico , Inmunodeficiencia Combinada Grave/inmunologíaRESUMEN
Using the equine infectious anemia virus (EIAV) lentivirus model system, we previously demonstrated protective effects of broadly neutralizing immune plasma in young horses (foals) with severe combined immunodeficiency (SCID). However, in vivo selection of a neutralization-resistant envelope variant occurred. Here, we determined the protective effects of purified immunoglobulin with more potent broadly neutralizing activity. Overall, protection correlated with the breadth and potency of neutralizing activity in vitro. Four of five SCID foals were completely protected against homologous challenge, while partial protection occurred following heterologous challenge. These results support the inclusion of broadly neutralizing antibodies in lentivirus control strategies.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anemia Infecciosa Equina/prevención & control , Enfermedades de los Caballos/prevención & control , Inmunoglobulinas/inmunología , Virus de la Anemia Infecciosa Equina/inmunología , Inmunodeficiencia Combinada Grave/veterinaria , Animales , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Antivirales/administración & dosificación , Anticuerpos Antivirales/inmunología , Anemia Infecciosa Equina/inmunología , Anemia Infecciosa Equina/virología , Enfermedades de los Caballos/inmunología , Enfermedades de los Caballos/virología , Caballos , Inmunoglobulinas/administración & dosificación , Inmunodeficiencia Combinada Grave/inmunología , Inmunodeficiencia Combinada Grave/virologíaRESUMEN
Molecular studies have provided convincing evidence that a unique deltaproteobacterium is the causative agent of epizootic bovine abortion (EBA). Bovine fetuses, infected following dam exposure, are the only identified susceptible mammalian host. The inability to cultivate the bacterial agent of EBA (aoEBA) in vitro, associated with the substantial cost of bovine experimentation, drove efforts to identify an alternative laboratory animal host. Mice with severe combined immunodeficiency (SCID) were chosen as a potential host after immunocompetent mice proved resistant to infection. SCID mice inoculated with aoEBA-infected bovine fetal thymus homogenates began to show clinical signs at 2 months and became increasingly cachectic over the next 1-2 months. Following a 2nd passage (P2) through SCID mice, three susceptible pregnant heifers were inoculated with P2 murine tissue homogenates. All three fetuses presented with lesions indistinguishable from naturally occurring EBA, confirming successful passage of the bacterial pathogen in SCID mice. All murine (P1 and P2) and bovine fetal tissues contained aoEBA as determined by PCR; 16S bacterial ribosomal nucleotide sequences were identical in all murine and fetal bovine tissues examined. Bacteria in fetal bovine tissues were determined to be heavily opsonized, based upon microscopic evaluation of tissues stained with either FITC-conjugated anti-bovine IgG or biotin-conjugated anti-bovine IgG in conjunction with avidin-FITC. Unlike the near-term bovine fetus, the absence of an antibody response in infected SCID mice permits harvest of unopsonized bacteria for development of serologic assays.
Asunto(s)
Aborto Veterinario/microbiología , Enfermedades de los Bovinos/microbiología , Inmunodeficiencia Combinada Grave/microbiología , Aborto Veterinario/inmunología , Aborto Veterinario/patología , Animales , Bovinos , Enfermedades de los Bovinos/patología , Criopreservación , Cartilla de ADN , Femenino , Enfermedades Fetales/microbiología , Enfermedades Fetales/veterinaria , Inmunoglobulinas/análisis , Insectos Vectores/virología , Riñón/inmunología , Riñón/patología , Hígado/inmunología , Hígado/patología , Pulmón/inmunología , Pulmón/patología , Ratones , Ratones Endogámicos C3H , Ratones SCID , Reacción en Cadena de la Polimerasa , Embarazo , Inmunodeficiencia Combinada Grave/inmunología , Inmunodeficiencia Combinada Grave/patología , Inmunodeficiencia Combinada Grave/veterinaria , Bazo/inmunología , Bazo/patología , Timo/inmunología , Timo/patologíaRESUMEN
Severe combined immunodeficiency disease (SCID) of horses is an autosomal, recessive hereditary disease occurring among Arabian or crossbred Arabian horses. The genetic defect responsible was previously identified as a 5-base pair deletion in the gene encoding the catalytic subunit of the DNA dependant protein kinase (DNA-PKcs). This study was carried out to determine the frequency of SCID and identify horses carrying the gene for SCID among Arabian and Arabian crossbred stallions and mares in Morocco using a DNA-based test. Twenty-one horses were SCID carriers: 14 (7%) Arabians, 6 (4%) Arab-Barbs and one (33%) Anglo-Arab. After analysing their genealogy, 3 imported stallions were identified that disseminated the mutant gene of DNA-PKcs in Morocco.
Asunto(s)
Cruzamiento , Frecuencia de los Genes/genética , Enfermedades de los Caballos/genética , Proteínas Serina-Treonina Quinasas/genética , Inmunodeficiencia Combinada Grave/veterinaria , Animales , Proteína Quinasa Activada por ADN , Femenino , Enfermedades de los Caballos/diagnóstico , Caballos , Masculino , Marruecos/epidemiología , Reacción en Cadena de la Polimerasa/veterinaria , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/genéticaRESUMEN
Immunodeficiencies are characterized as primary (genetic) or secondary (acquired). Primary immunodeficiencies are relatively uncommon; however, clinically, they present a significant challenge to the practitioner, especially if the underlying disorder goes unrecognized. Secondary immunodeficiencies may present at any age, but failure of passive transfer in neonatal foals is most commonly encountered. This article provides a general overview of clinical signs and diagnosis of primary and secondary immunodeficiencies currently recognized in horses.
Asunto(s)
Agammaglobulinemia/veterinaria , Enfermedades de los Caballos/inmunología , Inmunidad Materno-Adquirida , Síndromes de Inmunodeficiencia/veterinaria , Animales , Animales Lactantes/inmunología , Calostro/inmunología , Enfermedades de los Caballos/diagnóstico , Enfermedades de los Caballos/patología , Caballos , Inmunización Pasiva/veterinaria , Inmunoglobulina M/deficiencia , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/patología , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/inmunología , Inmunodeficiencia Combinada Grave/patología , Inmunodeficiencia Combinada Grave/veterinariaRESUMEN
Although CTL are important for control of lentiviruses, including equine infectious anemia virus (EIAV), it is not known if CTL can limit lentiviral replication in the absence of CD4 help and neutralizing antibody. Adoptive transfer of EIAV-specific CTL clones into severe combined immunodeficient (SCID) foals could resolve this issue, but it is not known whether exogenous IL-2 administration is sufficient to support the engraftment and proliferation of CTL clones infused into immunodeficient horses. To address this question we adoptively transferred EIAV Rev-specific CTL clones into four EIAV-challenged SCID foals, concurrent with low-dose aldesleukin (180,000U/m2), a modified recombinant human IL-2 (rhuIL-2) product. The dose was calculated based on the specific activity on equine PBMC in vitro, and resulted in plasma concentrations considered sufficient to saturate high affinity IL-2 receptors in humans. Despite specific activity on equine PBMC that was equivalent to recombinant equine IL-2 and another form of rhuIL-2, aldesleukin did not support the engraftment and expansion of infused CTL clones, and control of viral load and clinical disease did not occur. It was concluded that survival of Rev-specific CTL clones infused into EIAV-challenged SCID foals was not enhanced by aldesleukin at the doses used in this study, and that in vitro specific activity did not correlate with in vivo efficacy. Successful adoptive immunotherapy with CTL clones in immunodeficient horses will likely require higher doses of rhuIL-2, co-infusion of CD4+ T lymphocytes, or administration of equine IL-2.
Asunto(s)
Anemia Infecciosa Equina/inmunología , Anemia Infecciosa Equina/terapia , Inmunoterapia/veterinaria , Virus de la Anemia Infecciosa Equina/inmunología , Interleucina-2/administración & dosificación , Inmunodeficiencia Combinada Grave/veterinaria , Linfocitos T Citotóxicos/inmunología , Traslado Adoptivo/veterinaria , Animales , Animales Recién Nacidos , Temperatura Corporal/efectos de los fármacos , Temperatura Corporal/inmunología , Supervivencia Celular/inmunología , Anemia Infecciosa Equina/virología , Femenino , Caballos , Inmunoterapia/métodos , Inyecciones Subcutáneas/veterinaria , Interleucina-2/análogos & derivados , Masculino , ARN Viral/sangre , ARN Viral/genética , Proteínas Recombinantes/administración & dosificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/veterinaria , Inmunodeficiencia Combinada Grave/inmunología , Inmunodeficiencia Combinada Grave/virología , Linfocitos T Citotóxicos/virologíaRESUMEN
Canine X-linked severe combined immunodeficiency (XSCID) is due to mutations in the common gamma chain (gammac) gene and is identical clinically and immunologically to human XSCID, making it a true homologue of the human disease. Bone marrow-transplanted (BMT) XSCID dogs not only engraft donor T cells and reconstitute normal T-cell function but, in contrast to the majority of transplanted human XSCID patients, also engraft donor B cells and reconstitute normal humoral immune function. Shortly after our initial report of successful BMT of XSCID dogs, it soon became evident that transplanted XSCID dogs developed late-onset severe chronic cutaneous infections containing a newly described canine papillomavirus. This is analogous to the late-onset cutaneous papillomavirus infection recently described for human XSCID patients following BMT. Of 24 transplanted XSCID dogs followed for at least 1 year post-BMT, 71% developed chronic canine papillomavirus infection. Six of the transplanted dogs that developed cutaneous papillomas were maintained for >3 1/2 years post-BMT for use as breeders. Four of these six dogs (67%) developed invasive squamous cell carcinoma (SCC), with three of the dogs (75%) eventually developing metastatic SCC, an extremely rare consequence of SCC in the dog. This finding raises the question of whether SCC will develop in transplanted human XSCID patients later in life. Canine XSCID therefore provides an ideal animal model with which to study the role of the gammac-dependent signaling pathway in the response to papillomavirus infections and the progression of these viral infections to metastatic SCC.
Asunto(s)
Trasplante de Médula Ósea , Carcinoma de Células Escamosas/virología , Enfermedades de los Perros/virología , Enfermedades Genéticas Ligadas al Cromosoma X/virología , Infecciones por Papillomavirus , Inmunodeficiencia Combinada Grave/virología , Neoplasias Cutáneas/virología , Animales , Linfocitos B/patología , Linfocitos B/virología , Trasplante de Médula Ósea/efectos adversos , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/veterinaria , Enfermedad Crónica , Modelos Animales de Enfermedad , Enfermedades de los Perros/etiología , Enfermedades de los Perros/genética , Enfermedades de los Perros/patología , Perros , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Enfermedades Genéticas Ligadas al Cromosoma X/veterinaria , Humanos , Masculino , Metástasis de la Neoplasia/patología , Infecciones por Papillomavirus/etiología , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/veterinaria , Inmunodeficiencia Combinada Grave/complicaciones , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/patología , Inmunodeficiencia Combinada Grave/terapia , Inmunodeficiencia Combinada Grave/veterinaria , Transducción de Señal/genética , Neoplasias Cutáneas/patología , Linfocitos T/patología , Linfocitos T/virología , Factores de Tiempo , Trasplante HeterólogoRESUMEN
Gnotobiotic animals are highly valued for the study of infectious diseases wherein the clinical signs and lesions of disease can be directly related to host-pathogen interactions and not to the additive effects of environmental influences and other confounding factors. Gnotobiotic dogs have been used to study the pathogenesis of acquired immunodeficiencies associated with canine distemper virus (CDV). In recent years, the laboratory at OSU, in conjunction with University of Pennsylvania personnel have begun a series of long-term studies of dogs affected with the canine X chromosome-linked severe combined immunodeficiency (XSCID) syndrome. This fatal inherited defect is caused by mutation in the common gamma chain (IL2RG) gene and renders affected animals profoundly immunodeficient. XSCIDs dogs, raised within a gnotobiotic environment for up to 3 years remain clinically healthy and are, in every respect normal except for the persistent T-cell defect and the failure to develop lymph nodes. Bone marrow transplantation (unfractionated or enriched for CD34+ stem cells) is the treatment of choice for both the XSCID dogs and male human infants affected with this syndrome. In preliminary studies, we have shown that human CD34+ stem cells colonized XSCIDs-affected gnotobiotic dogs, migrated to the thymus and demonstrated post-thymic activation (CD45RA+ phenotype) in peripheral blood. While many issues are unresolved, these data suggest that, through the use of the gnotobiotic environment, xenotransplantation (human-to-dog) may yield a stable and immunologically functional human-dog chimera.
Asunto(s)
Vida Libre de Gérmenes/inmunología , Síndromes de Inmunodeficiencia/inmunología , Animales , Trasplante de Médula Ósea , Quimera/inmunología , Modelos Animales de Enfermedad , Enfermedades de los Perros/genética , Enfermedades de los Perros/inmunología , Enfermedades de los Perros/patología , Perros , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Enfermedades Genéticas Ligadas al Cromosoma X/veterinaria , Humanos , Síndromes de Inmunodeficiencia/patología , Síndromes de Inmunodeficiencia/terapia , Lactante , Masculino , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/inmunología , Inmunodeficiencia Combinada Grave/patología , Inmunodeficiencia Combinada Grave/veterinariaRESUMEN
This report describes the development and lesions of graft-versus-host disease (GVHD) in severe combined immunodeficiency/ beige (SCID/BG) mice after the administration of canine leukocytes. Intraperitoneal injections of 0.87 x 10(7) canine lymphocytes were given to each of 9 mice; 5 mice received no canine lymphocytes. Morphologic evidence of successful engraftment included peritoneal aggregates of lymphocytes and repopulation of spleen and lymph nodes by lymphocytes. Canine CD45R was expressed by 2.25% of peripheral blood leukocytes in the 1 mouse tested 65 d after engraftment but by none of the cells of a control mouse. Canine immunoglobulin G was detected in serum samples from 5 of the 6 tested mice given canine lymphocytes but none of the control mice. By 13 to 65 d after receiving canine lymphocytes, 5 of the 9 mice had died of GVHD or had been euthanized because of it; all the control mice remained healthy. Lesions of GVHD included hemolytic anemia, cholangiohepatitis, alveolitis, and disseminated intravascular coagulation. Serum from the donor dog and from all 15 randomly selected dogs caused agglutination of normal mouse erythrocytes, supporting a diagnosis of immune-mediated hemolytic anemia in the dog-mouse chimeras. All of the mouse serum tested contained murine immunoglobulin, and this "leakiness" may have contributed to the development of GVHD.