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PubMed2004

Mouse model characterisation for anthrax vaccine development: comparison of one inbred and one outbred mouse strain.

In order to evaluate the immunogenicity and protective efficacy of anthrax vaccine candidates a suitable small animal model is required. The inbred A/J strain of mouse has been selected as a potential model, and its immune response to immunisation with recombinant protective antigen (rPA) vaccine characterised, by assessment of rPA specific antibody production, and protection against injected challenge, with the unencapsulated STI strain of Bacillus anthracis. Studies were conducted to determine the time required post immunisation to develop a protective immune response, to define the minimum protective dose of vaccine required and to assess the long-term immune response to immunisation. From the results of these studies it was possible to establish that the A/J mouse is a consistent and robust small animal model for rPA vaccine testing. A comparison of the immune response to rPA vaccine immunisation in the Turner Outbred (TO) mouse strain was also conducted. Both inbred and outbred mouse strains displayed a predominantly Th2 biased immune response and showed a comparable antibody response to rPA immunisation. An assessment of protection in the TO mouse against aerosol challenge with the fully virulent strain of B. anthracis, Ames, was also made.

Animals↗
PubMed1989

The C5-sufficient A/J congenic mouse strain. Inflammatory response and resistance to Listeria monocytogenes.

A/J mouse strain poorly responds to an inflammatory stimulus and is highly susceptible to Listeria monocytogenes (Lm) infection. This defect in the phagocyte inflammatory response caused by the C5 component of C deficiency was shown, by linkage analysis, to be the major reason for the extreme susceptibility of A/J mice to Lm infection. The importance of this genetic defect in C5 in relation to the poor macrophage inflammatory response and to the susceptibility to Lm infection was evaluated by developing a C5-sufficient congenic A/J mouse strain. This A/J.C5 mouse strain was studied for its inflammatory response and for its susceptibility to Lm infection. C5-sufficient congenic A/J.C5 mice showed a slight improvement (2X) in their level of macrophage inflammatory response; however, they did not mount an as strong response as the Listeria-resistant C57BL/6J mice which donated the C5 allele. When infected with Lm, A/J.C5 mice were found to be as resistant as C57BL/6J mice. These results suggest that the presence of C5 on an A/J background partially improves the deficient macrophage inflammatory response of that strain. This increase is sufficient to render the A/J.C5 mouse strain highly resistant to Listeria infection. A/J.C5 mouse strain represents a new tool for the study of the importance of C5 in resistance to infection and in the regulation of the macrophage inflammatory response.

Animals↗
PubMed2006

Genetic analysis of the diabetes-prone C57BLKS/J mouse strain reveals genetic contribution from multiple strains.

The C57BLKS/J (BKS) inbred mouse strain is a widely used animal model of type 2 diabetes. In the presence of the diabetes (db) mutation, obese BKS-db mice develop severe diabetes. Genetic studies of diabetes-susceptibility in this strain are facilitated by the fact that BKS is a genetic composite between the diabetes-resistant C57BL/6J (B6) and susceptible DBA/2J (DBA) strains. On this basis, it has been hypothesized that diabetes-susceptibility in BKS is conferred by DBA-derived alleles. However, recent studies revealed non-B6/non-DBA genetic material in BKS. To identify the origin of this genetic component, we generated a genomic map of BKS using 537 microsatellite markers. Our results demonstrate that, in addition to B6 and DBA, BKS contains alleles from at least three other strains, including 129, C57BL/10 and an unidentified mouse strain. We also analyzed two congenic strains, B6-db and BKS-db, which are widely used for the genetic mapping of diabetes-susceptibility loci. We identified several donor-derived genomic regions introduced during the generation of these congenic strains. In summary, our study reveals novel aspects of the genetic fine-structure of BKS and related strains and facilitates the identification of diabetes-susceptibility loci in this mouse model.

Alleles↗
PubMed1993

Mouse strain differences in susceptibility to cerebral ischemia are related to cerebral vascular anatomy.

The consequences of cerebral ischemia were studied in three different strains (BDF, CFW, and BALB/C) of mice. The different strains exhibited significant differences in susceptibility to 24-h focal ischemia. Following middle cerebral artery occlusion (MCAO), infarct volumes (mm3) were 5 +/- 3 in BDF, 15 +/- 5 in CFW, and 23 +/- 3 in BALB/C mice (p < 0.05). MCAO plus ipsilateral common carotid artery occlusion (CCAO) resulted in infarct volumes of 15 +/- 9 in BDF, 38 +/- 10 in CFW, and 72 +/- 12 in BALB/C mice (p < 0.05). In addition, MCAO plus CCAO produced death by 24 h in 42% of CFW and 67% of BALB/C mice, but not in any BDF mice (p < 0.05). CCAO alone produced multifocal hemispheric infarctions in 36% of BALB/C mice but not in the other two strains. Brains of all mouse strains subjected to sham surgery were free of any ischemic injury. Arterial blood pressures, blood gases, and blood cell profiles were relatively similar for the three mouse strains. However, carbon black studies of the cerebrovascular anatomy revealed an incomplete circle of Willis (i.e., a significant decrease in the frequency of patent posterior communicating arteries) for BALB/C compared with BDF mice (p < 0.05), with CFW mice being intermediary. Based on these anatomical data, BALB/C mice also were evaluated following transient global brain ischemia produced by bilateral CCAO. BALB/C mice exhibited a > 85% reduction in cortical microvascular perfusion and EEG power within 1 min of bilateral CCAO. Also, hippocampal neuronal CA1 damage and mortality over 7 days were related to the duration of global brain ischemia (p < 0.05). These data demonstrate a significant difference between mouse strains in their sensitivity to cerebral ischemia that appears to be related, at least in part, to the functional vascular anatomy at the level of the posterior communicating arteries. In particular, we point out the potential usefulness of BALB/C mice as a sensitive and reproducible model of focal and global ischemia.

Animals↗
PubMed2006

Comparison of seizure phenotype and neurodegeneration induced by systemic kainic acid in inbred, outbred, and hybrid mouse strains.

We assessed inbred, outbred and hybrid mouse strains for susceptibility to seizures and neurodegeneration induced by systemic administration of kainic acid (KA). Each strain showed a unique pattern of susceptibility to seizures as assessed by the dose necessary to induce continuous tonic clonic seizures, progression through six seizure levels, the number of mice that failed to satisfy seizure criteria, and seizure-induced mortality. In general, the C57BL/6, ICR, FVB/N, and BALB/c strains were resistant to seizures while the C57BL/10, DBA/2 J, and F1 C57BL/6*CBA/J strains were vulnerable. Neuronal cell death was quantified in four subfields of the hippocampus: CA3, the hilus of the dentate gyrus, CA1, and the dentate granule cell layer. Neurodegeneration was also semiquantitatively assessed in other brain regions including the neocortex, striatum, thalamus, hypothalamus and amygdala. Although there was variability in the extent of cell death within strains, there were significant differences in the amount of hippocampal cell death between strains and also different patterns of neurodegeneration in affected brain areas. In general, the C57BL/6, C57BL/10, and F1 C57BL/6*CBA/J strains were resistant to neurodegeneration while the FVB/N, ICR and DBA/2 J strains were vulnerable. The BALB/c strain was unique in that neurodegeneration was confined to the hippocampus. Consistent with previous findings, the resistant neurodegeneration phenotype was dominant in an F1 cross of resistant and vulnerable inbred strains. Our results, using a large number of mouse strains, definitively demonstrate that a mouse strain's seizure phenotype is not related to its neurodegeneration phenotype.

Animals↗
PubMed1991

Experimental Borrelia burgdorferi infection in inbred mouse strains: antibody response and association of H-2 genes with resistance and susceptibility to development of arthritis.

We have investigated the specific humoral immune response and its correlation to the development of disease after experimental inoculation of B. burgdorferi in different inbred strains of mice. All mouse strains tested showed high levels of specific IgM antibodies during the initial 10 days of infection. Specific IgG antibodies predominantly of the IgG2a, IgG2b and IgG3 isotypes were found in increasing amounts by 14 days post infection. Antibody titers peaked at days 65 and 110. Particularly low titers of specific IgM and/or IgG antibodies were detected in sera of AKR/N and B10.BR mice. Antibodies specific for numerous B. burgdorferi antigens including the outer surface proteins A (31 kDa) and B (34 kDa) and a protein(s) of molecular mass of approximately 40 kDa, most probably 41 kDa (flagellin) and/or 39 kDa (p39), were induced in all inbred mouse strains within 2 weeks inoculation albeit in varying concentrations. Later during infection, the patterns of antibody specificities were much more complex. With regard to development of disease all strains of mice tested fall into three groups: (a) mice of H-2k haplotype (AKR/N, C3H/HeJ, C3H/HeN, B10.BR) developed a chronic progressive arthritis in the tibiotarsal joints, (b) mice of H-2 haplotypes, H-2b (C57BL/6), H-2j (B10.WB), H-2r (B10.R111) and H-2s (B10.S) developed arthritis of variable duration and intensity which was not progressive and (c) mice of H-2d haplotype (BALB/c, DBA/2, C.B-17, B10.D2, Cal.20), irrespective of their background genes or Igh allotype, showed no clinical signs of arthritis at any time point following inoculation of B. burgdorferi organisms. The finding of similar patterns of apparently protective antibodies in all mouse strains tested together with the striking association between the H-2d haplotype and resistance, and between the H-2k haplotype and the occurrence of B. burgdorferi-induced arthritis suggest a critical role of T cells in the development of the disease in mice.

Animals↗
PubMed1985

Characterization and chromosomal distribution of endogenous mouse mammary tumor viruses of European mouse strains STS/A and GR/A.

The endogenous mouse mammary tumor virus (MMTV) proviral copies in two genetically dissimilar mouse strains, STS/A, a European mouse strain, and BALB/c, were characterized. STS/A carries the same four MMTV proviral copies as GR.Mtv-2-; these strains share also most of the isoenzyme markers and are therefore highly related. Cellular DNA of GR.Mtv-2- contains a partial MMTV provirus that is not present in STS/A. GR.Mtv-2- is derived from GR; they differ in the locus Mtv-2 that contains one MMTV provirus. Expression of this Mtv-2 endogenous MMTV provirus is directly linked to mammary tumorigenesis in GR. MMTV proviral loci were studied using restriction enzyme analysis and the Southern transfer procedure using liver DNAs from recombinant inbred strains between BALB/c and STS/A. All segregating MMTV-specific EcoRI fragments were identified to MMTV proviral loci and most of these were localized by studying the cosegregation of the Mtv units and known chromosomal markers. Since STS/A, GR.Mtv-2-, and GR are highly related, the five complete endogenous MMTV proviruses of GR were located on the following chromosomes: Mtv-2 on chromosome 18, Mtv-3 on 11, Mtv-19 on 1, Mtv-20 on 4, whereas Mtv-8 has tentatively been located on chromosome 18 by Callahan et al. (R. Callahan, D. Gallahan, and Ch. Kozak (1984), J. Virol. 49, 1005-1008). GR and GR.Mtv-2 furthermore contain two incomplete MMTV proviral elements, one of which is also present in STS/A.

Animals↗
PubMed2006

Genetic variation in resistance to repeated infections with Heligmosomoides polygyrus bakeri, in inbred mouse strains selected for the mouse genome project.

Since the publication of the mouse genome, attention has focused on the strains that were selected for sequencing. In this paper we report the results of experiments that characterized the response to infection with the murine gastrointestinal nematode Heligmosomoides polygyrus of eight new strains (A/J, C57BL/6, C3H, DBA/2, BALB/c, NIH, SJL and 129/J), in addition to the well-characterized CBA (poor responder) and SWR (strong responder) as our controls. We employed the repeated infection protocol (consisting of 7 superimposed doses of 125L3 each administered at weekly intervals, faecal egg counts in weeks 2, 4 and 6 and assessment of worm burdens in week 6) that was used successfully to identify quantitative trait loci for genes involved in resistance to H. polygyrus. SWR, SJL and NIH mice performed indistinguishably and are confirmed as strong responder strains to H. polygyrus. CBA, C3H and A/J mice all tolerated heavy infections and are assessed as poor responders. In contrast, DBA/2, 129/J and BALB/c mice performed variably between experiments, some tolerating heavy worm burdens comparable to those in poor responders, and some showing evidence of resistance, although only in one experiment with female 129/J females and one with female BALB/c was the pattern and extent of worm loss much like that in SWR mice. Because the genetic relationships between six of the strains exploited in this study are now well-understood, our results should enable analysis through single nucleotide polymorphisms and thereby provide more insight into the role of the genes that control resistance to H. polygyrus.

Animals↗
PubMed2004

Bone intrinsic material properties in three inbred mouse strains.

This study assessed genetically based differences in intrinsic material properties of both cortical and cancellous bone in adult females of three inbred mouse strains [C57BL/6J (B6), DBA/2J (D2), C3H/HeJ (C3)]. These mouse strains have previously been shown to differ in bone mineral content (BMC) and density (BMD). Distal femoral cancellous bone and midshaft cortical bone in femurs and tibias were assessed for intrinsic material properties using nanoindentation technique. The intrinsic material properties tested were modulus (E(b)) and hardness (H) of the midshaft femoral and tibial cortical bone cross sections and of cancellous bone in the distal femur. Both femoral and tibial cortical bone intrinsic material properties were different among the three inbred mouse strains. Femoral modulus and tibial hardness in cortical bone and hardness in cancellous bone were either greatest or showed greater trends in C3 mice as compared to both D2 and B6. Cancellous bone modulus was similar among the three mouse strains. With the exception of the D2 mice, the femoral and tibial cortical modulus were similar within each mouse strain. The tibial cortical modulus was smaller than the femoral cortical modulus for D2 mouse strain. The cortical hardness was greater in tibiae compared with that in femora within each mouse strain. The nanoindentation data suggest that cortical and cancellous intrinsic material properties are influenced by the genetic background of the inbred mouse strains. The inbred mouse strain-related intrinsic material property phenotype can be used to locate responsible quantitative trait loci (QTLs) in future studies of recombinant inbred mouse strains.

Animals↗
PubMed2004

[Analyzing genetic quality of BALB/c mouse strains in China by microsatellite marking].

Eleven BALB/c mouse strains of Beijing, Shanghai, Shenyang, Haerbin, Guangzhou, Chongqing and Changchun were monitored in order to assure the genetic quality of inbred BALB/c mouse strains in China and to estimate the credibility of microsatllite markers. Fourteen microsatellites loci on different chromosomes were investigated by PCR analysis. It showed that all these microsatellites DNA loci displayed single allelic gene band in mouse strains of Beijing, Shanghai and Haerbin. But the mice came from Shenyang, Guangzhou, Chongqing and Changchun had polymorphisms or heterozygosis, among which the Shenyang and Changchun strains showed polymorphisms and heterozygosis at two separate loci. Four loci showed polymorphisms or heterozygosis in one of the Guangzhou mouse strains. The Chongqing strains showed polymorphisms and heterozygosis at seven loci, including the D10Mit180 locus as compared with the Shanghai strains.

Alleles↗
PubMed1997

Primary human immunodeficiency virus type 1 viremia and central nervous system invasion in a novel hu-PBL-immunodeficient mouse strain.

We established four new mouse strains with defective T and B cells as well as defects in innate immunological reactions using an NK cell depletion antibody and showed that all mutant mouse strains efficiently received human peripheral blood leukocyte (PBL) engraftment (hu-PBL-scid mice). Higher levels of human immunodeficiency virus type 1 (HIV-1) replication were observed in these new hu-PBL-scid mice than in conventional hu-PBL-C.B-17-scid mice. In one particular strain, hu-PBL-NOD-scid mice, high levels of HIV-1 viremia (more than 10(6) 50% infectious doses per ml) were detected after infection with HIV-1. The plasma viral load was about 100 to 1,000 times higher than that observed in other hu-PBL-scid mice infected with HIV-1. Although high-level viremia did not correlate with the total amount of HIV-1 RNA in cells from infected mice, high levels of free virions were detected only in hu-PBL-NOD-scid mice. HIV-1 viremia induced systemic HIV-1 infection involving the liver, lungs, and brain. PCR in situ hybridization confirmed that HIV-1-infected cells invaded the brain tissue of the hu-PBL-NOD-scid mice. Our results suggest that the genetic background, including innate immunity, is critical in the development of primary HIV-1 viremia and subsequent central nervous system invasion with HIV-1. The hu-PBL-NOD-scid mouse represents a useful model for the study of the pathogenesis of HIV-1 in vivo, especially brain involvement, and therapy of primary HIV-1 viremia.

Animals↗
PubMed1989

Comparison of immune responses to diphtheria and tetanus toxoids of various mouse strains.

Immune responses of 11 mouse strains with known genetical characteristics and two outbred strains to diphtheria and to tetanus toxoids were compared. Both diphtheria and tetanus antitoxins were titrated by passive hemagglutination. From the pattern of the immune response, the mouse strains tested may be classified into four groups. [1] Strains ddY (SPF) and ddY (conv) and those with haplotype H-2b, such as C57BL/6 and C57BL/10, were high responders to both toxoids. [2] Strains with H-2d, such as BALB/c, B10.D2 and DBA/2Cr, were intermediate responders to both toxoids. [3] Strains with H-2k, H-2a or, H-2m, such as C3H/He, B10.BR, B10.BR/SgSn, B10.A/SgSnJ and B10.AKM/O1a, were high responders to diphtheria toxoid but low responders to tetanus toxoid. [4] The strain with H-2h4, B10.A (4R), was a poor responder to both toxoids.

Animals↗
PubMed2004

Dysregulated inflammatory response to Candida albicans in a C5-deficient mouse strain.

Experimental infection of inbred mouse strains with Candida albicans provides a good model system to identify host genetic determinants that regulate onset of, response to, and ultimate outcome of disseminated candidiasis. The A/J mouse strain is exquisitely sensitive to infection with C. albicans, while the C57BL/6J strain is relatively resistant, as measured by survival following intravenous injection of Candida blastospores. This differential susceptibility is caused by an A/J-specific loss-of-function mutation in the C5 component of the complement pathway. C5 plays several critical roles in host response to infection, including target lysis and phagocyte recruitment. Therefore, to determine which of its functions were required for host resistance to candidiasis, a detailed comparative analysis of pathophysiology and host response to acute C. albicans infection was conducted in A/J and C57BL/6J mice. C5-sufficient C57BL/6J mice were found to succumb late in infection due to severe kidney pathology, typified by fungal replication and robust neutrophil-based inflammatory response associated with extensive tissue damage. In contrast, A/J mice were moribund within 24 h postinfection but displayed little if any kidney damage despite an inability to mobilize granulocytes and a high fungal load in the kidney. Rather, C5 deficiency in A/J mice was associated with higher levels of circulating cytokines tumor necrosis factor alpha, interleukin-6, monocyte chemotactic protein 1 (MCP-1), MCP-5, and eotaxin in response to C. albicans. Transfer of the C5-defective allele from A/J onto a C57BL/6J genetic background in recombinant congenic strain BcA17 recapitulated the phenotypic aspects of the susceptibility of A/J mice to C. albicans, confirming the causative role of C5 deficiency in the dysregulated cytokine response.

Animals↗
PubMed1989

Age-related changes in contact photosensitivity differ among mouse strains.

There are differences among mouse strains in the age-related changes in reactivity to the contact photosensitizer tetrachlorosalicylanilide (TCSA). We found a tendency to lower reactions in older mice, with some strains showing declines from an early age (BALB/cJ, MRL/MpJ +/+, MRL/MpJ lpr/lpr and SJL/J). Others had increasing reactions until about 30-50 weeks of age before declining (DBA/1J, C3H/HeJ, and A/J) and one strain (C57BL/6J) had increased reactivity with age. There are also differences in the role of cyclophosphamide-sensitive T-suppressor cells in these age-related changes. In some mouse strains, BALB/cJ, C57BL/6J, A/J, DBA/1J and C3H/HeJ, age-related changes in reactivity to TCSA are independent of changes in cyclophosphamide-sensitive suppressor cells. In other strains, MRL/MpJ +/+, MRL/MpJ lpr/lpr and SJL/J, the development of cyclophosphamide-sensitive suppressor cells is responsible for the initial, though not later, stages of the age-related decline in reactivity.

Aging↗
PubMed2003

Oocyte activation after intracytoplasmic injection with sperm frozen without cryoprotectants results in live offspring from inbred and hybrid mouse strains.

Re-establishment of mouse strains used for mutagenesis and transgenesis has been hindered by difficulties in freezing sperm. The use of intracytoplasmic sperm injection (ICSI) enables the production of embryos for the restoration of mouse lines using sperm with reduced quality. By using ICSI, simplified sperm-freezing methods such as snap freezing can be explored. We examined the capacity of embryos from the inbred C57Bl/6J and 129Sv/ImJ mouse strains, commonly used for transgenic and N-ethyl-N-nitrosourea mutagenesis purposes to develop to blastocysts in vitro and to term following ICSI with sperm frozen without cryoprotectant. The results were compared to F1 (C57BlxCBA) hybrid embryos. Following freezing, sperm were immotile but could fertilize oocytes at similar rates to fresh sperm. However, embryo development in vitro to the blastocyst stage was reduced in all three strains. No pups were born from C57Bl/6J or 129Sv/ImJ embryos obtained from frozen sperm following transfer to foster females, and only a limited number of F1 embryos developed to term. Activation of oocytes injected with frozen sperm with 1.7 mM Sr2+ (SrCl2) did result in the birth of pups in all three strains. We conclude that the inability of sperm frozen without cryoprotectants to effectively activate oocytes may affect embryo development to term and can be overcome by strontium activation. This may become an effective strategy for sperm preservation and the restoration of most popular strains used for genetic modifications.

Animals↗
PubMed2002

Production of a recombinant version of a Heligmosomoides polygyrus antigen that is preferentially recognized by resistant mouse strains.

Protective immunity to the mouse nematode parasite, Heligmosomoides polygyrus, has been characterized and found to be composed of the Th2 type. However, many inbred mouse strains cannot produce this protective immune response during a primary infection. A possible reason for this lack of protection in poor responding strains could be due to lack of recognition of specific protective antigens by these strains. Recently, evidence suggests that specific antigens exist that are only recognized by fast responding strains during a primary infection. Using monoclonal antibodies to screen an H. polygyrus cDNA library enabled the production of a recombinant protein, 3A4, which is antigenically similar to those found in the excretory/secretory antigens (E/S) of both L4 and adult parasites. Protein 3A4 shares approximately 70% sequence homology with an E/S protein that induces protection to Trichostrongylus colubriformis in guinea-pigs. Antibodies that bind to 3A4 are preferentially produced in SWR compared to BALB/c mice following immunization with L4 homogenate, although both strains of mice were able to produce comparable levels of specific antibodies after immunization with 3A4 protein. It is believed that 3A4 may have considerable importance in dissecting out the nature of the immune response to H. polygyrus infection, particularly in mouse strains of differing response phenotype.

Amino Acid Sequence↗
PubMed1982

Skin carcinogenesis and promoter binding characteristics in different mouse strains.

The sensitivity of various mouse strains to skin carcinogenesis has been investigated in two ways; (i) by comparing carcinogenesis induced by treatments involving both the application of tumour promoters and the application of single or multiple doses of a carcinogen, and (ii) by comparing the binding characteristics of the tumour promoter [3H]phorbol-12,13-dibutyrate to particulate skin preparations. The mouse strains tested were Swiss albino, Balb/c, C3H, LACA and AKR/J. Although some differences were apparent, Swiss albino, LACA and C3H mice were generally sensitive to skin carcinogenesis by both benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene, either with or without promotion with croton oil. AKR/J mice were sensitive to both carcinogens with promotion but relatively insensitive in the absence of promotion. Balb/c mice had low sensitivity except when exposed to repeated low doses of benzo[a]pyrene. The [3H]phorbol-12,13-dibutyrate binding characteristics of particulate skin preparations from all strains were indistinguishable.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2003

Enhanced susceptibility to end-organ disease in the lupus-facilitating NZW mouse strain.

OBJECTIVE: Although the NZW mouse strain is phenotypically normal, fulminant lupus glomerulonephritis (GN) develops when NZW mice are bred to several other strains, such as NZB, BXSB, B6.Sle1, and B6.Yaa. Based on the observation that aging NZW mice exhibit histologic evidence of GN, we sought to test our hypothesis that NZW mice may be more susceptible to immune-mediated renal damage. METHODS: NZW mice, as well as C57BL/6 (B6) and BALB/c control mice, were challenged with rabbit anti-glomerular basement membrane nephrotoxic sera (NTS), to induce renal disease. The different mouse strains were monitored for the degree of clinical disease, renal pathology, chemokine profiles, and cellular infiltrates. RESULTS: Although the NZW and control strains showed similar glomerular deposits of rabbit Ig and exhibited similar levels of anti-rabbit xenogeneic immune response, the NZW mice had significantly worse pathologic changes and disease. Compared with the control strains, the NTS-injected NZW mice demonstrated significantly increased proteinuria, elevated blood urea nitrogen levels, more severe histologic GN and tubulointerstitial nephritis, increased glomerular crescent formation with macrophage and neutrophil infiltrates, elevated expression of CC and CXC chemokines (monocyte chemoattractant protein 1, RANTES, KC), and significantly accelerated mortality. Importantly, these changes occurred within a few days after NTS administration. Finally, (B6 x NZW)F(1) mice were as susceptible as the NZW parents, which indicates dominant NZW contributions. CONCLUSION: Collectively, these findings support the notion that a lupus-facilitating genome may contribute to disease susceptibility by modulating the degree of immune-mediated end-organ damage. The availability of B6-based congenic strains bearing individual NZW-derived lupus susceptibility loci will permit future genetic dissection of end-organ susceptibility in murine lupus.

Animals↗