Interstrain differences in mice in developing migration inhibition factors to Candida albicans antigens

The authors studied the time course of MIF production by lymphocytes of CBA (H-2k), C57BL/6J (H-2b) and (CBA X C57BL/6J) F1 (H-2b/H-2k) mice sensitized to Candida albicans antigens. The interstrain differences in lymphokin production were identified, CBA mice appeared to be highly responsive, whereas C57BL/6J to be low-responsive. Partial hybridological analysis made it possible to ascertain the presence of the dominant type heredity of high MIF production in response to Candida albicans antigens.     

Genetic regulation of early survival and cyst number after peroral Toxoplasma gondii infection of A x B/B x A recombinant inbred and B10 congenic mice

Genetics of two traits, survival and brain cyst number after peroral Toxoplasma gondii infection, were studied by using recombinant inbred strains of mice derived from resistant A/J (A) and susceptible C57BL/6J (B) progenitors, F1 progeny of crosses between A/J and C57BL/6J mice, and congenic mice (B10 background). Analysis of strain distribution pattern of survival of A x B/B x A recombinant mice indicated that survival is regulated by a minimum of five genes. One of these genes appears to be linked to the H-2 complex and another is related to an as yet unmapped gene controlling resistance to Ectromelia virus. Associations of defined traits with resistance or susceptibility to Toxoplasma cyst formation were also analyzed. Cyst number is regulated by a locus on chromosome 17 within 0 to 4 centimorgans of the H-2 complex (p = 0.001). Mice with the H-2a haplotype are resistant and those with the H-2b haplotype are susceptible. This analysis also indicated that the Bcg locus on chromosome 1 may effect cyst number (map distance = 12 centimorgans, p = 0.05). Resistance to cyst formation is a dominant trait. To analyze relative roles of H-2 and Bcg loci on cyst numbers, C57BL10 (B10)-derived congenic strains of mice with known H-2 and Bcg type were studied. These studies indicated that the H-2 complex locus has the primary effect on cyst number.     

Chromosomal locations and gonadal dependence of genes that mediate resistance to ectromelia (mousepox) virus-induced mortality.

Four genetic loci were tested for linkage with loci that control genetic resistance to lethal ectromelia virus infection in mice. Three of the loci were selected because of concordance with genotypes assigned to recombinant inbred (RI) strains of mice derived from resistant C57BL/6 and susceptible DBA/2 (BXD) mice on the basis of their responses to challenge infection. Thirty-six of 167 male (C57BL/6 x DBA/2)F1 x DBA/2 backcross (BC) mice died (22%), of which 27 (75%) were homozygous for DBA/2 alleles at Hc and H-2D. Twenty-eight percent of sham-castrated and 6% of sham-ovariectomized BC mice were susceptible to lethal mousepox, whereas 50% of gonadectomized mice were susceptible. There was no linkage evident between Hc or H-2D and loci that controlled resistance to lethal ectromelia virus infection in 44 castrated BC mice. Mortality among female mice of BXD RI strains with susceptible or intermediate male phenotypes was strongly correlated (r = 0.834) with male mortality. Gonadectomized C57BL/6 mice were as resistant as intact mice to lethal ectromelia virus infection. These results indicate that two gonad-dependent genes on chromosomes 2 and 17 and one gonad-independent gene control resistance to mousepox virus infection, that males and females share gonad-dependent genes, and that the gonad-independent gene is fully protective.     

Retention of a memory trace of learning induced by a new and extinctive stimulus in C57BL/6J and BALB/c mice

Influence of preliminary habituation to the experimental box on passive avoidance learning was studied in mice of C57BL/6J and BALB/c strains. The 20-fold preexposure of mice to the environmental stimulus inhibited the acquisition and consequent retention of a memory trace in BALB/c mice and did not affect the acquisition in C57BL/6J mice. Subsequent retention in this strain was facilitated. The interstrain differences are discussed with respect to detected genetically determined types of behavior and exstinctive inhibition at the habituation stage.     

Role of interferon in the pathogenesis of viral diseases of mice as demonstrated by the use of anti-interferon serum. V. Protective role in mouse hepatitis virus type 3 infection of susceptible and resistant strains of mice

Potent sheep anti-mouse interferon globulin has been used to determine the role of virus-induced interferon in mouse hepatitis virus type 3-infected susceptible (C57BL/6), semiresistant (C3H/He), and resistant (A/J) strains of mice. Injection of anti-interferon globulin accelerated the onset of death in C57BL/6 mice, induced almost 100% mortality in C3H/He mice that usually do not die of acute disease, and caused death in 4- and 6-week-old A/J mice, but not in older mice. We conclude that interferon is an important host defense factor in the initial response of different strains of mice to MHV-3 infection. Other factors, however, such as the capacity of macrophages to restrict viral multiplication probably underlie the genetically determined susceptibility or resistance of mice to MHV-3 infection.     

Kinetics of ectromelia virus (mousepox) transmission and clinical response in C57BL/6j, BALB/cByj and AKR/J inbred mice

Research was undertaken to answer basic questions on susceptibility, clinical response and transmission of ectromelia virus in selected strains of inbred mice. C57BL/6J and AKR/J were found to be markedly more resistant to a virulent strain of ectromelia virus (isolated during the 1979-80 outbreak at the National Institutes of Health) than C57LJ, BALB/cByJ, DBA/2J, A.By/SNJ and C3H/HeJ when infected by footpad inoculation. In C57BL/6J and AKR/J the LD50 was about 7 logs higher than the ID50. With one exception, C57LJ, the LD50 and ID50 titers in the other strains were about equal. In C57LJ the LD50 titer was intermediate. Following intragastric inoculation, virus was isolated from feces of C57BL/6J mice for as long as 46 days and up to 29 days from BALB/cByJ mice. Transmission to cage mates from intragastrically infected C57BL/6J and BALB/cByJ occurred up to 36 and 30 days respectively after infection. Virus was isolated from the spleen in 2 of 5 BALB/cByJ mice and 1 of 7 C57BL/6J mice tested 95 days after gastric inoculation. Following footpad inoculation, BALB/cByJ mice consistently transmitted virus to cage mates before death at 10-12 days. C57BL/6J mice transmitted between days 8 and 17, but not beyond. Virus was maintained in C57BL/6J mice by exposure to infected cage mates for seven passages, which was the most attempted. Clinical signs in infected C57BL/6J mice were usually subtle or inapparent.     

Susceptibility to a mouse acquired immunodeficiency syndrome is influenced by theH-2

The development of a mouse acquired immunodeficiency syndrome (MAIDS) induced following LP-BM5 MuLV infection depends on host genetic factors. Susceptible mice, such as C57BL/6J mice, develop a profound impairment of lymphoproliferative response to mitogens and hyperplasia of lymphoid organs and succumb to infection within 6 months. These changes do not occur in resistant mice, such as A/J mice. Resistance to MAIDS is a dominant trait since (C57BL/6JxA/J)F₁ hybrid mice did not develop any immune dysfunctions following infection. Genetic regulation of the trait of resistance/susceptibility to MAIDS was determined in AXB/BXA recombinant inbred (RI) mouse strains (derived from resistant A/J and susceptible C57BL/6J progenitors). Two different criteria were used to determine their resistance or susceptibility to developing MAIDS: the gross pathologic evaluation of lymphoid organs at 13–15 weeks of infection, and survival. RI mouse strains segregated into two non-overlapping groups. The first group did not develop any significant pathology, and these mouse strains were considered as resistant to MAIDS. The second group showed the virus-induced pathological changes as well as an immunological dysfunction as seen in C57BL/6J progenitor mice, and these strains were thus considered as susceptible to MAIDS. This bimodal strain distribution pattern of resistance/susceptibility to MAIDS among the RI strains suggests that this phenotype is controlled by a single gene. Linkage analysis with other allelic markers showed a strong association between resistance/susceptibility to MAIDS and theH-2 complex. Possession of theH-2 ^b haplotype derived from C57BL/6J mice was associated with susceptibility to MAIDS, while theH-2 ^a haplotype conferred resistance to the disease. This finding was confirmed by demonstrating thatH-2 ^a congenics on the susceptible C57BL/10 background were as resistant to MAIDS as A/J mice which donated theH-2 ^a locus. Gene(s) within theH-2 complex thus represent the major regulatory mechanism of resistance/susceptibility to MAIDS.     

Mechanisms of protective immunity against Schistosoma mansoni infection in mice vaccinated with irradiated cercariae. IV. Analysis of the role of IgE antibodies and mast cells

Mice resistant to challenge infection with Schistosoma mansoni by vaccination with highly irradiated cercariae were examined for the presence of circulating IgE antibodies and peritoneal mast cells sensitized against schistosome antigens. Significant levels of SWAP- or CAP-specific IgE antibodies could not be detected by solid phase radioimmunoassay in the sera of C57BL/6 mice during the first 6 wk after vaccination. Similarly, heatlabile antibodies capable of passively sensitizing normal mast cells for degranulation in response to SWAP could not be identified in the same sera. In contrast, peritoneal mast cells harvested from C57BL/6 mice 2 wk or later after vaccination gave strong degranulation responses when challenged with SWAP or CAP. Thus, vaccination with irradiated cercariae induces an unusual form of immediate-type hypersensitivity in which mast cells become sensitized in the absence of detectable circulating IgE antibodies. Mice deficient in mast cells (W/Wv mutant strain) were observed to develop the same resistance to challenge infection after vaccination with irradiated cercariae as nondeficient littermates. Similarly, vaccinated SJL/J mice were found to mount an extremely weak IgE response as measured by mast cell degranulation yet displayed the same level of resistance to challenge infection as other inbred mice developing potent mast cell responses. These findings argue that IgE antibodies and mast cells are not essential components in the effector mechanism of irradiated vaccine-induced immunity against schistosome infection.     

Major histocompatibility complex-dependent cytotoxic T lymphocyte repertoire and functional avidity contribute to strain-specific disease susceptibility after murine respiratory syncytial virus infection

Susceptibility to respiratory syncytial virus (RSV) infection in mice is genetically determined. While RSV causes little pathology in C57BL/6 mice, pulmonary inflammation and weight loss occur in BALB/c mice. Using major histocompatibility complex (MHC)-congenic mice, we observed that the H-2(d) allele can partially transfer disease susceptibility to C57BL/6 mice. This was not explained by altered viral elimination or differences in the magnitude of the overall virus-specific cytotoxic T lymphocyte (CTL) response. However, H-2(d) mice showed a more focused response, with 70% of virus-specific CTL representing Vβ8.2(+) CTL directed against the immunodominant epitope M2-1 82, while in H-2(b) mice only 20% of antiviral CTL were Vβ9(+) CTL specific for the immunodominant epitope M187. The immunodominant H-2(d)-restricted CTL lysed target cells less efficiently than the immunodominant H-2(b) CTL, probably contributing to prolonged CTL stimulation and cytokine-mediated immunopathology. Accordingly, reduction of dominance of the M2-1 82-specific CTL population by introduction of an M187 response in the F1 generation of a C57BL/6N × C57BL/6-H-2(d) mating (C57BL/6-H-2(dxb) mice) attenuated disease. Moreover, disease in H-2(d) mice was less pronounced after infection with an RSV mutant failing to activate M2-1 82-specific CTL or after depletion of Vβ8.2(+) cells. These data illustrate how the MHC-determined diversity and functional avidity of CTL responses contribute to disease susceptibility after viral infection.     

Discordant susceptibility of inbred C57BL/6 versus outbred CD1 mice to experimental fungal sepsis

Individual susceptibility differences to fungal infection following invasive and/or immunosuppressive medical interventions are an important clinical issue. In order to explore immune response‐related factors that may be linked to fungal infection susceptibility, we have compared the response of inbred C57BL/6J and outbred CD1 mouse strains to different experimental models of fungal sepsis. The challenge of animals with the zymosan‐induced generalised inflammation model revealed poorer survival rates in C57BL/6J, consistent with lower Th1 cytokine interferon (IFN)‐γ serum levels, compared with CD1 mice. Likewise, ex vivo exposure of C57BL/6J splenocytes to zymosan but also bacterial lipopolisaccharide or lipoteichoic acid, resulted in lower IFN‐γ secretion compared with CD1 mice. C57BL/6J susceptibility could be reverted by rescue infusion of relative low IFN‐γ doses (0.2 μg/kg) either alone or in combination with the ß‐glucan‐binding CD5 protein (0.7 mg/kg) leading to improved post zymosan‐induced generalised inflammation survival. Similarly, low survival rates to systemic Candida albicans infection (2.86 × 10⁴ CFU/gr) were ameliorated by low‐dose IFN‐γ infusion in C57BL/6J but not CD1 mice. Our results highlight the importance of strain choice in experimental fungal infection models and provide a susceptibility rationale for more specific antifungal immunotherapy designs.     

Macrophage-mediated suppression of immune responses in Toxoplasma-infected mice. II. Both H-2-linked and -nonlinked control of induction of suppressor macrophages

The suppressive effect of Toxoplasma infection on initiation of memory cells to dinitrophenylated keyhole limpet hemocyanin (DNP-KLH) was drastically different among inbred strains of mice. C57BL/6 (B6), C57BL/10 (B10), and SJL mice showed markedly suppressed secondary anti-DNP responses when infected. In contrast, the suppression did not occur in BALB/c mice. The infected DBA/2 and C3H/He mice produced moderately suppressed responses. In B6 mice, an injection with 1 X 10(2) organisms of T. gondii induced a suppressed elicitation of the memory cells to DNP-KLH. However, in BALB/c mice, the responses were not affected even by inoculation with 1 X 10(4) organisms. The difference in the suppressive effect of infection between B6 and BALB/c mice was also observed in the primary anti-DNP antibody responses to DNP-KLH. Both H-2-linked and -nonlinked genes appeared to be responsible for the regulation of the immunosuppression, since the suppressive effect of infection in B10.D2 mice, which have the B10 background and the same H-2 haplotype as BALB/c, was weaker than that of B10 mice, but stronger than in BALB/c mice. In vitro studies using a primary anti-sheep erythrocytes (SRBC) antibody response system demonstrated that the activation of plastic-adherent suppressor cells by Toxoplasma infection, in which suppressor macrophages have been proved to be the responsible cells for the suppressive activity, was controlled by both H-2-linked and -nonlinked genes.     

Strain difference in the radiosensitivity of immunocompetent cells and its influence on the residual host-vs-graft reaction in lethally irradiated mice grafted with semiallogeneic bone marrow

A striking difference in radiosensitivity was noted between C3H/He (H-2k) and C57BL/6J (H-2b) strain mice when assessed by primary anti-SRBC PFC response of intact animals and primary cell-mediated lympholysis (CML) response of spleen cells to allogeneic cells in vitro, the C3H strain being more radioresistant. On the other hand, when C3H and B6 mice were exposed to 6.62 to 10.40 grays (Gy) of x-rays and then were transplanted with 2 X 10(6) bone marrow cells from B6C3F1 (H-2b/k) donor mice within 3 hr or at 24 hr after radiation exposure, the early mortality caused by residual host-vs-graft (HVG) reaction was much higher when C3H mice were used as recipients. Furthermore, the proportion of surviving animals manifesting host-type lymphohemopoiesis, i.e., host-type revertants, was much higher in B6C3F1 to C3H than in B6C3F1 to B6 combination. Spleen cells from such host-type revertants manifested strong anti-donor reactivity when assessed by mixed lymphocyte reaction (MLR) and/or CML in vitro. Increase of radiation doses to the recipients to 10.40 Gy resulted in 100% survival and 100% donor-type lymphohemopoiesis in both groups of chimeras. These results indicate strongly that a genetic difference in radiosensitivity of immune system of the recipients can greatly influence the magnitude of residual HVG reactions observed in hybrid to parental strain bone marrow transplantation in mice.     

Genetic differences in BCG-induced resistance to Schistosoma mansoni are not controlled by genes within the major histocompatibility complex of the mouse.

Induction of nonspecific resistance to Schistosoma mansoni infection after the i.v. injection of viable BCG was investigated in outbred mice and a panel of inbred and H-2 congenic strains. Significant protection was induced in CF1, A/J, C57BL/6, C57BL/10, DBA/2, C57BR, and SJL mice. BALB/c mice were not protected whereas CBA and C3H mice expressed intermediate degrees of protection. Expression of the protective phenomenon is not controlled by genes within the MHC as shown by the marked differences in response between BALB/c and DBA/2 (H-2d) as well as between C57BR and C3H (H-2k) mice. H-2 congenic strains with C57BL/10 background (B10.A and B10.D2) were high responders. BALB.B10 mice carrying the high responder (B10) MHC on the nonresponder (BALB/c) background were not protected. The degree of splenic hypertrophy did not correlate with the expression of nonspecific resistance. These results demonstrate that, in addition to controlling specific immune responses, genetic differences influence the nonspecific protective phenomena related to BCG administration as well.     

Radiation-induced pulmonary endothelial dysfunction and hydroxyproline accumulation in four strains of mice

C57BL mice exposed to 14 Gy of whole-thorax irradiation develop significant histologic lung fibrosis within 52 weeks, whereas CBA and C3H mice do not exhibit substantial fibrosis during this time. The purpose of the present study was to determine whether this strain-dependent difference in radiation histopathology is associated with genetic differences in pulmonary endothelial metabolic activity or in endothelial radioresponsiveness. C57BL/6J, C57BL/10J, CBA/J, and C3H/HeJ mice were sacrificed 12 weeks after exposure to 0 or 14 Gy of 300-kV X rays to the whole thorax. Lung angiotensin converting enzyme (ACE) activity and plasminogen activator (PLA) activity were measured as indices of pulmonary endothelial function; and lung hydroxyproline (HP) content served as an index of pulmonary fibrosis. Lung ACE and PLA activities in sham-irradiated C57BL/6J and CB57BL/10J mice were only half as high as those in sham-irradiated CBA/J and C3H/HeJ mice. Exposure to 14 Gy of X rays produced a slight but nonsignificant reduction in lung ACE and PLA activity in the C57BL strains, and a significant reduction in the CBA/J and C3H/HeJ mice. Even after 14 Gy, however, lung ACE and PLA activities in CBA/J and C3H/HeJ mice were higher than those in sham-irradiated C57BL/6J and C57BL/10J mice. Lung HP content in all four strains increased significantly after irradiation, but this increase was accompanied by an increase in lung wet weight. As a result, HP concentration (per milligram wet weight) remained constant or increased slightly in both C57BL strains and actually decreased in the CBA/J and C3H/HeJ mice. These data demonstrate significant genetic differences in both intrinsic pulmonary endothelial enzyme activity and endothelial radioresponsiveness among the four strains of mice. Specifically, strains prone to radiation-induced pulmonary fibrosis (C57BL/6J, C57BL/10J) exhibit only half as much lung ACE and PLA activity as do strains resistant to fibrosis (CBA and C3H).     

Strain-specific modification of lethality in fucose-deficient mice

The FX locus encodes an essential enzyme in the de novo pathway of GDP-fucose biosynthesis. Mice homozygous for a targeted mutation of the FX gene manifest a host of pleiotropic abnormalities including a lethal phenotype that is almost completely penetrant in heterozygous intercrosses on a mixed genetic background. Here we have investigated genetic suppression of FX-mediated lethality. Reduced recovery of heterozygous mice was observed while backcrossing the null FX allele to C57BL/6J (B6), but was less dramatic in an outcross to CASA/Rk and absent in an outcross to 129S1/SvImJ, indicating that genetic background modifies survival of FX+/- progeny. Substantial strain-specific differences in pre- and postnatal survival of FX-/- progeny were also detected in heterozygous crosses of C57BL/6J congenic, 129S1B6F1, and B6CASAF1 mice. Specifically, intrauterine survival of FX-/- mice was greatly increased during a heterozygous intercross on a uniform C57BL/6J genetic background compared with survival on a hybrid genetic background consisting of a mixture of C57BL/6J and 129S2/SvPas. In addition, statistically significant clustering of FX-/- progeny into litters and specific breeding cages was noted during a B6CASAF1 FX+/- intercross, suggesting a rare mechanism for modifier gene action in which parentally expressed genes define the phenotype, in this case the survival potential, of mutant offspring. Our results disclose that lethality in FX mutant mice is determined by one or more strain-specific modifier loci.     

Prolonged fasting in mice: a more sensitive approach to genetic diabetes.

Effects of two different periods of fasting were studied on glucose tolerance and insulin response to glucose in genetically diabetic KK and nondiabetic C57BL/6J mice. Blood sugar levels of the KK mice did not differ markedly from those of the C57BL/6J mice at the fed state or after 8 h fasting. They were, however, significantly higher in the KK mice when fasted for 18 h. The serum IRI levels, which were at least twice as high in the KK mice, decreased more markedly after 18 h fasting. The KK mice showed impaired glucose tolerance after 8 h fasting, which became more pronounced after 18 h fasting. The insulin response to glucose in the KK mice was not altered after an 8-hour fast; it was, however, diminished greatly after an 18-hour fast. These data suggest that prolonged fasting is necessary to detect the diabetic traits in the KK mice. The C57BL/6J mice showed neither impaired glucose tolerance nor diminished insulin response to glucose at both periods of fasting. Studies with the F1 hybrids (KK male X C57BL/6J female), which carry half of the diabetic genes, suggest that the mode of inheritance of diabetes in the KK mice might be polygenic.     

Helicobacter pylori-induced mucosal inflammation is Th1 mediated and exacerbated in IL-4, but not IFN-gamma, gene-deficient mice

To elucidate the pathogenesis of Helicobacter pylori-associated gastritis, we studied immune responses of C57BL/6J wild-type (WT), SCID, and gene deficient (IFN-gamma-/- and IL-4-/-) mice following infection with a pathogenic isolate of H. pylori (SPM326). During early infection in WT mice, mononuclear and polymorphonuclear cells accumulated in the gastric lamina propria, and the numbers of cells in the inflamed mucosa expressing IFN-gamma, but not IL-4, mRNA rose significantly (p < 0.005), consistent with a local Th1 response. Splenic T cells from the same infected WT mice produced high levels of IFN-gamma, no detectable IL-4, and low amounts of IL-10 following in vitro H. pylori urease stimulation, reflecting a systemic Th1 response. Infected C57BL/6J SCID mice did not develop gastric inflammation despite colonization by many bacteria. Infected C57BL/10J and BALB/c mice also did not develop gastric inflammation and displayed a mixed Th1/Th2 splenic cytokine profile. These data imply a major role for the Th1 cytokine IFN-gamma in H. pylori-associated gastric inflammation in C57BL/6J mice. Compared with WT animals, infected IL-4-/- animals had more severe gastritis and higher levels of IFN-gamma production by urease-stimulated splenocytes (p < 0.01), whereas IFN-gamma-/- mice exhibited no gastric inflammation and higher levels of IL-4 production by stimulated splenocytes. These findings establish C57BL/6J mice as an important model for H. pylori infection and demonstrate that up-regulated production of IFN-gamma, in the absence of the opposing effects of IL-4 (and possibly IL-10), plays a pivotal role in promoting H. pylori-induced mucosal inflammation.     

Strain differences in the development of auto-anti-idiotypic antibody regulation with age: genetic linkage to the Igh-C locus

The effect of age on the appearance of anti-idiotype (Id)-blocked, hapten-augmentable plaque-forming cells (PFC) in various strains of mice was investigated. Strains of mice at 2 and 6-11 months of age were immunized with 500 micrograms trinitrophenylated bovine gamma-globulin (TNP-BGG) in complete Freund's adjuvant (CFA) intraperitoneally. Splenic IgM and IgG anti-TNP PFC responses were assayed for anti-Id-blocked, hapten-augmentable PFC 14 days after immunization. It was found that strains differ with regard to the age at which they produce anti-Id-blocked, hapten-augmentable PFC. C57BL/6J (B6), DBA/1J, and C3H/HeJ mice produced a significantly high percentage of hapten-augmentable IgG anti-TNP PFC at 8-9 months of age as compared with the 2-month-old group. In contrast, 129/J, AKR/J, and C57L/J mice produced a significantly low percentage of hapten-augmentable PFC at 6-7 months of age as compared with the 2-month-old group. The CBA/J mice were high-hapten-augmentable plaque producers at both 2 and 7 months of age. SJL/J mice were, on the other hand, low producers at 2 and 11 months of age. Immune sera from high hapten-augmentable plaque-producing strains caused a hapten-reversible block of plaque formation by spleen cells from TNP-BGG-immune C57BL/6J mice and also revealed anti-(anti-TNP F(ab')2-IgG) titer as assayed by passive hemagglutination. This PFC-inhibiting activity in the immune sera of old C57BL/6J mice was an antibody of the IgG2a and IgG3 classes, lacked anti-TNP antibody activity, but reacted with anti-TNP antibody of C57BL/6J origin. Genetic analysis between high hapten-augmentable plaque production and allotypes in the (129/J X B6) crosses of the same H-2b haplotypes revealed that all of the backcrosses and F2 with high hapten-augmentable plaque production had the Igh-1a allele of the high-producer, 129/J mouse. In contrast, the crosses with low hapten-augmentable plaque production were homozygous for the Igh-1b allele of the low-producer, B6 mouse. The data suggest strain differences in the development of auto-anti-idiotypic antibody regulation with age which may be controlled by a gene(s) linked to the Igh-C locus.     

Raccoon poxvirus recombinants expressing the rabies virus nucleoprotein protect mice against lethal rabies virus infection.

Raccoon poxvirus (RCN) recombinants expressing the rabies virus internal structural nucleoprotein (RCN-N) protected A/WySnJ mice against a lethal challenge with street rabies virus (SRV). Maximum survival was achieved following vaccination by tail scratch and footpad (FP) SRV challenge. RCN-N-vaccinated mice inoculated in the FP with SRV were resistant to infection for at least 54 weeks postvaccination. Protection was also elicited by RCN recombinants expressing the rabies virus glycoprotein (RCN-G). Vaccination with RCN-G evoked rabies virus neutralizing antibody. Rabies virus neutralizing antibody was not detected in RCN-N-vaccinated mice prior to or following SRV infection. Radioimmunoprecipitation assays showed that sera from RCN-N-vaccinated mice which survived SRV infection did not contain antibody to SRV structural protein G, M, or NS. The mechanism(s) of N-induced resistance appears to correlate with the failure of peripherally inoculated SRV to enter the central nervous system (CNS). Support for this correlation with resistance was documented by the observations that SRV-inoculated RCN-N-vaccinated mice did not develop clinical signs of CNS rabies virus infection, infectious SRV was not detected in the spinal cord or brain following FP challenge, and all RCN-N-vaccinated mice died following direct intracranial infection of the CNS with SRV. These results suggest that factors other than anti-G neutralizing antibody are important in resistance to rabies virus and that the N protein should be considered for incorporation with the G protein in recombinant vaccines.     

Autosomal recessive inheritance of airway hyperreactivity to 5-hydroxytryptamine

We have previously reported that airway hyperresponsiveness to acetylcholine (ACh) is inherited as an autosomal recessive trait in A/J and C3H/HeJ mice and the progeny of crosses between them (FASEB J. 2: 2605-2608, 1988). In the present report, we have extended these studies by evaluating the biological variability in the airway response to 5-hydroxytryptamine (5-HT) and ACh among multiple genetically standardized inbred strains of mice. The pattern of airway responsiveness to ACh differed significantly from that of 5-HT in nine inbred strains of mice. A/J mice showed nonspecific airway hyperresponsiveness to both 5-HT and ACh. DBA/2J mice were hyperresponsive to 5-HT but not to ACh. An airway phenotype that resembled these inbred strains is termed HYPERREACTIVE. The C3H/HeJ and C57BL/6J inbred strains were minimally reactive to either ACh or 5-HT. Airway phenotypes that resembled these minimally reactive strains are termed HYPOREACTIVE. The frequency of HYPERRACTIVE and HYPOREACTIVE offspring from crosses between A/J and C3H/HeJ mice or DBA/2J and C57BL/6J mice is consistent with a single autosomal recessive gene, primarily determining airway hyperresponsiveness to 5-HT. We report linkage studies which suggest that these genes are not closely linked and that 5-HT and ACh airway hyperresponsiveness is inherited independently. The results of these studies suggest that murine nonspecific airway hyperresponsiveness is determined by multiple genes.