Mechanism of antibody-mediated protection against herpes simplex virus infection in athymic nude mice: requirement of Fc portion of antibody

Experiments were performed to investigate the resistance of the host due to antibody-mediated mechanisms to herpes simplex virus (HSV) infection. Transfer of hyperimmune anti-HSV mouse serum inhibited the development of skin lesions and prolonged the survival of lethally HSV-infected nude mice. Relatively high concentrations of antibody were required to achieve this protection. Antisera prepared in heterologous animals were also effective, while administration of anti-cowpox virus serum or interferon provided no protection. This type of protection is therefore due to specific antibody and cannot be attributed to interferon. In order to delineate the requirement for antibody in antibody-mediated protection, human gamma globulin preparations were transferred to lethally HSV-infected nude mice. Transfer of intact human gamma globulin (GG) was effective in controlling infection. S-sulfonation of GG did not diminish the protective ability. However, purified F(ab')2 did not have any protective action even when it was administered frequently to maintain serum neutralizing antibody titer. GG was effective in C5-deficient mice lethally infected with HSV. These results indicate that in vivo antibody-mediated protection to HSV infection requires the Fc region of the intact IgG molecule and suggest that antibody-dependent cell-mediated cytotoxicity may be operative in vivo.     

In vitro drug metabolism in male and female athymic,nude mice

Drug metabolism was studied in hepatic microsomal and post microsomal supernatant fractions from male and female athymic nude mice (nu/nu) and heterozygous (+/nu) and homozygous (+/+) wild-type controls. In males, the following enzyme activities were higher in athymic mice than in the wild-type: NADPH cytochrome c reductase, ethylmorphine and aminopyrine N-demethylases, native UDP glucuronyltransferase, and glutathione (GSH) S-aryltransferase. No differences were observed between groups in UDPNAG-activated UDP-glucuronyltransferase, N-acetyltransferase, or aniline hydroxylase activities or in amounts of cytochrome P-450. In female athymic mice, only ethylmorphine and aminopyrine N-demethylase activities were significantly higher than in female wild-type controls (+/+). The female athymic mice had mixed function oxidase activities that were less than the male athymic mice. There were no sex or strain differences in response to treatment with phenobarbital or 3-methylcholanthrene.     

Study of camelpox virus pathogenesis in athymic nude mice

Camelpox virus (CMLV) is the closest known orthopoxvirus genetically related to variola virus. So far, CMLV was restricted to camelids but, recently, three human cases of camelpox have been described in India, highlighting the need to pursue research on its pathogenesis, which has been hampered by the lack of small animal models. Here, we confirm that NMRI immunocompetent mice are resistant to intranasal (i.n.) CMLV infection. However, we demonstrate that CMLV induced a severe disease following i.n. challenge of athymic nude mice, which was accompanied with a failure in gaining weight, leading to euthanasia of the animals. On the other hand, intracutaneous (i.c.) infection resulted in disease development without impacting the body weight evolution. CMLV replication in tissues and body fluids was confirmed in the two models. We further analyzed innate immune and B cell responses induced in the spleen and draining lymph nodes after exposure to CMLV. In both models, strong increases in CD11b(+)F4/80(+) macrophages were seen in the spleen, while neutrophils, NK and B cell responses varied between the routes of infection. In the lymph nodes, the magnitude of CD11c(+)CD8α(+) lymphoid and CD11c(+)CD11b(+) myeloid dendritic cell responses increased in i.n. challenged animals. Analysis of cytokine profiles revealed significant increases of interleukin (IL)-6 and IL-18 in the sera of infected animals, while those of other cytokines were similar to uninfected controls. The efficacy of two antivirals (cidofovir or HPMPC, and its 2, 6-diaminopurine analog) was evaluated in both models. HPMPC was the most effective molecule affording 100% protection from morbidity. It appeared that both treatments did not affect immune cell responses or cytokine expression. In conclusion, we demonstrated that immunodeficient mice are permissive for CMLV propagation. These results provide a basis for studying the pathogenesis of CMLV, as well as for evaluating potential antiviral therapies in an immunodeficiency context.     

Lack of susceptibility of congenitally athymic nude mice to human non-A, non-B hepatitis

Nude mice were inoculated intravenously with chimpanzee serum containing a human non-A, non-b hepatitis agent. Control groups of nude mice were inoculated with normal saline or normal chimpanzee serum. During 77 days of observation, evidence of non-A, non-B hepatitis was not detected. Serum alanine aminotransferase levels remained within normal limits, and normal liver histology was seen in serially killed mice.     

Establishment of a primary human sarcoma model in athymic nude mice

Improvement of soft tissue sarcoma patient outcome requires well-characterized animal models in which to evaluate novel therapeutic options. Xenograft sarcoma models are frequently used, but commonly with established cell lines rather than with primary human sarcoma cells. The objective of the present study was to establish a reproducible xenograft model of primary human soft tissue sarcoma in athymic nude mice. Primary soft tissue sarcoma cells from four resected human sarcomas were isolated, cultured until the third passage and injected subcutaneously into athymic nude mice. The sarcoma xenograft was further analyzed by histological and immunohistochemical staining. In two out of four sarcomas tumor growth could successfully be established leading to solid tumors of up to 540 mm³ volume. Histological and immunohistochemical staining confirmed the mouse xenograft as identical sarcoma compared with the original patient’s tissue. In the present study a reproducible xenograft model of primary human soft tissue sarcoma in athymic nude mice was established. This animal model is of great interest for the study of sarcomogenesis and therapy.     

Hymenolepis nana: worm recovery from congenitally athymic nude and phenotypically normal rats and mice

When eggs or mouse-derived cysticercoids of Hymenolepis nana were inoculated into previously uninfected congenitally athymic nude (rnu/rnu) rats of an outbred Rowett strain, they failed to mature in the intestinal lumen. They also failed to mature in phenotypically normal (rnu/+) littermates, except when these hosts were treated with cortisone acetate from the beginning of the lumen phase. The Rowett rat, either thymus-deficient or not, was susceptible to tissue cysticercoids but resistant to luminal adults. It is therefore considered to be an unnatural host, at least for mouse-derived H. nana. There was little or no difference in susceptibility to initial tissue cysticercoids between these nude rats and phenotypically normal ones. The normal rats became completely resistant to reinfection with eggs and no secondary cysticercoids developed in their intestinal tissue, whereas the nude rats showed unaltered susceptibility to secondary tissue cysticercoids. Thus, acquired resistance to egg challenge, assessed by the failure of tissue cysticercoid recovery, was thymus-dependent. However, innate resistance to both a primary egg dose, assessed by the low recovery rates of tissue cysticercoids, and to a primary cysticercoid dose, assessed by the failure of luminal adult recovery, were thymus-independent. The effect of cortisone acetate to initiate maturation of H. nana appeared to be unrelated to thymus function. In contrast, all mice, either thymus-deficient or not, were highly susceptible to both phases. The number of worms recovered was more than 10 times greater than that of cysticercoids established in the rat's intestinal tissue.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of T-lymphocytes on normal haemopoiesis: studies in congenitally athymic nude mice.

The germ-free nude mouse represents a most useful animal for investigating the effects of a congenital deficiency of T-lymphocytes on various physiological processes, including haemopoiesis. Nude mice (nu/nu) of the CBA strain, nonmutant inbred CBA mice, and inbred C3H mice were reared in germ-free isolators and used to compare (1) the haematological parameters of nu/nu mice and CBA mice at different ages and (2) the labelling pattern of circulating leucocytes at various times after a single intraperitoneal injection of 3H-thymidine into 3-month-old nu/nu and C3H mice. The data suggest that the deficiency of T-lymphocytes in nu/nu mice may lead to a disturbance of haemopoiesis in 2 to 6-month animals which is characterised by a mild macrocytosis and a very marked reduction in the proportion of labelled leucocytes which can be seen in the blood after an injection of 3H-thymidine. Despite these perturbations, unstressed nu/nu mice were able to maintain adequate numbers of blood cells (other than lymphocytes) in their circulation. Nine-month-old nu/nu mice did not show a macrocytosis and the disappearance of the marcrocytosis at this age was associated with an increase both in the blood lymphocyte count and in the mass of lymphoid tissue in the spleen and mesenteric lymph nodes.     

The use of athymic nude mice for the study of human keloids

Keloid tissue has been implanted in the athymic nude mouse in order to develop an experimental animal model for the study of human keloids and hypertrophic scars. Untreated keloid tissues maintained essentially the same morphological patterns and glycosaminoglycan distributions for at least 60 days after implantation in the athymic mice. Normal human skin implanted in the same way was maintained without change in glycosaminoglycan distribution or morphologic characteristics. We suggest that this model may be useful for basic research of keloids and hypertrophic scars in that it will allow studies of morphologic, biochemical and therapeutic interrelationships under controlled conditions.     

Experimental infection of athymic nude New Zealand mice, nu nu strain with mycetoma agents

Experiments with athymic nude mice "nu nu" strain showed grains of Madurella mycetomi as early as 9 days, and they were well developed by 21 days, after inoculation. Grains were similar to those of humans, in pigment production and tissue reaction.     

The lymphatic pathology of Brugia pahangi in nude (athymic) and thymic mice C3H/HeN

The nude (congenitally athymic) mouse, C3H/HeN is highly susceptible to infection with Brugia pahangi (Nematoda: Filarioidea). Normal, hairy mice show a strong thymus-dependent resistance and usually terminate the infection in the larval stages. The present study examined chronological histopathologic changes in the lumbar lymph nodes and adjacent lymphatic vessels of both hosts. In thymic mice, lymphangitis and perilymphangitis reached a maximum 14 to 17 days PI, about the time of disappearance of live worms. The infiltrate showed characteristics of both acute and chronic inflammation: eosinophils, neutrophils, eosinophilic precipitates, and sometimes necrotizing lymphangitis, as well as macrophages and plasma cells. The cellular infiltrate in nude mice was weaker and developed more slowly. Inflammatory responses to identifiable dead worms were seen in both types of hosts but appeared more frequently in thymic mice. Although variable in both models, the granulomas of thymic mice generally showed more tendency to cavitation, greater macrophage or epithelioid cell infiltration, more granulocytes, and appeared to be more destructive than the foreign body responses of nude mice. Whereas lymphangiectasis was generally progressive in nude mice, it was arrested before the end of the third week in thymic mice. In thymic mice, at maximum lumbar lymph node size (17 days), there were large areas of lymphocyte hyperplasia and heavy infiltration of plasma cells. Most nodes returned to normal mean size by the end of the second month. Little or no reactivity was seen in athymic mouse nodes. Our results suggest that some lesions of lymphatic filariasis are potentially thymus-independent: lymphatic fibrosis, lymphangiectasis, accumulations of macrophages and giant cells around disintegrating worms, calcification of worms, intralymphatic thrombosis, and moderate vascular infiltrates including eosinophils.     

Intracranial growth of pulmonary small cell carcinoma cells in nude athymic mice

Pulmonary small cell carcinoma of the lung cells were inoculated intracranially and subdermally in nude athymic mice (Balb/c strain). There was a 100% intracranial tumor incidence in response to 1/10th the cell dose required to produce subdermal tumors in immunosuppressed nude mice. Tumors did not grow in the brains of Balb/c normal (haired) mice.     

Absence of insulitis and overt diabetes in athymic nude mice with NOD genetic background

NOD mice spontaneously develop diabetic syndrome similar to that of insulin-dependent diabetes mellitus in man. Insulitis, i.e., lymphocytic infiltration into the pancreatic islets is the etiologic pathological lesion in the development of diabetes mellitus in NOD mice. In the present study, we examined the role of the T cell in the development of insulitis and overt diabetes in NOD mice using NOD athymic and euthymic congenic mice. None of the NOD athymic mice developed insulitis at 9 weeks of age or overt diabetes up to 30 weeks of age. In contrast, NOD euthymic littermates showed almost the same incidences of insulitis and overt diabetes as those of NOD mice. These observations suggest that T cells are essential for the development of insulitis and overt diabetes in NOD mice.