RESUMO
BACKGROUND: F1 hybrids of New Zealand Black (NZB) and New Zealand White (NZW) mice develop autoimmune glomerulonephritis resembling human lupus nephritis. Susceptibility to this complex autoimmune syndrome in humans and mice has been linked to genes mapping in or near the major histocompatibility complex that govern immune responses and levels of certain complement components. Previous studies showed that both parental strains contribute major histocompatibility complex-linked genes that are important for disease of the F1 hybrid. EXPERIMENTAL DESIGN: New inbred strains of New Zealand Mixed (NZM) mice were derived by selective inbreeding of progeny of a cross between NZB and NZW mice. Twelve of the 27 new NZM strains were selected for analysis. Mice were observed for up to 10 months of age to document the occurrence of nephritis and strain-specific differences in disease expression. H-2, Hc, and coat color loci were determined for each strain to establish homozygosity of NZB and NZW polymorphic markers. Strains were screened for the presence of anti-dsDNA autoantibodies. RESULTS: In some NZM strains early onset of lupus nephritis in females resembled the (NZB x NZW)F1 model, whereas in other strains early disease also occurred in males. Age at death and severity of nephritis vary among the lines; a few strains remain relatively free of glomerular lesions. Histocompatibility (H-2) typing showed that all strains are homozygous for the NZW haplotype (Ku, Au, Sz, Dz). Coat color analysis for four loci on chromosomes 2, 4, and 7 was consistent with specific reassortments and recombinations to explain the grey, tan, and white mice with red/pink eyes and the presence or absence of the fifth component of serum complement (C5) (Hc, chromosome 2). Anti-dsDNA autoantibodies were found in all but one of the NZM strains reported here. CONCLUSIONS: The NZM strains of mice are a unique set of inbred strains that have inherited various genomic segments of the two parental strains that lead to phenotypic differences in disease expression. These results indicate that the previously proposed strict requirement for H-2 heterozygosity for the development of nephritis in the (NZB x NZW)F1 hybrid mice may not be valid. It is assumed that both the Lpn-1 locus of NZB and the Lpn-2 locus of NZW and a sufficient number of other disease-associated genes of both ancestral strains have been recombined in these new strains to produce the various patterns of renal disease.
Assuntos
Homozigoto , Nefrite Lúpica/genética , Criação de Animais Domésticos , Animais , Anticorpos Antinucleares/análise , DNA/imunologia , Feminino , Marcadores Genéticos , Teste de Histocompatibilidade , Hibridização Genética , Glomérulos Renais/patologia , Nefrite Lúpica/patologia , Masculino , Camundongos , Camundongos Endogâmicos/genéticaRESUMO
(NZB x NZW)F1 hybrid (B/W) female mice were treated intermittently with dactinomycin beginning at 6--6.5 months of age. Survival was greatly prolonged relative to control mice. IgG antibody to DNA did not decline significantly in the treated mice until they were more than 18 months old, but circulating levels of the first complement component (Cl) rose during the first 4 weeks of treatment and were back into the normal range after 8 weeks. Thus these two humoral indexes of disease activity varied independently, and only Cl reflected the improved status of the treated mice.
Assuntos
Anticorpos Antinucleares/análise , Complemento C1/análise , DNA/imunologia , Dactinomicina/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Fatores Etários , Animais , Feminino , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Fatores de TempoAssuntos
Dactinomicina , Modelos Animais de Doenças , Esquema de Medicação , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Animais , Dactinomicina/administração & dosagem , Dactinomicina/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Doenças do Complexo Imune/tratamento farmacológico , Nefropatias/tratamento farmacológico , Camundongos , Camundongos Endogâmicos NZB , Proteinúria/complicaçõesAssuntos
Modelos Animais de Doenças , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Animais , Complexo Antígeno-Anticorpo , Dactinomicina/uso terapêutico , Feminino , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/veterinária , Propiltiouracila/uso terapêutico , Doenças dos Roedores/imunologia , Vincristina/uso terapêuticoRESUMO
Sera from periodic bleedings of B/W female mice were assayed for C1 hemolytic activity. It peaked at 3 to 4 months of age and declined to very low levels by 6 to 7 months. Activity remained low even in long-lived animals.
Assuntos
Complemento C1 , Animais , Feminino , Nefropatias/imunologia , Camundongos , Camundongos Endogâmicos NZB , Fatores de TempoRESUMO
Dactinomycin treatment a of group of (NZB X NZW)F1 hybrid female mice was delayed until the age of 6-6 1/2 months, by which time the immune complex disease was well established. Three animals of the original twenty-eight had already died, ten had heavy proteinuria and a few were oedematous. The dactinomycin dose was 3.5 microgram per day, which was suspended when significant weight loss occurred. Twelve of the thirteen experimental mice were alive at 12 months of age, eleven at 15 months, but only eight by 20 months, whereas all twelve control animals had died by the age of 11 months. These results and the supporting data on body weight and renal function indicate that dactinomycin can at least arrest the disease process and may improve it. The mechanism is not known, but it may be the result of a reduced availability of DNA or an alteration in its properties following combination with dactinomycin.
Assuntos
Dactinomicina/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Animais , Peso Corporal , Feminino , Lúpus Eritematoso Sistêmico/mortalidade , Camundongos , Camundongos Endogâmicos , Fatores de TempoRESUMO
Three groups of female (NZB X NZW)F1 hybrid mice were treated with an intermittent regimen of dactinomycin (actinomycin D), 3.5 microgram. daily. Median survival was doubled in two of the groups and increased by more than 75 per cent in the third. Most of the treated animals never had significant proteinuria. When kidneys from 14 treated mice, which died between the ages of 11 and 20 months, were examined by light and fluorescence microscopy, most showed the lesions of normal aged CBA and C57BL/6 mice, some expansion of the mesangial matrix and increased cellularity, consistent with deposition of immunoglobulins and complement components in the mesangium, generally sparing the capillary loops. Four of the 14 animals, three of them long-lived, had advanced renal glomerular disease. These data indicate that dactinomycin, by whatever therapeutic mechanism, permits very extended survival of B/W female mice, the large majority of them without significant renal disease.
Assuntos
Dactinomicina/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Animais , Complexo Antígeno-Anticorpo , Modelos Animais de Doenças , Imunofluorescência , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/mortalidade , Glomerulonefrite/patologia , Doenças do Complexo Imune/tratamento farmacológico , Doenças do Complexo Imune/mortalidade , Doenças do Complexo Imune/patologia , Lúpus Eritematoso Sistêmico/mortalidade , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Microscopia EletrônicaRESUMO
(NZB X NZW)F1 hybrid female mice were transfused fortnightly with 1 ml of packed buffy-coat-poor syngeneic erythrocytes, beginning at 3--4 months of age, in an effort to suppress erythropoiesis selectively and perhaps limit availabiliity of DNA for immune complex formation. The mean increase in survival was about 8 weeks (P less than 0-05). Repeatedly phlebotomized donor female mice tended to sicken earlier and die at younger ages. This is initial support for the hypothesis that erythroblast DNA may be involved in this SLE-like disease.
Assuntos
Transfusão de Sangue , Eritropoese , Camundongos Endogâmicos , Animais , Complexo Antígeno-Anticorpo , Feminino , Rim/patologia , Longevidade , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/terapia , Camundongos , Camundongos Endogâmicos NZBRESUMO
Antisera to human C4 can discriminate circulating Ss protein (C4) levels in mice. Since there has been no information on early complement components (C1, C4, C2) in the renal lesions of B/W mice, we applied the indirect immunofluorescence technique to post-mortem sections of kidney from B/W female mice with advanced renal disease. C4 was present in fifteen of the sixteen specimens, usually in a distribution similar to that of IgG or C3. Specificity was demonstrated by differential absorptions with high-Ss serum from C57BL/6 male mice and low-Ss serum from C3H/HeJ female mice. High-Ss-absorbed antiserum did not stain, while low-Ss-absorbed antibody retained much of its activity. This finding parallels the demonstration of early complement components in lesions of clinical lupus nephritis, and is consistent with classic complement pathway activation in B/W disease.
Assuntos
Complemento C4 , Proteínas do Sistema Complemento , Nefropatias/imunologia , Animais , Complemento C3/análise , Feminino , Imunoglobulina G/análise , Glomérulos Renais/imunologia , Camundongos , Camundongos Endogâmicos NZB , Camundongos EndogâmicosRESUMO
Skin biopsies were performed on female (NZB X NZW)F1 mice (B/W) at ages ranging from 1 to 12 months. The control strain was the C57B1/6. Immunoglobulin G and beta 1C globulin deposition was sought using the indirect immunofluorescence method. Both globulins were detected consistently at the dermal-epidermal junction from the age of 6 months. The pattern of staining was granular, and progressed from focal deposition to confluent and diffuse involvement of the basement membrane at 9-10 months of age. No staining was observed in any of the C57B1/6 mice up to 14 months of age. These findings increase the resemblance of B/W disease to human systemic lupus erythematosus.
Assuntos
Complexo Antígeno-Anticorpo , Modelos Animais de Doenças , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Pele/imunologia , Animais , Membrana Basal/imunologia , beta-Globulinas , Feminino , Imunofluorescência , Hibridização Genética , Imunoglobulina G , Camundongos Endogâmicos NZBRESUMO
The recently discovered association of adenosine deaminase (ADA) deficiency and combined immune deficiency (CID) has emphasized the critical role of purine salvage in the function of lymphoid tissue. Known enzymatic properties of ADA are presented. In addition, known phenotypic data and possible genetic mechanisms for the occurrence of ADA deficiency in CID are discussed. A hypothesis based on considerations of known metabolic pathways in human erythrocytes is proposed to account for the selectivity of ADA deficiency for lymphoid tissue. Finally, some inhibitors of ADA are discussed as well as some immunosuppressive agents.