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The role of natural killer (NK) cells in tumor growth and metastasis was studied in syngeneic normal and beige inbred C57BL/6 mice. Mice with the beige point mutation have been shown to be deficient in nonstimulated NK activity. Tumor-passaged B16 malignant melanoma cells were refractory to NK activity as determined by in vitro assay, but after in vitro culture they became sensitive to NK activity. The NK-insensitive B16 tumor grew and metastasized similarly in normal and beige mice. However, the NK-sensitive B16 tumors grew more slowly and produced fewer metastases in normal mice than in NK-deficient beige mice. Activation of NK cells by lymphocytic choriomeningitis virus infection decreased the rate of growth and number of metastases of both NK-sensitive and NK-insensitive tumors in both normal and beige mice. These results suggest the importance of NK cells as a determinant of tumor growth and metastasis.

The Chediak-Higashi syndrome (CHS) is a genetic disorder of man, cats, and four other animal species. Enlarged cytoplasmic granules, including lysosomes and melanosomes, characterize the syndrome. Cats affected with CHS lack funduscopically visible tapeta. In normal cats, the tapetum is the light reflecting cellular layer located in the choroid. The tapetal cells contain bundles of parallel cytoplasmic rods. In this study, eyes from CHS and control cats were examined by light microscopy and transmission electron microscopy. The CHS kittens up to 14 days of age had tapeta which appeared similar to those of the controls. By 28 days of age some of the CHS tapetal rods had degenerated. Degeneration of the tapetal rods progressed rapidly and by 56 days of age there was a dramatic difference in the ultrastructural appearance of the tapetal cells. All the rods had degenerated and the contents of the tapetal cells were disorganized. The tapetal layer gradually thinned over a period of several months until the layer was absent or nearly so in CHS cats over one year of age. This study demonstrated that there is a previously overlooked degenerative component of the Chediak-Higashi syndrome.

Interspecific somatic cell hybrids were analyzed by genetic complementation to determine if a lysosomal storage disease in sheep associated with deficiencies of beta-galactosidase and alpha-neuraminidase was homologous with any of four beta-galactosidase-deficient human diseases. Fibroblasts from beta-galactosidase-deficient sheep, cats, and human patients were fused and assayed histochemically for beta-galactosidase, with 5-bromo-4-chloro-3-indolyl beta-D-galactoside. We observed complementation in heterokaryons consisting of fibroblasts from beta-galactosidase-deficient sheep and fibroblasts from patients with galactosialidosis or mucolipidosis type II, but no complementation in heterokaryons consisting of fibroblasts from beta-galactosidase-deficient sheep and fibroblasts from human or feline GM1 gangliosidosis (type I) or from human mucopolysaccharidosis type IVB fibroblasts. We conclude that the ovine disease is due to a mutation at the genetic locus homologous with that of GM1 gangliosidosis and mucopolysaccharidosis type IVB, suggesting that the primary defect in the ovine disease is a mutation of the beta-galactosidase structural gene.

Using trisomy 19 produced experimentally in mice, we examined the genetic control of the survival of trisomic fetuses. Data are presented that show clearly that the prevalence of experimentally produced trisomy 19 in mice, observed on day 15 of gestation, is genetically influenced. There appeared to be an inverse relationship between strain differences in frequency of trisomy 19 fetuses and frequency of fetal loss, suggesting that the observed differences in prevalence of trisomy 19 fetuses resulted from differential survival of trisomic fetuses.

Fawn-hooded (FH) rats were shown to lack the genetically conditioned defect of natural killer (NK) activity hypothesized to be present by analogy with the Chediak-Higashi syndrome (CHS) in mice and human beings. In 4-h 51Cr release assays, splenic NK cells from FH rats killed YAC-1, RL male l and G1-TC tumor targets without deficiency based upon comparison with cells from BD-IV, BD-IX and NBR inbred rat strains. Progeny of BD X FH F1 rats backcrossed to FH failed to reveal a correlation of reduced NK activity and dilute coat color. From these, and other data presented, it is concluded that despite similarities in coat color dilution and platelet storage pool deficiency. FH rats do not closely resemble CHS mice or human beings in having deficient NK activity and cannot be considered the rat homolog of the CHS.

Familial canine dermatomyositis, an inflammatory disease of skin, muscle, and sometimes vessels, was first reported in 1984. 1,2 Canine dermatomyositis (DM) has been recognized only in collies and Shetland sheep dogs (Shelties). 1,3,4 The condition in collies, diagnosed in dogs in 19 states in the United States, is well documented and widespread. 5 The condition in Shelties is less well characterized. 3,4 Dermatomyositis develops spontaneously in juvenile dogs as a variably severe dermatitis in the skin of the face, ears, distal extremities over bony prominences, and tip of the tail. 1,6 Myositis develops later, principally in muscles of mastication and muscles of extremities below the elbow and stifle. 7,8 Severely affected dogs have more generalized dermatitis and myositis. 7,8

The melanin granules in hair of black, smoke, blue, Chediak-Higashi-smoke, and pink-eyed dilution cats were studied. The hair of black cats contains numerous small dark brown to black melanin granules uniformly distributed throughout all portions. The basis for the dilution in smoke cats is a paucity of melanin granules in the basal portions of the hair. Blue cat hair has a larger basic melanin granule, some very large but relatively regularly shaped granules, and a non-uniform distribution of granules. The granules in the blue cat hair resemble those in the hair of dilute mice. The Chediak-Higashi trait causes even larger basic melanin granules than the blue dilution and enlarged and relatively irregularly shaped granules. The melanin granules in the hair of the pink-eyed dilution cat are very small, and are yellowish brown compared to the dark brown to black of those of black, smoke, and blue cats.

The internal genitalia of female normal rabbits and mutant lysozyme-deficient rabbits, which lack genetically the leukocytic isozyme of lysozyme, were assayed for lysozyme activity. The ovaries, uteri, and vaginas of the lysozyme-deficient rabbits had less than 20% of the lysozyme activity of normals. The oviducts, and in particular the caudal portions of the oviducts, had lysozyme activities up to 71% of the levels in normals. These observations suggest that the lysozymes of oviduct and leukocytes of rabbits are under the control of different genes.

The phenotypes with respect to congenital myasthenia gravis of 132 smooth fox terrier dogs from 25 matings were analyzed. These included both prospective and retrospective matings. It was determined that congenital myasthenia gravis in the smooth fox terrier dog breed is inherited in an autosomal recessive manner with complete penetrance. We propose the symbol mg for the gene for congenital myasthenia gravis in the smooth fox terrier. Attempts to maintain live affected dogs to adulthood were unsuccessful and it is concluded that this is a lethal trait.

In this study designed to characterize the renal lesions in cats with the autosomal recessive Chediak-Higashi-Steinbrinck syndrome (CHS), the renal tubular epithelial cells of CHS cats were examined by light microscopy. Numerous cells of proximal convoluted and straight tubules, thin loop of Henle, distal convoluted and straight tubules, and collecting tubules contained enlarged cytoplasmic granules morphologically consistent with lysosomes. In general, the enlarged lysosomes were larger and more numerous in proximal convoluted and straight tubular cells and were generally more massive in older cats. The lesions observed were similar to those in the renal epithelial cells of other species with CHS and were consistent with those reported previously in other tissues of CHS cats. It is concluded that CHS cats are an appropriate model in which to study the effects of the CHS renal lesions on renal function in this syndrome.

The Chediak-Higashi syndrome (CHS) is an autosomal recessive genetic disease of humans, and clinically similar diseases occur in cats, mink, cattle, mice, killer whales, blue foxes, and silver foxes. It is characterized by incomplete albinism, increased susceptibility to infection, and the most distinctive hallmark, the presence of enlarged cytoplasmic granules in many cell types. The acid phosphatase-positive granules, lysosomes, of fibroblasts from control and CHS humans, cats, mink, cattle, and mice were examined. These studies represent the initial characterization of the lesions in fibroblasts of CHS cats, mink, and cattle. Fibroblasts from each species and genotype were stained histochemically for acid phosphatase, and morphometric analysis of the distribution of acid phosphatase-positive granules was performed. The lysosomes in the CHS fibroblasts tended to be restricted to the perinuclear area of the cytoplasm, whereas the lysosomes in the normal fibroblasts were generally more widely distributed in the cytoplasm. The lysosomes in the CHS fibroblasts of all species examined were also more enlarged and heterogeneous than those in the control fibroblasts.

Cleidocranial dysplasia in mice, a radiation-induced skeletal mutation, showed striking homology with cleidocranial dysplasia in humans. Genetic studies indicated that the condition in mice is inherited as an autosomal dominant trait with variable expressivity and almost complete penetrance. The homozygous condition was lethal in utero. Radiographic and alcian blue/alizarin red S-stained whole-skeletal preparation studies were used to determine the extent, pattern, incidence, and distribution of skeletal abnormalities in heterozygous mice. Cleidocranial dysplasia in mice was characterized by variable clavicular hypoplasia, delayed closure of cranial fontanelles and sutures, and variable hypoplasia of pelvic bones, in particular ischiopubic rami. The gene symbol Ccd is proposed for the cleidocranial dysplasia mutation in mice and humans.