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Anti-H-Y responses of H-2b mutant mice.

Two strains of H-2b mutant mice, H-2ba and H-2bf, in which the mutational event took place at H-2K, make anti-H-Y cytotoxic T cell responses which are H-2-restricted, Db-associated and indistinguishable in target cell specificity from those of H-2b mice. Thus, alteration of the H-2K molecule affects neither the Ir gene controlling the response, nor the associative antigen. On the other hand, one H-2Db mutant strain, H-2bo, although it makes a good anti-H-Y cytotoxic response, shows target cell specificity restricted to its own Dbo antigen(s), and neither H-2b, H-2ba or H-2bf anti-H-Y cytotoxic cells kill H-2bo male target cells. Thus, the alteration of the H-2Db molecule does not affect the Ir gene of H-2b mice, but it does alter the H-2Db-associative antigen.

Animals

Neural tube defects in curly-tail mice. II. Effect of maternal administration of vitamin A.

Vitamin A, a known teratogen of the central nervous system, was administered in various doses, at the time of active neural tube closure, to pregnant curly-tail mice which have a genetic predisposition to neural tube defects (n.t.d.), and to A Strong mice, which are not so predisposed. The curly-tail mice showed an enhanced susceptibility to the teratogenic effect of vitamin A given on day 8 of gestation, demonstrating a clear gene-environment interaction. There was a differential response by the two sexes. Females seemed to be more affected by the vitamin A than males. When vitamin A was administered on day 9, instead of day 8, of gestation, the incidence of n.t.d. decreased rather than increased. Furthermore, the number of mice affected by n.t.d. was markedly lower even than that found spontaneously in untreated curly-tail mice.

Animals

Comparative patterns of serum immunoglobulin levels in specific-pathogen-free congenitally athymic (nude), hereditarily asplenic (Dh/+), congenitally athymic-asplenic (lasat) and splenectomized athymic mice.

Serial determinations of serum immunoglobulin levels were assessed in congenitally athymic (nude), hereditarily asplenic (Dh/+) and congenitally athymic-asplenic (lasat) mice and the results compared to normal intact littermate controls (nu/+), neonatally splenectomized nu/+ and neonatally splenectomized nude mice. Quantification of Ig levels was accomplished by radial immunodiffusion, for IgM, IgG1, IgG2a, IgG2b and IgA antibody isotypes. Intact spleen and/or thymus function was shown to have marked effects on the age-dependent development of serum IgM, IgG2b and IgA production. Furthermore, because of higher levels of IgA in congenitally athymic-asplenic mice and neonatally splenectomized nude mice v. sham splenectomized nude mice, it is suggested that an IgA-specific suppressor population resides in the spleen. Finally, because of frequent problems in the literature in interpretation of immunoglobulin values, the criteria for the statistical evaluation of such data in establishing normal serum Ig values and ascertaining real differences between treatment groups are emphasized.

Aging

Neural tube defects in curly-tail mice. I. Incidence, expression and similarity to the human condition.

The incidence of neurovertebral defects in mutant mice of the curly-tail strain was investigated and found to be similar to that observed in the same mice twenty-five years ago. The results of breeding experiments support the hypothesis of Grüneberg that the defects in these mice are probably caused by a recessive gene, the expression of which is markedly affected by the genetic background. Selection against the curly-tail phenotype for six generations did not affect the incidence of abnormalities. A marked excess of females was found among exencephalic mice, as among humans with neural tube defects. Similarly, polyhydramnios, hydrocephaly, high levels of amniotic fluid alphafoetoprotein and distinctive, rapidly adhering cells in the amniotic fluid also occurred in these mice, as in humans. The curly-tail mice thus provide a useful model for the investigation of neural tube defects in man.

Amniotic Fluid

The additive effects of two mutant genes on otolith formation in mice: an animal model to assess otolith function.

This study examined the additive effects of two mutant genes, pallid (pa) and tilted head (th), on otolith formation in mice. Four strains of mice were bred: (1) a control strain, heterozygous for both pa and th. (2) a pallid strain, homozygous for pa, (3) a tilted head strain, homozygous for th, and (4) a double mutant strain, homozygous for both pa and th. The results were confirmed (1) behaviorally, by the animals' ability to swim, and (2) by histological examination of the inner ear. The findings suggest significant differences in mean otolith scores between all possible pairs of strains. As expected, the controls had normal otoliths and the pa/th strain the most severe otolith defects. Furthermore, there was a significant directional asymmetry in mean otolith scores between the utricle and saccule of the R and L ears for both pa and th strains. The results also showed a highly significant linear relationship between poor swimming ability and reduction of otoconia (r = 0.94, F = 92.14, p less than .001).

Animals

Lysosomal dysfunctions associated with mutations at mouse pigment genes.

Melanosomes and lysosomes share several structural and biosynthetic properties. Therefore, a large number of mouse pigment mutants were tested to determine whether genes affecting melanosome structure of function might also affect the lysosome. Among 31 mouse pigment mutants, six had 1.5- to 2.5-fold increased concentrations of kidney beta-glucuronidase. Three mutants, pale ear, pearl and pallid, had a generalized effect on lysosomal enzymes since there were coordinate increases in kidney beta-galactosidase and alpha-mannosidase. The effects of these three mutations are lysosome specific since rates of kidney protein synthesis and activities of three nonlysosomal kidney enzymes were normal. Also, the mutants are relatively tissue specific in that all had normal liver lysosomal enzyme concentrations.--A common dysfunction in all three mutants was a lowered rate of lysosomal enzyme secretion from kidney into urine. While normal C57BL/6J mice daily secreted 27 to 30% of total kidney beta-glucuronidase and beta-galactosidase, secretion of these two enzymes was coordinately depressed to 1 to 2%, 8 to 9% and 4 to 5% of total kidney enzyme in the pale-ear, pearl and pallid mutants, respectively. Although depressed lysosomal enzyme secretion is the major pigment mutant alteration, the higher lysomal enzyme concentrations in pearl and pallid may be partly due to an increase in lysosomal enzyme synthesis. In these mutants kidney glucuronidase synthetic rate was increased 1.4- to 1.5-fold.--These results suggest that there are several critical genes in mammals that control the biogenesis, processing and/or function of related classes of subcellular organelles. The mechanism of action of these genes is amenable to further analysis since they have been incorporated into congenic inbred strains of mice.

Animals

[Interaction of anti-Kb and anti-Dd effector lymphocytes with target cells of mouse mutant haplotypes].

The magnitude of the cytotoxic effect (CE) of immune lymphocytes R101 anti-Kb (C57BL/6) and R101 anti-Dd (B10.D2) upon target cells (TC) of mutants Kba (Hzl) and Kbd (M505), as well as Dda (M504) was considerably less than that on the TC of the original C57BL/6 and B10.D2 strains, respectively. A decrease of the CE on the H (zl) and M504 TC was more prominent than that on the M505 TC. "Monospecific" lymphocytes anti-Kb and anti-Dd were separated into two distinct subpopulations by absorption on the monolayers of macrophages from the mutant strains of mice. One of the subpopulations reacted with the TC of the original strain only, whereas the other one - with the TC of both the original and mutant strains.

Alleles

Cadmium metabolism in cdm/cdm mice.

The uptake and metabolism of cadmium by cadmium-susceptible (+/+) and cadmium-resistant (cdm/cdm) strains of mice have been compared. These strains did not differ with respect to the quantitative uptake of cadmium into liver, kidney, or testis. After intraperitoneal administration of a nontoxic dose, more than 80% of the cadmium in liver and testis of both strains is bound to low molecular weight proteins. The chromatographic behavior of these cadmium-binding proteins is not affected by cdm genotype.

Animals

Asymmetry in the serological response and mixed lymphocyte reactions between C57Bl/6 and the congenic mutant C57Bl/6.CH-2ba [H(Zl)].

Asymmetry in the relationship between the H-2K mutant strain C57Bl/6.CH-2ba (H-2ba) and the wild-type congenic C57Bl/6 has been demonstrated both in MLR and serologically by haemagglutination. MLR between these strains, when B6 was the responder, was as strong as that toward allogeneic stimulator cells: H-2ba was regularly less responsive toward B6. Responses in both directions were increased, in terms of augmented proliferative responses, by prior immunization. In this context the MLR resembles that towards minor H-locus antigens rather than those controlled by the H-2 locus. Immunization of (H-2ba X BALB/c)F1 hybridgs with B6 lymphoid cells induced the production of a haemagglutinating antibody not directed toward any known H-2 specificity. The B6 haemagglutinogen, termed He, was present on B6 lymphoid as well as red blood cells. Segregation studies of F2 and back-cross progeny of (H-2ba X BALB/c)F1 hybrids suggest that the response to He is controlled by two Ir genes, one of which is linked to H-2.

Animals

Defect in regulation of membrane transport of monosaccharides in dystrophic muscle.

The penetration of a nonmetabolized glucose analogue, 3--O-methyl-D-glucose, across the plasma membranes of tissues from dystrophic mice and cardiomyopathic (dystrophic) hamsters has been compared with that of normal controls. Under basal conditions the penetration of test sugar was similar in lens and diaphragm of normal and dystrophic 129/ReJ mice. Stimulation of sugar transport by 2,4-dinitrophenol did occur in normal but not in dystrophic diaphragm. A submaximal concentration of insulin had a more variable effect in dystrophic than in normal muscle while a supramaximal concentration of the hormone increased the uptake of the glucose analogue to an equal extent in the two tissues. In the BIO 14.6 strain of cardiomyopathic hamsters, uncoupling of oxidative phosphorylation did not increase sugar transport in extensor digitorum longus muscles, while the normal effect was observed in dystrophic soleus and in both these muscles of the random bred controls. The absence of an effect by a condition simulating anoxia suggests that in dystrophy, certain muscles are unable to accelerate the entry of glucose when this is required.

Animals

Regulation of lipopolysaccharide-induced granulopoiesis and macrophage formation by spleen cells. I. Relationship between colony-stimulating factor release and lymphocyte activation in vitro.

Addition of bacterial lipopolysaccharide (LPS), a B cell mitogen, to mouse spleen cultures strongly stimulated production of colony-stimulating factor (CSF), the humoral regulator of granulopoiesis, and macrophage formation in vitro. Secretion of CSF from LPS-stimulated spleen cells coincided with cellualr DNA synthesis and cell transformation and both activities could be attributed to the lipid A moiety of the molecule. Different experimental approaches were used to study the relationship of CSF release and lymphocyte activation in response to LPS: a) modification of LPS with polymyxin B, an antibiotic bactericidal for most Gram-negative bacteria, caused a marked reduction in mitogenic activity, although the ability to induce CSF was not significantly altered; b)spleen cells from CBA/N mice, a mutant strain with an x-linked genetic defect in immunologic and mitogenic responses to polyclonal activators including LPS, showed diminished mitogeinc responses; however, high levels of CSF were produced; c) mitotic and DNA inhibitors (colchicine and cytosine arabinoside) did not affect CSF release although they completely inhibited mitogenicity. Thus, the spleen cell population participating in the process of LPS-induced CSF generation is probably a nondividing, terminally differentiated one without need for DNA synthesis. In addition, it was also shown that active RNA and protein synthesis are needed in this process.

Animals