Role of T-cell function in recovery from murine influenza infection.

Athymic (nude) mice and their normal littermates were intranasally inoculated with graded doses of A/WSN influenza virus. At a dose of 10³ EID₅₀, all mice survived the infection. In contrast, at a dose of 5 × 10⁴ EID₅₀, all mice died by 7 days. At intermediate doses of 5 × 10³ and 10⁴ EID₅₀, the nude mice were less resistant to the infection than their normal littermates, so that a higher proportion always died. Given a dose of 5 × 10³ EID₅₀, lung virus levels in both groups reached similar high levels by Day 5. Thereafter, virus levels in the normal mice rapidly fell so that no infectious virus could be detected by Day 18. In nude mice, the levels fell very slowly so that relatively high levels were still present at Day 18 in the surviving mice. At the height of the infection, high levels of cytotoxic T-cell activity was detected in the lungs of normal but not nude mice. Transfer to the nude mice of specific immune T cells raised from infected normal littermates enhanced survival of the nude mice and reduced the lung virus levels. Nude mice consistently showed a greater degree of lung consolidation than their normal littermates. Microscopically, the nude mouse lungs showed greater respiratory epithelial hyperplasia with minimal inflammatory cell infiltration in the foci of consolidation compared with their infected normal littermates. Under the conditions of these experiments, influenza-immune T cells seemed to inhibit rather than contribute to the generation of virus-mediated pulmonary pathology. The findings strongly suggest that T cells play an important positive role in the process of recovery from murine influenza infection.     

Ovarian tumorigenesis in mice transgenic for murine inhibin alpha subunit promoter-driven Simian Virus 40 T-antigen: ontogeny, functional characteristics, and endocrine effects

We previously reported formation of ovarian granulosa cell tumors with 100% penetration in a transgenic mouse model with murine inhibin alpha subunit promoter-driven (inhalpha)/Simian Virus 40 T-antigen (Tag). The tumor-bearing inhalpha/Tag mice showed highly elevated serum levels of immunoreactive inhibin. To investigate the onset of tumorigenesis and related endocrine consequences, 6-8 female mice of two inhalpha/Tag lines and their mating control littermates were killed monthly between 1 and 6 mo of age. We also investigated tumorigenesis-related fertility aspects of these two mouse lines. The ontogeny and progression of tumors could be monitored in both inhalpha/Tag lines by alterations of ovarian weights and serum hormone levels. Serum progesterone levels increased in both inhalpha/Tag lines in an age-dependent manner as ovarian tumorigenesis progressed, and a reciprocal decrease occurred in serum LH and FSH. Neither serum estradiol (E(2)) nor uterine weights were significantly altered during tumorigenesis, suggesting that the ovarian tumors represented late stages of granulosa cell differentiation. In conclusion, the present findings show in the inhalpha/Tag TG mice a relation between endocrine consequences of granulosa cell tumorigenesis, and a connection of onset of tumor formation with aberrant steroidogenesis and gonadotropin secretion. These findings indicate that tumors are endocrinologically active and able to exert enhanced negative feedback effects on pituitary function. The tumors provide a good model for endocrinologically active hormone-dependent tumors.     

Immunosuppression of congenitally athymic (nude) mice with heterologous anti-immunoglobulin heavy-chain antisera

Congenitally athymic (nude) mice have been shown to be far more sensitive than their phenotypically normal littermates to immunosuppression by anti-Ig antisera. Anti-μ suppression of nude mice was seen to result in complete and stable loss of IgM and IgA as well as severe reductions in IgG1 and IgG2 levels. Anti-α treatment of nudes resulted only in complete and stable loss of IgA; similarly, anti-γ1γ2 treatment achieved only class-specific reductions of IgG1 and IgG2 levels, but these reductions recovered slightly during suppression. Nude mice were more severely immunosuppressed than their phenotypically normal littermates upon anti-Ig treatment and demonstrated much less ability to recover from such suppressive effects. The significance of these observations regarding thymus dependency of immunoglobulin synthesis in nude mice is discussed.     

Endocrine characterization of a human ovarian carcinoma (BG-1) established in nude mice

The steroid receptor-positive human ovarian cancer (BG-1) was evaluated to determine its usefulness as a tumor model. This tumor grows in intact male and female nude mice without hormone supplements. Moreover, its growth was significantly accelerated in ovariectomized mice, and the increased growth rate could be reversed by estradiol administration. Evaluation of tumor growth following endocrine therapy revealed that, while antiandrogens did not affect the tumor growth, both an aromatase inhibitor and a luteinizing hormone-releasing hormone agonist significantly impaired growth of this human ovarian tumor. Estradiol was also shown to up-regulate both estrogen and progesterone receptors in tumors grown in ovariectomized mice. Therefore, the BG-1 human ovarian carcinoma grows without hormonal supplements and yet responds to specific forms of endocrine therapy. Moreover, the steroid receptors present in this tumor respond to exogenous steroids. In conclusion, this tumor may serve as an ideal model for the study of hormonal regulation of ovarian tumor growth.     

Identification of a regulatory loop for the synthesis of neurosteroids: a steroidogenic acute regulatory protein-dependent mechanism involving hypothalamic-pituitary-gonadal axis receptors

Brain sex steroids are derived from both peripheral (primarily gonadal) and local (neurosteroids) sources and are crucial for neurogenesis, neural differentiation and neural function. The mechanism(s) regulating the production of neurosteroids is not understood. To determine whether hypothalamic‐pituitary‐gonadal axis components previously detected in the extra‐hypothalamic brain comprise a feedback loop to regulate neuro‐sex steroid (NSS) production, we assessed dynamic changes in expression patterns of steroidogenic acute regulatory (StAR) protein, a key regulator of steroidogenesis, and key hypothalamic‐pituitary‐gonadal endocrine receptors, by modulating peripheral sex hormone levels in female mice. Ovariectomy (OVX; high serum gonadotropins, low serum sex steroids) had a differential effect on StAR protein levels in the extrahypothalamic brain; increasing the 30‐ and 32‐kDa variants but decreasing the 37‐kDa variant and is indicative of cholesterol transport into mitochondria for steroidogenesis. Treatment of OVX animals with E₂, P₄, or E₂ + P₄ for 3 days, which decreases OVX‐induced increases in GnRH/gonadotropin production, reversed this pattern. Suppression of gonadotropin levels in OVX mice using the GnRH agonist leuprolide acetate inhibited the processing of the 37‐kDa StAR protein into the 30‐kDa StAR protein, confirming that the differential processing of brain StAR protein is regulated by gonadotropins. OVX dramatically suppressed extra‐hypothalamic brain gonadotropin‐releasing hormone 1 receptor expression, and was further suppressed in E₂‐ or P₄‐treated OVX mice. Together, these data indicate the existence of endocrine and autocrine/paracrine feedback loops that regulate NSS synthesis. Further delineation of these feedback loops that regulate NSS production will aid in developing therapies to maintain brain sex steroid levels and cognition.     

Rôle du peptide vasoactif intestinal (VIP) dans la stéroïdogenèse et le vieillissement testiculaire

VIP (vasoactive intestinal peptide) neuropeptide has long been considered to be putative regulator of testicular functions.In vitro evidence suggests that VIP could play an important role in testosterone biosynthesis. However, the endogenous role of VIP on testicular functions remained to be demonstrated. In C57BL/6 mice exhibiting complete disruption of the VIP gene, the authors observed that male fertility remained intact but serum testosterone levels were lower than those of WT littermates. At the age of 4 months, this phenotype was accompanied by reduced steroidogenesis due to inhibition of the expression of StAR (steroidogenic acute regulatory protein) and 3ßHSD (3ß-hydroxysteroid dehydrogenase) in the testis. In addition, serum levels of FSH (Follicle-stimulating hormone) but not LH (Luteinizing hormone) were reduced in young KO males. Testicular anatomy also revealed a subtle but significantly higher percentage of degenerated seminiferous tubules in 4-month-old VIP-/-animals compared to WT. In aging animals (15 months old), control males showed typical testicular aging including severe degeneration of seminiferous tubules, a dramatic decrease in serum testosterone levels and a reduction in StAR and 3ß-HSD gene expression. In age-matched VIP-/-males, serum levels of testosterone and steroidogenic enzymes were still very low. Interestingly, in contrast with young mice, testicular degeneration at 15 months was significantly less severe marked in VIP-/-mice than in WT mice. Altogether, these results suggest that: 1) VIP is an important factor for regulating testosterone biosynthesis and FSH secretion and 2) VIP regulates testicular aging.     

Essential Role of T Cells in the Postexposure Prophylaxis of Rabies in Mice

Athymic nude mice injected intramuscularly with a street strain of rabies virus were not protected against rabies by postexposure administration of beta-propiolactone-inactivated rabies vaccine. In contrast, their normal littermates were completely protected from death by the same vaccination regimens. Nude mice did not produce IgG antibody as a result of the vaccine during the test period of 15 days, whereas normal littermates produced IgG antibody from day 5 after vaccination. However, passive immunization with antirabies hyperimmune mouse ascites showed that antibody was completely ineffective in protecting either nude mice or their normal littermates against rabies when given later than 2 days after infection. No significant difference in the induction of circulating interferon by the vaccination was noted in these mice. Passive transfer of immune spleen cells to nude mice immediately after infection resulted in 30 to 37.5% protection of the mice. Passively transferred spleen cells did not produce detectable amounts of neutralizing antibody in the recipient mice except on day 2 after the transfer, when a low level of antibody was detected. These observations demonstrate the essential role of T cells in the postexposure prophylaxis of rabies in mice. The mechanisms of the failure of postexposure vaccination in nude mice are discussed.     

In vivo growth stimulation of collagen gel embedded normal human and mouse primary mammary epithelial cells

A new system for studying growth of normal human mammary epithelial cells in an in vivo environment using athymic nude mice is described. Human mammary epithelial cells dissociated from reduction mammoplasty specimens were embedded within collagen gels and subsequently transplanted subcutaneously into nude mice. Histological sections of recovered collagen gels showed epithelial cells arranged as short tubules with some branching. Proliferation of mammary epithelial cells was quantitated in vivo by 3 days' continuous infusion with 5 bromo-2′-deoxy-uridine followed by immunostaining of sections from recovered gels. Ovarian steroids administered to the host animals, resulting in blood serum levels normally found in the human female, had little or no effect on the proliferation of human mammary epithelial cells. Collagen gel embedded mouse mammary epithelial cells, mouse mammary explants, and host mammary glands all responded similarly to ovarian steroids, suggesting that the unresponsiveness of the human mammary epithelial cells under these conditions was not due to dissociation per se. However, an increased dose of 17β-estradiol or a growth factor combination containing epidermal growth factor, cholera toxin, and cortisol significantly stimulated the proliferation of human outgrowths. The growth factor response was dependent on the location of the cells, with the greatest response seen in the part of the gel proximal to the osmotic pump delivering the growth factors and the effect gradually waning in area more distal to the pump. The effect was especially striking since the mitotic figures could be easily identified and the labeling index was as high as 75%. The host mouse mammary gland also responded to growth factors, resulting in ductal hyperplasia. The proliferative and morphogenetic effects of various agents on normal human mammary epithelial cells embedded in collagen gel can be studied in vivo in nude mice. © 1995 Wiley-Liss, Inc.     

Proliferation of hemolysin-plaque-forming cells in nude mice and normal littermates subjected to antigenic competition.

The increase of PFC per spleen and the development of hemolytic foci were examined to clarify the patterns of clonal expansion of B-lymphocytes in athymic nude mice (nu/nu) and normal littermates (nu/+) subjected to the procedure for antigenic competition between horse erythrocytes (HRBC) and sheep erythrocytes (SRBC). In normal littermates without pretreatment with HRBC, a small number of PFC and hemolytic foci of small size were detected 2-days after the challenge with SRBC. The number of PFC increased progressively from day 2 to day 4, and hemolytic foci increased in the number and size during the period. In nude mice, a small number of PVFC were detected on day 2 and the number increased only slightly from day 2 to day 4. No large hemolytic foci were detected during the period. In normal littermates subjected to the procedure for antigenic competition, the patterns of increase of PFC and development of hemolytic foci were similar to those in nude mice. In nude mice, the procedure for antigenic competition exerted almost no effect on the patterns.     

Reaction of human lymphocytes with aggregated IgG columns. Effect on antibody-dependent cytotoxicity and EAC rosette formation.

The origin and life span of long-lived small lymphocytes in the bone marrow of mice have been evaluated by the use of radioautography, scintillation counting, and anti-theta serum. Thymus-deprived BALB/C mice and nude mice had a smaller percentage of long-lived lymphocytes in bone marrow and in thoracic duct lymph than sham-operated or normal littermates. Furthermore, the long-lived lymphocytes in the marrow of nudes have more varied—but generally shorter—life spans than long-lived lymphocytes from mice having a thymus. In thoracic duct lymph of nude mice a more homogeneous long-lived population—according to life span—was found.It was concluded that both long-lived T cells and long-lived B cells are normal residents in the bone marrow. Furthermore, it was concluded that cells of variable life spans comprise the B lymphocyte population: short-lived cells with life spans of 3–5 days and long-lived lymphocytes with life spans of weeks to months.     

Resistance of nude mice to herpes simplex virus and correlation with in vitro production of interferon.

Homozygous nude mice and their phenotypically normal littermates were infected intraperitoneally with herpes simplex virus (HSV). Nude mice did not show increased mortality rates. In fact, at lower virus doses they were consistently less susceptible than the controls. Spleen cells from nude mice, when challenged in vitro with HSV, produced equal amounts of interferon as spleen cells from the normal littermates.     

Serum intact parathyroid hormone concentration measured by a two-site immunoradiometric assay in normal subjects and patients with various parathyroid disorders.

Serum intact parathyroid hormone (PTH) concentration was measured by a two-site immunoradiometric assay (IRMA) in normal subjects and patients with various parathyroid disorders. Serum intact PTH levels were all within the detection limit of the IRMA in normal subjects, and there was a significant negative correlation between serum calcium (Ca) and intact PTH levels. Although 3 out of 26 patients (11.5%) with primary hyperparathyroidism had a normal serum intact PTH concentration, these patients could be readily discriminated from normal subjects by plotting serum intact PTH against the serum Ca concentration. In contrast, serum intact PTH was undetectable in 16 out of 17 patients (94.1%) with idiopathic hypoparathyroidism. Patients with pseudohypoparathyroidism (PHP) type I, mostly under treatment with active vitamin D, exhibited wide distribution of serum intact PTH concentration, and appeared to belong to two distinct subgroups. One group of patients demonstrated a similar relationship between serum intact PTH and Ca levels to normal subjects. The other exhibited much higher serum intact PTH levels despite a normal serum Ca concentration, and no obvious relationship could be observed between the two parameters. These results demonstrate that an inverse relationship between serum Ca and intact PTH can be demonstrated in normal subjects with normocalcemia, that most of the parathyroid disorders can be diagnosed by measuring serum Ca and the intact PTH concentrations simultaneously, and that patients with PHP can be divided into two subgroups: one with a normal relationship between serum Ca and intact PTH, and the other with a high serum PTH level in the face of normocalcemia.     

Pituitary control of cholesterol metabolism in normal and LDL receptor knock-out mice: effects of hypophysectomy and growth hormone treatment

The pituitary is important in the control of lipid metabolism and studies of hypophysectomized (Hx) rats have shown strong effects of growth hormone (GH) on bile acid synthesis, hepatic LDL receptor (LDLR) expression and on the sensitivity to dietary cholesterol. It is unclear if mice may be used in such studies. The aim of the current study was to evaluate if Hx mice may be used to further explore how GH modulates cholesterol and bile acid metabolism, and to define the importance of the LDLR in this regulation by studying LDLR-deficient mice (LDLRko). Experiments on three mouse strains showed that, following Hx, HDL were reduced and LDL increased. Cholesterol/fat feeding of Hx mice increased serum cholesterol levels 2- to 3-fold. Serum triglycerides were reduced 50% in Hx mice; a further 30% reduction was seen after dietary cholesterol/fat. A serum marker for CYP7A1-mediated bile acid synthesis (C4) increased 2-fold in intact mice on cholesterol/fat diet. In Hx mice C4 levels were reduced by 50% as compared to intact controls, but were unexpectedly increased to levels seen in normal mice upon cholesterol/fat feeding. Hx of LDLRko mice moderately increased LDL-cholesterol and reduced triglycerides and GH treatment attenuated these effects; serum C4 levels were increased by GH treatment in all groups. In conclusion, mice can be used to explore the role of the pituitary in lipid metabolism. CYP7A1 is generally reduced in Hx mice but has a normal stimulatory response following dietary cholesterol suggesting that faulty regulation of CYP7A1 is not important for the reduced resistance to dietary cholesterol in Hx mice. Further, the LDLR is only to a minor part involved in the pituitary regulation of serum cholesterol in mice.     

Tumoricidal responses in vitro of peritoneal macrophages from conventionally housed and germ-free nude mice

Peritoneal macrophages from untreated nude mice were nonspecifically cytotoxic to tumor cells in vitro and were more responsive to chemotactic stimuli than macrophages from normal mice or from phenotypically normal littermates of nude mice. Tumoricidal and chemotactic responses of activated macrophages from nude mice were quantitatively comparable to responses of macrophages from BCG-infected normal mice. Peritoneal macrophages from germ-free nude mice, however, were not tumoricidal in vitro. These observations suggest that environmental stimuli, rather than thymic deficiency per se, induced activated macrophages in nude mice.     

Gender dependent effects of testosterone and 17β-estradiol on bone growth and modelling in young mice

This study examined the effects of estrogen (17β-estradiol) and testosterone on the growth of long bones in male and female mice, with and without gonadectomy. Weight and nose-to-tail length were determined at 3 weeks of age at time of gonadectomy, 7 days later at the onset of hormone therapy, and throughout the treatment period. Gonadectomized mice exhibited an initial weight gain during the pretreatment period but length was unaffected. Hormone treatment altered weight gain in surgical and intact animals in a gender- and hormone-dependent manner. Estradiol enhanced weight gain in intact mice, but inhibited weight gain in ovariectomized mice. Lower doses of estradiol increased weight gain in orchiectomized mice at early time points. Testosterone increased weight in intact females and males, but not in gonadectomized mice. Estradiol increased nose-to-tail length in intact females at early time points, but inhibited length in ovariectomized females at later times, and it decreased length in intact males. Testosterone increased length in normal females and normal males. Serum Ca was unaffected by ovariectomy, but orchiectomy resulted in decreased levels. Estradiol reduced serum Ca in gonadectomized animals; serum Ca was increased by estradiol treatment in intact females. Changes in tibial bone weight, ash weight and mineral composition, and relative sizes of epiphyseal and metaphyseal bone were gender-, gonadectomy- and hormone-specific. Bone weight was greater in ovariectomized mice. Ash weight per bone was comparable, but there was an increase in Ca and P content with ovariectomy. Estradiol increased bone weight, ash content, and bone Ca and P in ovariectomized and intact females. Orchiectomy alone did not alter bone weight, ash content, or Ca and P, but orchiectomized mice were sensitive to estradiol; all parameters were increased in the orchiectomized animals treated with estradiol. Analysis of the ash content and Ca and P per mg bone, rather than per bone, demonstrated estradiol and testosterone alter net bone formation, but not the amount of mineral per unit bone. Ovariectomy increased hypertrophic cartilage. While estradiol did not alter tibial area in ovariectomized mice, it caused an increase in intact females. The total amount of growth plate cartilage in ovariectomized animals was decreased by estradiol to levels typical of intact animals due to a greater decrease in the hypertrophic cartilage in the ovariectomized mice, as well as a greater increase in metaphyseal bone area. Testosterone had no effect on these parameters in the females. Orchiectomy decreased the amount of growth plate cartilage, but increased the hypertrophic zone. Estradiol increased growth plate cartilage in intact male mice, but decreased it in orchiectomized mice. This difference was also seen in the hypertrophic zone. Total growth plate cartilage and hypertrophic cartilage were increased by testosterone in intact males, whereas metaphyseal and epiphyseal bone area were decreased. The results show for the first time that there is a gender-specific response in both male and female mice to both estradiol and testosterone, whether or not the animals have been gonadectomized. For many parameters, orchiectomized mice behave like females in response to both sex steroids, indicating that the male gonad is needed for mouse bone to exhibit the male phenotypic response to estradiol and testosterone.     

Gastrointestinal microecology of BALB/c nude mice.

The aerobic, facultative, and anaerobic microorganisms cultivable from the stomachs, ilea, ceca, and colons of BALB/c athymic (nu/nu) mice (normal and wasting), thymus-implanted normal nude mice, and their heterozygous (nu/+) littermates were investigated. Ninety-one species representing 23 genera of bacteria and yeasts were isolated from the 27 mice. The wasting nude mice showed significantly lower numbers of lactobacilli in their stomach microbiota than did mice from the other three groups. The littermate animals appeared unique among the four groups in having corynebacteria as a major constituent of their stomach and ileal flora. The normal nude mice appeared to have a more diverse anaerobic stomach flora than their heterozygous littermates. These minor differences are discussed with respect to possible immunological, physiological, and environmental factors as their cause. Because the gastrointestinal microfloras of the mice from the four groups were not radically divergent from each other, it was concluded that loss of T-cell function does not dramatically alter the makeup of the cultivable gastrointestinal microflora in these mice.     

Role of GnRH in the regulation of pituitary GnRH receptors in female mice

The fall in pituitary GnRH receptors in female mice after ovariectomy (Ovx) was further decreased (greater than 50%), rather than prevented, by treatment with a GnRH antiserum, despite suppression of the post-gonadectomy increase in serum gonadotrophins, suggesting that increased endogenous GnRH secretion is not the mediator of GnRH receptor fall after ovariectomy in mice. Furthermore, GnRH antiserum reduced GnRH receptors by 30-50% in intact normal females, without altering receptor affinity, and rendered serum LH and FSH undetectable but did not reduce receptors in GnRH-deficient, hpg mice. When GnRH was administered to ovariectomized mice this failed to restore receptor values (fmol/pituitary) (intact = 55.3 +/- 2.4; Ovx = 30.1 +/- 2; Ovx + GnRH = 31.6 +/- 2.8), but serum LH was reduced from high post-ovariectomy values (231 +/- 42 ng/ml) to values normal for intact females (24 +/- 2 ng/ml). In contrast, multiple GnRH injections to intact female mice increased GnRH receptor by 35%, while serum LH was reduced to just detectable levels. A marked dissociation between GnRH receptor and serum gonadotrophin concentrations was observed. Administration of oestrogen (E2) plus progesterone (P) to ovariectomized mice in which endogenous GnRH had been immunoneutralized reversed the inhibitory effect of GnRH antiserum on GnRH receptors and increased values above those of ovariectomized controls, although no increase in serum or pituitary gonadotrophin levels was seen in ovariectomized mice treated with E2 + P + GnRH antiserum. Treatment with E2 and P of intact females receiving GnRH antiserum did not prevent the inhibitory effect of antiserum on receptors, while E2 + P treatment alone of intact female mice reduced GnRH receptors by 30%. These data suggest that the gonadal steroids reduce GnRH receptors in intact female mice by inhibiting hypothalamic GnRH secretion, and that a certain degree of pituitary exposure to GnRH is required for maintenance of a normal receptor complement. These results suggest that (1) the fall in GnRH receptors after ovariectomy is primarily attributable to removal of gonadal factors. The fall is not a reflection of alteration in endogenous GnRH interaction with the gonadotroph; (2) homologous ligand 'up-regulation' of GnRH receptors in female mice depends upon the presence of the ovaries; (3) endogenous GnRH is also required for GnRH receptor maintenance in intact female mice; and (4) GnRH receptor and serum gonadotrophin responses to hormonal changes can be dissociated and their relationship is complex.     

Influence of gender and the endocrine environment on the distribution of androgen receptors in the lacrimal gland

Androgens are known to regulate both the structure and function of lacrimal tissue in a variety of species. To explore the endocrine basis for this hormone action, the following study was designed to: (1) determine the cellular distribution of androgen receptors in the lacrimal gland; and (2) examine the influence of gender and the endocrine environment on the glandular content of these binding sites. Lacrimal glands were obtained from intact, castrated, hypophysectomized, diabetic or sham-operated male or female adult rats, mice or hamsters, as well as from orchiectomized rats exposed to placebo compounds or physiological levels of testosterone. The cellular of androgen receptors was evaluated by utilizing an immunoperoxidase protocol, in which a purified rabbit polyclonal antibody to the rat androgen receptor was used as the first antibody. Our findings with lacrimal glands showed that: (1) androgen receptors are located almost exclusively in nuclei of epithelial cells; (2) the cellular distribution or intranuclear density of these binding sites is far more extensive in glands of males, as compared to females; (3) orchiectomy or hypophysectomy, but not sham-surgery or diabetes, lead to a dramatic reduction in the immunocytochemical expression of androgen receptors; and (4) testosterone administration to orchiectomized rats induces a marked increase in androgen receptor content, relative to that in placebo-exposed glands. Our results also reveal that a 10 kb androgen receptor mRNA exists in the rat lacrimal gland. Overall, these findings demonstrate that gender and the endocrine system may significantly influence the distribution of androgen binding sites in rat lacrimal tissue. Moreover, our results show that androgens up-regulate their own lacrimal gland receptors.     

Immunologic abnormality in NZB/NZW F1 mice. Thymus-independent occurrence of B cell abnormality and requirement for T cells in the development of autoimmune disease, as evidenced by an analysis of the athymic nude individuals

Both NZB nu/+ and NZW nu/+ mice were microbially clean by cesarean section. The (NZB x NZW)F1 hybrid (NZB/W) nu/nu mice and nu/+ littermates were then generated by mating of NZB nu/+ with NZW nu/+mice under specific pathogen-free conditions. The female NZB/W F1 nu/nu mice did not develop autoimmune kidney disease, whereas all of nu/+ female littermates mice exhibited proteinuria and died of renal failure with a 50% survival time of 35 wk. Namely, nude mice had no signs of proteinuria up to the time of their death caused by other diseases rather than glomerulonephritis, and their mean survival time was greater than 45 wk. Nude mice had also no anti-ssDNA antibody in their serum. However, splenic B cells of NZB/W nude mice exhibited hyper-responsiveness to both LPS and B151-TRF2, a T cell-derived polyclonal B cell-stimulation factor, and produced large numbers of Ig-secreting cells and anti-TNP plaque-forming cells as well as anti-ssDNA antibody comparable to the nu/+ littermate mice. Interestingly, thymus-engrafted NZB/W nude mice developed autoimmune disease exemplified by the induction of anti-ssDNA antibody and proteinuria at approximately the same time as their nu/+ littermates. These results indicate that the B cell hyper-responsiveness found in NZB/W mice is apparently determined by the T cell-independent process, and T cells are obligatorily required for the development of autoimmune disease in NZB/W mice.     

Neonatally induced tolerance to soluble protein antigens. II. A role for the thymus in prolonging tolerance

Mice were rendered tolerant to bovine serum albumin (BSA) or fowl γ-globulin (FGG) by neonatal injection. Spleen and thymus cells from tolerant mice were able to suppress responsiveness of normal adult spleen cells, but only if tolerant donor mice were between the ages of 6 weeks and the age at which mice were no longer tolerant (10 weeks for BSA tolerance and 20 weeks for FGG tolerance). To determine whether T-cell-dependent suppression was obligatory for the maintenance of tolerance, neonatal nude and euthymic littermate mice were injected with tolerizing doses of FGG. FGG-specific B-cell tolerance in nude mice lasted until the mice were 8 weeks of age. In sharp contrast, B-cell tolerance in euthymic littermates lasted until 22 weeks of age. These results are consistent with a “fail-safe” role of T-cell-dependent immune suppression in the maintenance of tolerance.