Induction of early-phase endotoxin tolerance in athymic (nude) mice, B-cell-deficient (xid) mice, and splenectomized mice.

Early-phase endotoxin tolerance was inducible in mice which were T cell deficient (nude), B cell deficient (xid), or asplenic, which suggests that these lymphoid cell subsets and the spleen do not contribute significantly to the induction of acquired lipopolysaccharide hyporesponsiveness. C3H/HeJ mice did not exhibit the hematopoietic changes observed in mice made endotoxin tolerant, which suggests that multiple mechanisms may underlie lipopolysaccharide hyporesponsiveness.     

Ovarian development in athymic nude mice. The size and composition of the follicle population.

Mice homozygous for the Mendelian recessive mutation nude show a reduction in the size and changes in the composition of the ovarian follicle population. Follicular loss was first evident at 2 months of age and was specifically due to a reduction in the numbers of small (primordial) follicles and medium follicles in the initial growth stages. The first ovulation was delayed until 2 1/2 months of age. By 4 months an overall reduction in all fractions of the follicle population had occurred and ovulation had ceased. These developmental changes are discussed in relation to the role of the thymus gland in sexual maturation and reproductive function in the female mouse.     

Surface carbohydrate composition of murine thymocytes and of lymph node cells from normal and athymic (nude) mice.

Surface glycoproteins (papain digests) have been isolated from lymph node cells of normal mice which contain mainly T cells, and from lymph node cells of nude (athymic) mice, which essentially represent B cells. Gaschromatographic analysis revealed that the glycoproteins from the lymph node cells of the euthymic mice contain less galactose than the glycoproteins from lymph node cells of the athymic mice, but contain still more galactose than glycoproteins from thymocytes. Lymph node cells from both sources contain about equal amounts of neuraminic acid, while thymocytes contain slightly less sialic acid. The observed differences provide a molecular explanation for the different reactivity of murine B cells and T cells towards soybean agglutinine and other galactose-binding plant lectins.     

Ovarian development in athymic nude mice. II. The growth of the oocyte and follicle.

Congenitally athymic mice homozygous for the Mendelian recessive mutation "nude" develop well defined morphological and quantitative changes in the ovarian follicle population. A decline in follicle numbers at 2 months of age is preceded by a retardation in follicle growth at 1 month of age. The growth of the oocyte and its nucleus are not affected by the nude mutation. However, the rate of growth and maximum size of the oocyte nucleolus are reduced in nudes. These developmental events are discussed in relation to the genetic activity of the oocyte, the role of pituitary gonadotrophins in follicular and oocyte growth and the possible role of the thymus gland in these processes.     

Interferon production in athymic nude mice.

Athymic (homozygous nude) mice of a non-inbred stock had relatively little antiviral activity in their serum compared with normal control mice at 4, 6 and 6.5 h after the intraperitoneal injection of Newcastle disease virus. The antiviral activity in the serum had the characteristics of interferon. At 10 h after injection and thereafter, the serum titres were comparable in nude and normal control mice. Exceptional nude mice with thymus-like tissue sometimes produced interferon more or less normally. Transfer of spleen cells from normal donor mice, but not from nude donors, led to increased serum interferon levels in nude recipient mice at 4 h after virus injection.     

Murine cytomegalovirus adrenalitis in athymic nude mice

Summary During studies of the pathogenesis of murine cytomegalovirus (MCMV) infection in athymic nude mice, we noted striking virus involvement of the adrenal glands. Because patients with the acquired immunodeficiency syndrome (AIDS) have recently been reported to have adrenal necrosis and evidence of infection of the adrenal gland with human cytomegalovirus (HCMV), we have further evaluated adrenal involvement during MCMV infection. Following virus inoculation, MCMV replicated to high titer in the adrenal glands of T-cell deficient, homozygous nude mice, but not heterozygous littermates with intact T-cell function. Concomitant with the high titers of virus, there appeared overt histological evidence of herpesvirus infection accompanied by patchy necrosis of adrenal cortical and medullary tissues. Acyclovir, which inhibits growth of MCMV, reduced virus replication in the adrenal gland. Similarly, virus replication was diminished in homozygous nude mice immunologically reconstituted by infusion of normal spleen cells three weeks prior to infection. Thus, in the absence of functioning T lymphocytes, MCMV can infect and replicate in adrenal tissues causing a progressive destructive adrenalitis.With 1 Figure     

Alpha-fetoprotein and phagocytosis in athymic nude mice

Alpha-fetoprotein (AFP) was found to suppress the phagocytic activity of the blood monocytes and neutrophils in vitro. The amounts of AFP detectable by immunofluorescence in the livers of nu/nu, nu/+ and +/+ mice were quite comparable, and thus could not have been responsible for the alterations in phagocytosis found in leukocytes of athymic nude mice during their ontogenetic development.     

Adoptive transfer of nontransgenic mesenteric lymph node cells induces colitis in athymic HLA-B27 transgenic nude rats

HLA-B27 transgenic (TG) rats develop spontaneous colitis when colonized with intestinal bacteria, whereas athymic nude (rnu/rnu) HLA-B27 TG rats remain disease free. The present study was designed to determine whether or not HLA-B27 expression on T cells is required for development of colitis after transfer of mesenteric lymph node (MLN) cells into rnu/rnu HLA-B27 recipients. Athymic nontransgenic (non-TG) and HLA-B27 TG recipients received MLN cells from either TG or non-TG rnu/+ heterozygous donor rats that contain T cells. HLA-B27 TG rnu/rnu recipients receiving either non-TG or TG MLN cells developed severe colitis and had higher caecal MPO and IL-1beta levels, and their MLN cells produced more IFN-gamma and less IL-10 after in vitro stimulation with caecal bacterial lysate compared to rnu/rnu non-TG recipients that remained disease free after receiving either TG or non-TG cells. Interestingly, proliferating donor TG T cells were detectable one week after adoptive transfer into rnu/rnu TG recipients but not after transfer into non-TG recipients. T cells from either non-TG or TG donors induce colitis in rnu/rnu TG but not in non-TG rats, suggesting that activation of effector T cells by other cell types that express HLA-B27 is pivotal for the pathogenesis of colitis in this model.     

Leishmania mexicana amazonensis infections in ''resistant'' inbred mice following removal of the draining lymph node.

Highly resistant (C57BL/10) and intermediately resistant (DBA/2) mice were infected subcutaneously with Leishmania mexicana amazonensis in a hind footpad subsequent to removal of the draining popliteal node. These mice developed greatly exacerbated Leishmania infections as compared to sham-operated controls or to mice infected in the contralateral footpad. The majority of mice in which the draining lymph nodes were removed prior to infection developed metastases, lost their delayed hypersensitivity responses to Leishmania, and some died. Significantly fewer metastases and no deaths were observed in the control groups. The results emphasize the importance of lymphatic control of Leishmania m. amazonensis infection in relatively resistant mouse strains.     

Pathogenesis of K papovavirus infection in athymic nude mice

The fatal outcome of K virus infection in infant mice and cytoxan-treated adult mice is related to their inability to mount a prompt antibody response to the virus. Athymic nude mice infected with K virus exhibited no clinical illness and no detectable virus-specific immunoglobulin G (IgG) response, but they did exhibit a low level of virus-specific immunoglobulin M response. Transfer of spleen cells from K virus-primed nude mice to infected infant mice conferred complete protection against K virus-induced mortality. This protection was diminished by the depletion of B cells but not by the depletion of adherent cells from the primed spleen cells. B cell response is therefore important in the recovery of nude mice from K virus infection.     

Chronic infection with Trypanosoma musculi in congenitally athymic nude mice.

Trypanosoma musculi produces a chronic infection with a consistently elevated parasitemia in nude mice. Thymic reconstitution of nude mice restores immunity to the infection.     

Foreign body reaction against cellophane in the athymic nude mice

There are no differences in the multinucleate cell formation in normal and athymic mice after the subcutaneous implantation of a cellophane strip. The number of Ia+ epitheloid cells and multinucleate foreign body giant cells was lower and the number of epitheloid cells sharing the marker of activated macrophages (M 57) was higher in athymic compared to normal mice. The epitheloid cells of athymic and euthymic animals exhibited no difference in the expression of Mac-2 molecule. The difference of the expression of surface markers between athymic and euthymic animals does not influence the foreign body giant cell formation.     

Herpetic keratitis in athymic (nude) mice.

The inflammatory response to herpes simplex virus infection of the cornea was studied in athymic nude (nu/nu) and heterozygote (nu/+) BALB/c mice. Although athymic mice were highly susceptible to HSV infection and died 13 to 17 days after corneal inoculation, they failed to develop necrotizing keratitis of the cornea. Heterozygote mice survived the initial virual infection, but many of these mice developed necrotizing keratitis and permanent corneal scarring. Light and electron microscopy showed numerous inflammatory cells (polymorphonuclear leukocytes and lymphocytes) in the corneas of heterozygote mice, but not in the athymic mice. These studies suggest that the immune system plays a dual role in herpes simplex virus infection of the cornea: protection against dissemination of the virus and immunopathogenesis of necrotizing keratitis in the cornea.     

同种异基因移植引流淋巴结及外周血T细胞活化分析

目的:研究同种异基因移植早期局部引流淋巴结和外周血T细胞的活化情况。方法:以小鼠前臂皮下非血管化心肌移植为模型,利用流式细胞术分析前臂引流淋巴结及外周血不同T细胞亚群的CD69表达水平。结果:同种异基因移植后72h,引流淋巴结CD4⁺T细胞和CD8⁺T细胞的CD69表达百分率均明显高于移植前(P＜0.01),且CD8⁺T细胞的表达水平高于CD4⁺T细胞(P＜0.01);各组外周血CD4⁺T细胞和CD8⁺T细胞的CD69表达百分率均无显著差异;局部应用弗氏完全佐剂和全身应用CsA可分别增强和抑制同种异基因移植后CD4⁺T细胞和CD8⁺T细胞的CD69表达(P＜0.05或P＜0.01)。结论:局部引流淋巴结T细胞CD69的表达水平可及时反映受者T细胞对同种异基因抗原的识别情况。     

Antigen-bearing dendritic cells in the draining lymph nodes of contact sensitized mice: cluster formation with lymphocytes.

Following topical exposure to skin-sensitizing chemicals, Langerhans' cells, a significant proportion of which bear antigen, are induced to migrate from the epidermis to the regional lymph node. There is evidence that the antigen-bearing cells which arrive in the draining lymph nodes have the functional characteristics of mature dendritic cells (DC) and efficiently induce T-lymphocyte activation in vitro and contact sensitization in vivo. In contrast, freshly isolated Langerhans' cells are known to be relatively inefficient antigen-presenting cells. Evidence exists that during culture in the presence of granulocyte/macrophage colony-stimulating factor, Langerhans' cells undergo a functional maturation and assume the characteristics of dendritic cells. We have speculated that, in response to chemical exposure and the stimulus to migrate. Langerhans' cells undergo a similar maturation in vivo. To investigate this we have examined the capacity of draining lymph node DC to form antigen-independent clusters with T lymphocytes. Previous studies have confirmed that freshly isolated Langerhans' cells are unable to form such clusters. We report, however, that the antigen-bearing DC which arrive in the draining lymph nodes following skin sensitization, and which are recently derived from epidermal Langerhans' cells, efficiently form clusters with lymphocytes. Thus, antigen-bearing DC were found to have formed clusters with lymphocytes in situ in the draining lymph node, and to readily form clusters with lymphocytes in vitro. In both cases a higher proportion of lymphocytes associated with DC in clusters were T cells. An interesting observation was that DC within draining nodes appeared more efficient at cluster formation than DC in resting nodes, and that within draining nodes antigen-bearing DC formed clusters with greater affinity and/or greater stability than DC which lacked antigen. Taken together these data demonstrate that Langerhans' cell-derived antigen-bearing cells which accumulate in the draining lymph nodes following skin sensitization form clusters with lymphocytes in the manner of mature DC. This is compatible with the hypothesis that, while in transit from the skin, Langerhans' cells are subject to a functional maturation comparable to that witnessed in vitro.     

High incidence of Langerhans cells in lymph nodes of athymic nude mice: an ultrastructural and morphometric study

Cervical and axillary lymph nodes of athymic nude mice were compared morphometrically and ultrastructurally with those of normal littermates. The lymph nodes of the nude mice were larger and the volumes of the follicle, paracortex, and medulla of the lymph nodes were all larger. The paracortex of nude mice had few lymphocytes and a large number of interdigitating cells (IDC) and Langerhans cells (Lc). The results suggest that the high incidence of Lc and IDC in the lymph nodes of nude mice is due to cell accumulation and not lymphocyte depletion.     

Enhanced phagocytic activity of blood leukocytes in athymic nude mice

After 30-min incubation, blood leukocytes of adult athymic BALB/c nude mice (nu/nu) have a distinctly higher methacrylate or yeast particle uptake than leukocytes of euthymic nu/+ or +/+ mice. This permanent enhancement is not due to humoral factors, since the percentage of phagocytosing nu/nu leukocytes increases further in nu/+ littermate's plasma. Also, chronic infection or intraperitoneal immunization causes an additional transitory increase of the percentage of phagocytosing leukocytes and numbers of particles ingested; the phagocytic performance of leukocytes of euthymic mice is raised under these conditions by a greater factor. In fetuses enhanced phagocytosis of nu/nu mice is found only in monocytes. The bulk of ingestion of methacrylate particles is mediated by Fc receptors and significantly more receptors for IgG2B, IgG1, and IgG2A are demonstrable on nu/nu neutrophils; ingestion of particles via these receptors is again higher in nu/nu neutrophils, whereas nu/nu monocytes display a higher uptake via Fc(IgG1) receptors.     

Transplantation of ACTH-secreting pituitary tumor cells in athymic nude mice

Summary Chronic excess of glucocorticoids results in cushing's syndrome in humans. A common cause of excess cortisol secretion is the presence of an adrenocorticotropin secreting pituitary tumor which stimulates the adrenal cortex to produce excess glucocorticoids. ACTH-secreting AtT-20 mouse pituitary cells transplanted subcutaneously in oestrogenized athymic nude mice form tumors rapidly. Six weeks after receiving the tumor transplants, the mice weighed 45% more than normal mice due to the increase in body fat. The tumor-bearing mice exhibit the familiar buffalo hump appearance due to the abnormal distribution of body fat. The adrenal glands of the tumor-bearing animals are enlarged due to hypertrophy of the zona fasciculata. The foamy looking fasciculata cells in normal mice were converted to dense, eosinophilic cells in the tumor-bearing mice. Transplantation of normal pituitary glands to athymic nude mice with or without oestrogen treatment did not produce these morphological changes. The experimental model described here may be useful for future studies of Cushing's syndrome.Supported by Medical Research Council of CanadaScholar, Medical Research Council of Canada