Parental Strain Mice Research Articles

Mouse Chromosome 4 Is Associated with the Baseline and Allergic IgE Phenotypes.

Regulation of IgE concentration in the blood is a complex trait, with high concentrations associated with parasitic infections as well as allergic diseases. A/J strain mice have significantly higher plasma concentrations of IgE, both at baseline and after ovalbumin antigen exposure, when compared to C57BL/6J strain mice. Our objective was to determine the genomic regions associated with this difference in phenotype. To achieve this, we used a panel of recombinant congenic strains (RCS) derived from A/J and C57BL/6J strains. We measured IgE in the RCS panel at baseline and following allergen exposure. Using marker by marker analysis of the RCS genotype and phenotype data, we identified multiple regions associated with the IgE phenotype. A single region was identified to be associated with baseline IgE level, while multiple regions wereassociated with the phenotype after allergen exposure. The most significant region was found on Chromosome 4, from 81.46 to 86.17 Mbp. Chromosome 4 substitution strain mice had significantly higher concentration of IgE than their background parental strain mice, C57BL/6J. Our data presents multiple candidate regions associated with plasma IgE concentration at baseline and following allergen exposure, with the most significant one located on Chromosome 4.

Effects of Cdh23 single nucleotide substitutions on age-related hearing loss in C57BL/6 and 129S1/Sv mice and comparisons with congenic strains

A single nucleotide variant (SNV) of the cadherin 23 gene (Cdh23c.753A), common to many inbred mouse strains, accelerates age-related hearing loss (AHL) and can worsen auditory phenotypes of other mutations. We used homologous recombination in C57BL/6 NJ (B6N) and 129S1/SvImJ (129S1) embryonic stem cells to engineer mouse strains with reciprocal single base pair substitutions (B6-Cdh23c.753A>G and 129S1-Cdh23c.753G>A). We compared ABR thresholds and cochlear pathologies of these SNV mice with those of congenic (B6.129S1-Cdh23Ahl+ and 129S1.B6-Cdh23ahl) and parental (B6N and 129S1) strain mice. Results verified the protective effect of the Cdh23c.753G allele, which prevented high frequency hearing loss in B6 mice to at least 18 months of age, and the AHL-inducing effect of the Cdh23c.753A allele, which worsened hearing loss in 129S1 mice. ABR thresholds differed between 129S-Cdh23c.753A SNV and 129S1.B6-Cdh23ahl congenic mice, and a linkage backcross involving these strains localized a Chr 10 QTL contributing to the difference. These results illustrate the large effects that strain background and congenic regions have on the hearing loss associated with Cdh23c.753alleles. Importantly, the B6-Cdh23c.753Gstrain can be used to eliminate the confounding influence of the Cdh23c.753Avariant in hearing studies of B6 mice and mutant mice on the B6 background.

Induction of antigen specific transplantation tolerance using chimeric antigen receptor type T cells engineered to kill allospecific T cells by a gene therapy immunotherapeutic approach (TRAN2P.968)

Abstract Development of specific immunotherapies to prevent graft rejection and graft-versus-host disease offers the promise of selectively deleting only allospecific immune responses. Veto activity is the ability of a cell to specifically suppress/delete only T cells directed against antigens of the veto cells themselves, but not against third-party antigens. In the present study, we reasoned that providing TCR-like signaling to allogeneic major histocompatibility complex (MHC) molecules on the surface of CD8+CTLs might result in enhanced veto function. To generate the donor antigen specific veto cells, we have utilized the Chimeric Antigen Receptor (CAR) T cell approach, in which CD8+CTLs express an MHC alloantigen fused to signaling molecule apparatuses. We fused mouse MHC class I alloantigen (H-2Dd) to the hinge and trans-membrane domains of the mouse CD8 chain plus intracellular signaling sequences derived from mouse 4-1BB, and CD3-ζ chain creating various CAR constructs. These CARs were cloned into retroviral vectors. Ex-vivo transduced T cells (FVB-Dd) were adoptively transferred in the recipient parental mice strain (FVB-H-2q) which do not express Dd. Two weeks post-adoptive transfer, we detected low levels of Dd+CD8+ T cells in lymph node and spleen, ranging from 0.2-1.2% of total CD8+ T cells. Veto activity of these Dd+CD8+T cells will be examined by in vitro Dd specific CTL assays, proliferation assays, and rejection of Dd skin grafts in parental strain (FVB) mice.

MHC Disparate Resting B Cells Are Tolerogenic in the Absence of Alloantigen-Expressing Dendritic Cells

Resting B cell (rB) populations have been shown to tolerize to soluble proteins and to minor-H but not to MHC alloantigens. We speculated that the reason for failing to tolerize to MHC alloantigen is that the few remaining dendritic cells (DCs) contaminating purified rB cell populations efficiently activate MHC allospecific T cells which are present at a higher frequency than T cells specific for minor-H alloantigen and soluble proteins. We established that MHC disparate rB cells are indeed tolerogenic when devoid of DC populations, as parental strain mice showed delayed skin graft rejection when infused with rB cells from mice in which MHC class I alloantigen was specifically targeted to T and B cells (CD2- transgenic mice). In contrast, treatment of parental strain mice with allogeneic rB cells purified from MHC- transgenic mice, in which is ubiquitously expressed, including DCs, induced accelerated graft rejection. We also showed that adding only 5,000 expressing DCs to CD2- rB cells abrogated the tolerogenic effect. Surprisingly, allogeneic rB cells prolonged graft survival in -primed mice. Thus, MHC disparate rB cells are tolerogenic and their failure to delay graft rejection can be explained by contaminating allogeneic DCs.

The cellular cancer resistance of the SR/CR mouse

The SR/CR mouse phenotype, first described in 1999 in BALB/c and later bred into C57BL/6 mice, is resistant to cancer formation following high doses of cancer cells administered intraperitoneally. The tumor cell targeting and destruction mechanisms have not been identified. By fluorescence-activated cell sorting analysis, the immune response of SR/CR mice after intraperitoneal injection of cancer cells was investigated and compared with parent strain mice. A massive influx of leukocytes into the peritoneal cavity was found. A large fraction of these leukocytes were polymorphonuclear granulocytes, macrophages and natural killer cells. A relative decrease in influx of B-cells compared with controls was demonstrated. Increased proportions of leukocytes belonging to the innate immune system were also demonstrated in splenocytes of SR/CR mice. Cytospins of peritoneal fluid from SR/CR mice after cancer cell injection showed formations of immune cells morphologically resembling polymorphonuclear granulocytes and macrophages adjoining the cancer cells. The results point to the potential involvement of innate immune cells in cancer immunology. Our data support migration of polymorphonuclear granulocytes, macrophages and NK cells into the peritoneum of the SR/CR mouse in response to intraperitoneal injection of S180 cancer cells. The cell composition of spleens of SR/CR mice reflected the differential regulation of the innate immune cells in peritoneal exudates. Both peritoneal exudates and the spleens of SR/CR mice contained decreased proportions of B-cells compared with BALB/c and C57BL/6 mice. We reproduce important aspects of previous published data and further extend them by showing differentially regulated populations of splenocytes including B-lymphocytes in SR/CR mice compared with parent strain controls. Importantly, this differentially regulated immune response of SR/CR mice could not be found in response to challenge with the lymphoma cell line EL-4.

Effect of Mouse Chromosome 13 Terminal Fragment on Liability to Catalepsy and Expression of Tryptophane Hydroxylase-2, Serotonin Transporter, and 5-HT1A Receptor Genes in the Brain

Congenic mice obtained by genome fragments transfer from one strain to another are a potent tool for studies of the molecular mechanisms of behavioral mutations. The 59-70 cM fragment of chromosome 13 containing the locus determining predisposition to freezing reaction (catalepsy) and the gene encoding 5-HT(1A) receptor were transferred from cataleptic CBA/Lac mice into the genome of catalepsy-resistant AKR/J mice. The impact of this fragment for the severity of catalepsy and expression of genes encoding tryptophane hydroxylase-2, serotonin transporter, and 5-HT(1A) receptor was studied. Half of mice of the resultant congenic AKR.CBA-D13Mit76 strain exhibited pronounced catalepsy, similarly to donor CBA animals. The expression of 5-HT(1A) receptor gene in the midbrain of AKR animals was significantly higher than in CBA. The level of 5-HT(1A) receptor mRNA in AKR.CBA-D13Mit76 animals was significantly higher than in the donor strain. Mice of parental AKR and CBA strains did not differ from each other and from AKR.CBA-D13Mit76 animals by the levels of tryptophane hydroxylase-2 and serotonin transporter genes mRNA. These data prove the location of catalepsy regulating gene in the distal fragment of chromosome 13. The recipient strain genome enhanced the expression of 5-HT(1A) receptor gene in the brain without modulating the expression of catalepsy gene.

Genome scan for exercise training responses

The genetic factors determining the magnitude of the response to exercise training are poorly understood. The aim of this study was to identify quantitative trait loci (QTL) associated with adaptation to exercise training in mice. Based on the marked differences in training responses in inbred B6 and FVB mice and intermediate phenotype of F1 offspring, an intercross breeding scheme was used to generate 188 F2 mice. Mice completed an exercise performance test before and after a 4-week treadmill running program. Male and female mice (n=84, 44.5%) were selected from the phenotypic extremes based on changes in distance run. Mean values for high (HIGH F2) and low (LOW F2) responders were 1195.5±7.9 m and 19.8±3.2 m, respectively. Changes in distance run were greater in HIGH F2 compared with all other groups, including mice from the parental FVB strain. Mice from the LOW F2 group showed responses similar to mice from the parental B6 strain and sedentary F2 mice indicating that the range of phenotypic responses in F2 mice were similar to or greater than the differences between FVB and B6 parental strains. Mice were genotyped at ~20 cM intervals using a panel of 103 SNPs. Using R/qtl software, significant QTL for post-training distance run were identified on chromosome 2 (peak at 74 cM, 5.72 LOD), chromosome 12 (41 cM, 3.49 LOD), and chromosome 14 (54 cM, 6.25 LOD). Significant or suggestive QTL for changes in distance run, post-training work, and changes in work were also identified at these same loci. Allele effects for the peak marker were plotted for the two most significant QTL (Chr. 2 and 14). At both loci, the allele for high post-training distance run came from the FVB and showed additive inheritance. These data suggest that one or more QTL determine exercise-training responses in mice. Supported by AHA SDG (M. P. M.) and NHLBI Grant HL-62826 (B. C. B).

Identification of Estrogen-responsive Genes in p53+/- Knockout and Isogenic Wild-type Parent Strain Mice by CDNA Macroarray Analysis

Identification of Estrogen-responsive Genes in p53+/- Knockout and Isogenic Wild-type Parent Strain Mice by CDNA Macroarray Analysis

TNF Receptor 1, IL-1 Receptor, and iNOS Genetic Knockout Mice Are Not Protected from Anthrax Infection

Anthrax produces at least two toxins that cause an intense systemic inflammatory response, edema, shock, and eventually death. The relative contributions of various elements of the immune response to mortality and course of disease progression are poorly understood. We hypothesized that knockout mice missing components of the immune system will have an altered response to infection. Parent strain mice and knockouts were challenged with LD95 of anthrax spores (5 × 106) administered subcutaneously. Our results show that all genetic knockouts succumbed to anthrax infection at the same frequency as the parent. TNF antibody delayed death but TNF receptor 1 knockout had no effect. IL-1 receptor or iNOS knockouts died sooner. Anthrax was more abundant in the injection site of TNF-α and iNOS knockouts compared to parent suggesting that attenuated cellular response increases rate of disease progression. With the exception of edema and necrosis at the injection site pathological changes in internal organs were not observed.

The Role of Metalloelastase in Immune Complex-Induced Acute Lung Injury

Matrix metalloproteases (MMPs) are a group of zinc-dependent endopeptidases that can degrade every component of the extracellular matrix. Under normal circumstances, the levels of MMPs are tightly regulated at both transcriptional and posttranscriptional levels. However, they are up-regulated in pathological states such as inflammation. Previous investigations have suggested that MMP-12 (metalloelastase) may be an important mediator in the pathogenesis of chronic lung injury. In this study we investigated the role of metalloelastase in the pathogenesis of acute lung injury using mice containing a targeted disruption of the metalloelastase gene. Neutrophil influx into the alveolar space in metalloelastase-deficient animals was reduced to approximately 50% of that observed in parent strain mice following the induction of injury by immune complexes. In addition, lung permeability in metalloelastase-deficient mice was approximately 50% of that of injured parent strain animals with normal levels of metalloelastase and this was correlated with histological evidence of less lung injury in the metalloelastase-deficient animals. Collectively, the data suggest that metalloelastase is necessary for the full development of acute alveolitis in this model of lung injury. Further, the data suggest that reduced injury in metalloelastase-deficient mice is due in part to decreased neutrophil influx into the alveolar space.

Genetic and epigenetic influence on EAE phenotypes induced with different encephalitogenic peptides

Different encephalitogenic peptides can induce two distinct experimental autoimmune encephalomyelitis (EAE) phenotypes in different mouse strains. To determine whether different peptides induce distinct phenotypes in genetically identical mice, parental strain and (SJLXC3H/HeJ)F1 mice were sensitized with myelin proteolipid protein peptide p139-151 or p215-232. p139-151 was non-encephalitogenic in C3H/HeJ mice and p215-232 was non-encephalitogenic in SJL mice. p139-151 induced typical acute EAE in SJL and F1 mice with most CNS inflammatory/demyelinating lesions located in the spinal cord. p215-232 induced mild clinical disease in only two of 10 C3H/HeJ mice; in 11 of 13 F1 mice (85%) it induced a disease spectrum that included typical paralytic acute EAE with a predominance of spinal cord lesions and later-onset mild EAE with predominance of brain stem/cerebellar lesions. Thus, the EAE phenotype induced in F1 mice by one encephalitogen, e.g. p139-151, can be the same as that induced in the susceptible parent. However, other encephalitogenic peptides, e.g. p215-232, may induce a broad range of heterogeneous EAE phenotypes in syngeneic mice. These data indicate that in some encephalitogenic responses, epigenetic factors influence EAE incidence, time of onset, severity, neurological signs and CNS lesion distribution.

Host H-2 haplotype modulates the induction of host-versus-graft disease after the induction of neonatal tolerance to H-2 alloantigens.

Mice injected at birth with semiallogeneic spleen cells develop a host-versus-graft disease (HVGD) characterized by the polyclonal activation of donor B cells by alloreactive host CD4+ T cells, the production of autoantibodies (autoAb) and the development of an inmmunocomplex-mediated glomerulonephritis. It has been demonstrated that the recognition of MHC class II, but not class I or non MHC, alloantigens triggers the development of the autoimmune syndrome (AIS). The finding of different expression patterns of Ia molecules in different mouse strains, and a closed restriction of some immune responses to particular H-2 haplotypes, prompted us to analyze whether variations in the expressed MHC class II molecules modify the HVGD. First, newborn BALB/c mice received spleen cells from F1 hybrid mice obtained by mating BALB/c mice with several mouse strains differing in the H-2 haplotype. Second, spleen cells from different F1 mice were neonatally injected in mice of both parental strains. All groups of BALB/c mice injected with different combinations of F1 mice showed an HVGD with a very similar serological course. However, in some instances, duration was different when comparing both parental strains injected with spleen cells from the mutual F1 hybrids. These results suggest that host MHC, but not donor MHC haplotype may modulate the AIS associated with the induction of neonatal tolerance.

Intrathymic and Extrathymic Tolerance in Bone Marrow Chimeras

Parent-->F1 bone marrow (BM) chimeras provide a useful model for studying self tolerance induction. When prepared with supralethal irradiation (1300 cGy) and conditioned with anti-T cell antibodies, parent-->F1 BM chimeras are devoid of host BM-derived cells; host H-2 expression is apparent in both the intrathymic and extrathymic environments but is limited to non BM-derived cells. When parent-->F1 chimeras are injected with T cells from normal parental strain mice, the expression of host H-2 antigens on nonprofessional APC might be expected to induce tolerance through induction of clonal anergy. In practice, this does not occur. Instead, a small proportion of the injected T cells is induced to proliferate and differentiate into effector cells. Tolerance is not seen. Similarly, tolerance is not apparent when thymectomized parent-->F1 chimeras are given parental strain thymus grafts. These findings suggest that the expression of host H-2 antigens in the post-thymic environment of chimeras is not intrinsically tolerogenic for mature T cells or recent thymic emigrants. Interestingly, post-thymic tolerance does occur when parental strain T cells differentiate in the endogenous thymus of chimeras. Thus, when mature CD8+ cells are prepared from thymus vs lymph nodes (LN) of parent-->F1 chimeras, tolerance to host class I antigens is more marked in LN than thymus; this applies to cytotoxic T lymphocyte (CTL) precursors, generated by limiting dilution analysis. It would appear therefore that many of the host-reactive CTL precursors generated in the thymus of chimeras undergo tolerance induction (deletion or irreversible inactivation) in the post-thymic environment. We suggest that such tolerance is a reflection of a covert form of tolerance induced in the thymus: intrathymic contact with host antigens on thymic epithelial cells (TEC) in chimeras does not delete typical CTL precursors, but these cells are rendered "semi-tolerant". When cultured in vitro in the presence of lymphokines, the cells are able to recover and differentiate into CTL. In vivo, however, the cells recognize antigen in the periphery in the relative absence of lymphokines and the cells die. Although host class I expression on TEC in chimeras deletes only a small proportion of CTL precursors, contact with TEC induces strong tolerance of CD8+ cells in terms of helper-independent proliferative responses in vitro and induction of lethal graft-versus-host disease in vivo. We postulate that these latter responses are controlled by high-affinity T cells, whereas typical CTL generated in LDA are predominantly low-affinity cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Tolerance of CD8+ T cells developing in parent-->F1 chimeras prepared with supralethal irradiation: step-wise induction of tolerance in the intrathymic and extrathymic environments.

Tolerance of CD8+ cells was examined in parent-->F1 bone marrow chimeras (BMC) prepared with supralethal irradiation; host class I expression in the chimeras was limited to non-BM-derived cells. In terms of helper-independent proliferative responses in vitro and induction of graft-vs.-host disease on adoptive transfer, CD8+ cells from long-term chimeras showed profound tolerance to host antigens irrespective of whether the cells were prepared from the thymus or from spleen or lymph nodes. By limiting dilution analysis, cytotoxic T lymphocyte (CTL) precursors specific for host antigens were rare in the extrathymic lymphoid tissues. In the thymus, by contrast, host-specific CTL precursors were only slightly less frequent than in normal parental strain mice. These host-specific CD8+ cells survived when BMC thymocytes were transferred intravenously to a neutral environment, i.e., to donor strain mice. When transferred to further BMC hosts, however, most of the host-reactive cells disappeared. Collectively, the data suggest that tolerance of CD8+ cells in BMC hosts occurs in both the intrathymic and extrathymic environments. In the thymus, contact with host antigens on thymic epithelial cells deletes CD8+ cells controlling helper-independent proliferative responses and in vivo effector functions but spares typical helper-dependent CTL precursors. After export from the thymus, most of the CTL precursors are eliminated after contacting host antigens on stromal cells in the extrathymic environment.

Homopoietic histocompatibility (Hh-1) phenotype and the regulation of its expression

Hybrid resistance (HR) is primarily controlled by the genes of the Hemopoietic histocompatibility-1 (Hh-1) locus within the H-2 complex. HR is a consequence of the Hh-1-controlled target determinants in homozygous parental strain mice and their absence in heterozygous F1 hybrid mice. To examine the mechanism that controls the Hh-1 phenotype, three independent clones of somatic cell hybrids between parental lines EL-4 (C57BL/6 origin, H-2b) and R1 (C58 origin, H-2k) were studied. The line EL-4 is Hh-1b-positive and is subject to HR by H-2b heterozygous F1 mice, but R1 lacks the Hh-1b allele and is not susceptible to HR. Of the three hybrid clones, F263.2 is Hh-1b-positive, whereas the other two, F262.2 and F264.2, are Hh-1b-negative, as judged by these cells' capacity to compete in vivo with the grafted parental C57BL/6 bone marrow cells in the resistant (C57BL/6 x C3H)F1 mice. All three clones express the H-2b and H-2k class I antigens equally well, are susceptible to activated NK cells to the same extent, and all carry four copies of chromosome 17. However, Southern analysis reveals that clone F263.2 contains three copies of H-2b chromosome and one H-2k, whereas the other two clones carry two copies each of the parental chromosome 17. The results suggest that the relative copy number of specific alleles is the crucial determinant of the Hh-1 phenotype, and render unlikely both the gene dosage hypothesis and the trans-acting dominant suppression hypothesis to account for the noncodominant expression of the Hh-1 phenotype.

Stimulation of genetic resistance to marrow grafts in mice by interferon-alpha/beta.

Lethally irradiated mice were infused with syngeneic, H-2 allogeneic, parental strain, or H-2 heterozygous bone marrow cells. They were injected daily with rabbit anti-mouse interferons (IFN)-alpha/beta or gamma or with IFN-alpha/beta. The growth of donor-derived cells was judged 5 days later by measuring splenic incorporation of 5-iodo-2'-deoxyuridine-125I into DNA. Antibodies to IFN-alpha/beta, but not to IFN-gamma, weakened genetic (both hybrid and allogeneic) resistance to marrow cell grafts. IFN-alpha/beta stimulated hybrid and allogeneic resistance, the latter even in genetically "poor responder" mice. Mice pretreated with silica, which weakens genetic resistance, were stimulated by IFN-alpha/beta to resist incompatible marrow cell grafts; however, IFN-alpha/beta failed to reverse the effects of antiasialo GM1 serum on marrow graft rejection. IFN-alpha/beta did not inhibit the growth of syngeneic marrow cells and did not stimulate resistance to H-2 heterozygous bone marrow cells. We propose that genetic resistance occurs in two discrete steps. In the first step, hemopoietic histocompatibility (Hh) antigens are recognized by one host cell type, and this recognition leads to IFN-alpha/beta secretion by a silica-sensitive cell. In the second step, asialo GM1-positive natural killer cells stimulated by IFN-alpha/beta recognize Hh antigens on marrow stem cells and cause rejection. The defects in resistance observed in genetically poor responder mice and in mice treated with silica appear to involve the first step in recognition. The lack of rejection of H-2 heterozygous (Hh-) marrow cells by parental strain mice injected with IFN-alpha/beta indicated that specific Hh recognition is critical in the second step of genetic resistance.

Aging of natural and acquired immunity of mice. I. Decreased natural killer cell function and hybrid resistance.

Two "natural resistance" functions, natural killer (NK) cell activity against YAC-1 lymphoma cells and rejection by irradiated mice of parental-strain or H-2 allogeneic bone marrow cell grafts (hybrid or allogeneic resistance) were compared in mice at ages between 10 weeks and 26 months. NK cell numbers, as assessed by target-binding cells, decreased to one-half that of young mouse spleen cells, whereas NK lytic function was much more depressed. Hybrid, but not allogeneic, resistance to marrow grafts was weakened by 17 months of age. The immunogenicity of marrow stem cells of old Fl hybrid mice had not changed. The interferon inducer polyinosinic:polycytidylic acid (pI:pC) restored hybrid resistance to marrow grafts but only weakly boosted NK cell function in old mice. Incubation of spleen cells of old mice with beta interferon resulted in a weak boosting of NK cell activity. No cells capable of inhibiting NK cell function were detected in the spleens of old mice. These findings in old mice were similar to findings in young mice treated with 89Sr, with the exceptions that both hybrid and allogeneic resistance to marrow grafts are defective in 89Sr-treated mice and pI:pC failed to restore hybrid resistance in mice treated with 89Sr. This loss of "natural resistance" by aged mice, perhaps mediated by marrow-dependent effector cells, can partially explain the increased incidence of tumors in aging populations.

Features of cells controlling H-2-restricted presentation of antigen to T helper cells in vivo.

Information was sought on the nature of cells presenting antigen (sheep red blood cells) in an H-2-restricted fashion to T helper cells in vivo. The approach used was to examine the capacity of F1 hybrid T cells to collaborate with parental strain B cells after prior positive selection of the T cells to antigen in irradiated parental strain mice in the presence of various sources of Thy 1-negative cells taken from F1 or parental strain mice. The results showed that H-2-restricted presentation of antigen to T cells is controlled by radioresistant, nylon-wool adherent. Thy 1-negative cells, which are enriched in spleen and peritoneal exudates, rare in lymph node cell suspensions, and undetectable in thoracic duct lymph; pretreatment in vitro with anti-Ia reagents directed either to I-A or I-E subregion determinants abolished antigen-presenting activity. These findings correlate closely with the known characteristics of cells that present antigen in vitro. Studies in which re-irradiated parent leads to F1 chimeras were used as hosts for positive selection suggested that nonhematopoietic cells do not play a discernible role in antigen presentation.

Genetic and nongenetic factors in expression of infectious murine leukemia viruses in mice of the DBA/2 × RF cross

Mice of the RF and DBA/2 strains possess endogenous ecotropic murine leukemia virus (E-MuLV) genomes but express only low to undetectable levels of infectious virus in their lymphoid tissues. F1 mice of this cross showed high levels of infectious E-MuLV if DBA/2 was the maternal parent but very low levels if RF was the maternal parent. E-MuLV expression, if present, was always higher in the spleen than in the thymus. Studies of reciprocal backcross generations with both parental strains indicated that the presence of the virus was governed by a single dominant autosomal locus present in the RF strain, and that RF females, but neither RF males nor DBA/2 females or males, transmitted a non-Mendelian factor which powerfully suppressed virus expression in their progeny. Some but not all (DBA/2♀ × RF♂)F1 females also possessed the capacity to transmit this maternal suppression to their progeny. Xenotropic murine leukemia virus (X-MuLV) showed a different pattern of expression in this cross. In the thymus it was detected in a minority of DBA/2 and in no RF mice; in crosses the presence of X-MuLV in this organ was independent of the presence of E-MuLV. In the spleen, X-MuLV was detected only in a percentage of E-MuLV-positive mice. The maternal factor from RF mothers which suppressed E-MuLV did not suppress thymic expression of X-MuLV. Skin painting with 3-methylcholanthrene induced a high incidence of thymic lymphoma in mice of both parental strains and in F1 hybrids, all of which normally show only low incidences of the diseases; the treatment did not induce markedly increased expression of E-MuLV or X-MuLV in mice of either parental strain, although it did abrogate the diminution of E-MuLV titers seen with age in (DBA/2♀ × RF♂)F1 mice beyond the age of three months.

H-2 gene products influence susceptibility of target thyroid gland to damage in experimental autoimmune thyroiditis.

The restriction of the pathogenesis of experimental autoimmune thyroiditis (EAT) by H-2 gene products was investigated. EAT was induced by injecting thyroglobulin extract plus adjuvant into F1 hybrid mice that had been implanted under the kidney capsules with thyroid glands originating from either the EAT-susceptible or -resistant parental strain mice. We found relative H-2 restriction of thyroid damage to those glands originating from the H-2 susceptible parental strain. H-2 restriction of damage at the level of the target thyroid gland implicates cytotoxic effector T lymphocytes as a pathogenic agent of EAT.