Development of murine lupus in CD4-depleted NZB/NZW mice. Sustained inhibition of residual CD4+ T cells is required to suppress autoimmunity.

Chronic administration of anti-CD4 mAb prevents autoimmune disease in NZB/NZW F1 (B/W) mice. This may be due either to CD4 cell depletion or to inhibition of CD4 cell function. To evaluate the relative importance of these mechanisms, we devised a system in which the consequences of cell depletion could be analyzed independent of the inhibitory effects of chronic mAb therapy.

Thymic influences on autoimmunity in MRL-lpr mice.

We have examined the role of the thymus in the development of autoimmunity in MRL/Mp-lpr/lpr (MRL-lpr) mice. MRL-lpr mice develop a lymphoproliferative disorder characterized by features of systemic lupus erythematosus and by massive proliferation of a subpopulation of Lyt-1+23- T cells. Using fluorescein-conjugated monoclonal antibodies and the fluorescence-activated cell sorter, we have found an abnormal pattern of differentiation within the MRL-lpr thymus characterized by a loss of Lyt-123+ thymocytes and an increased frequency of Lyt-1+23- thymocytes.

Clearance of sensitized erythrocytes in NZB/NZW mice. Effects of castration and sex hormone treatment.

The clearance of particulate immune complexes consisting of erythrocytes sensitized with IgG or complement was investigated in (NZB x NZW)F1 (B/W) mice. Treatment of castrated B/W mice with androgen or estrogen was able to modulate this clearance. Young (3-month-old) male and female B/W mice cleared IgG-sensitized mouse erythrocytes rapidly, whereas older males (13 months) and females (7 months) showed a marked impairment in their ability to clear these cells.

Quantitative immunofluorescence microscopy of renal glomeruli from mice exhibiting murine lupus erythematosus.

Pathologic changes in renal glomeruli of mice with systemic murine lupus erythematosus were quantified using microfluorophotometry. Cryostat sections were taken from kidneys of affected mice, stained with fluorescein-conjugated anti-mouse immunoglobulin, and the extent of immune complex glomerulonephritis was determined. A subjective microscopic examination procedure, which has been used previously, was compared with quantitative microfluorophotometry and a close correlation between the results using each of the two methods was found.

Short gastric veins as the major portal of entry for milk-borne murine mammary tumor virus.

The flow pattern of the short gastric veins that drain the fundic portion of the stomach appeared to influence mammary tumorigenesis. In I and C57BL mice, strains that are highly resistant to murine mammary tumor virus (MuMTV)-induced mammary tumorigenesis, the short gastric veins empty directly into the splenic vein outside the spleen, connecting with the portal system. In (C57BL X I)F1 mice, which are highly susceptible to MuMTV-induced mammary tumorigenesis, the short gastric veins empty directly into the superior hilus of the spleen, connecting with the splenic parenchyma.

Delayed androgen treatment prolongs survival in murine lupus.

Female NZB/NZW F1 mice were treated as adults with 5-alpha-dihydrotestosterone powder packed into subcutaneous implants. Two treatment protocols were followed: (a) 3-mo-old mice received 6 mg of androgen, and (b) 6-mo-old mice were castrated and given 12 mg of androgen. Sham females received empty implants.

Age-related changes in antibody-dependent cell-mediated cytotoxicity in mouse spleen.

The age-related variation in antibody-dependent cell-mediated cytotoxicity (ADCC) in spleen was examined in four different mouse strains (DBA/2, Balb/c, NZB and NZB/NZW). The ADCC effector activity against antibody-coated chicken red blood cells in untreated spleen from all four strains was roughly comparable. An initial rise in activity with increasing age until two to three months was followed by a sharp decline in effector activity.

beta-Estradiol reduces natural killer cells in mice.

beta-estradiol was administered to mice continuously by diffusion from a silastic tube that was implanted subcutaneously at 4 weeks of age. Four to 6 weeks of estrogen administration caused a substantial reduction in natural killer cell activity in the spleens from mice of either sex. Androgen (5alpha-dihydrotestosterone) did not.

Lipopolysaccharide induction of IgM antibodies to polyadenylic acid in normal mice.

Lipopolysaccharide (LPS) is able to induce autoantibodies reversibly in normal mice. Single or multiple doses of LPS induced a rapid and dose-dependent rise in antibodies to Poly A from 113 ng to 590 ng/ml serum as determined by Millipore filter radioimmunoassay. The response peaked at day 3 and was over by day 21.

Effect of castration and sex hormone treatment on survival, anti-nucleic acid antibodies, and glomerulonephritis in NZB/NZW F1 mice.

NZB/NZW F1 mice of both sexes were castrated at 2 wk of age and implanted subcutaneously with silastic tubes containing either 5-alpha-dihydrotestosterone or estradiol-17-beta. Mice receiving androgen showed improved survival, reduced anti-nucleic acid antibodies, or less evidence of glomerulonephritis as determined by light, immunofluorescent, and electron microscopy. By contrast, opposite effects were observed in castrated mice receiving estrogen.

Immunological regulation of spontaneous antibodies to DNA and RNA. III. Early effects of neonatal thymectomy and splenectomy.

NZB/NZW F (B/W) mice were subjected to sham surgery or neonatal thymectomy and/or splenectomy and studied for immunoglobulin class of antibodies to double stranded DNA and polyadenylic acid (Poly A) at 1 and 2 months of age. These antibodies occur spontaneously during the course of autoimmune disease in B/W mice. The serum from sham-operated female mice bound DNA predominantly in the 7S fraction, whereas serum from sham-operated male mice bound DNA primarily in the 19S fraction.

Androgenic hormones modulate autoantibody responses and improve survival in murine lupus.

Antibodies to native DNA and to polyadenylic acid (Poly A) occur spontaneously and undergo a regulated switch from IgM to IgG during the course of autoimmune disease in NZB/NZW F(1) (B/W) mice. B/W females have higher titers and earlier commitment to 7S antibodies to DNA and Poly A, whereas B/W males bind DNA and Poly A primarily by 19S antibodies. We have performed castration experiments to determine the effects of sex hormones on this switch from IgM to IgG.

Effects of neonatal thymectomy and splenectomy on survival and regulation of autoantibody formation in NZB/NZW F1 mice.

NZW F1 (B/W) mice were subjected to sham surgery or neonatal thymectomy and/or splenectomy and studied for immunoglobulin class of antibodies to double-stranded DNA and polyadenylic acid (Poly A) at 4 to 13 months of age. These antibodies occur spontaneously during the course of autoimmune disease in B/W mice. Sera were fractionated by sucrose density gradient ultracentrifugation and assayed for antibodies by a filter radioimmunoassay method.

Inhibition of mammary tumors by incomplete T-cell depletion.

The effects of neonatal and perinatal thymectomy on mammary tumorigenesis in (C57BL X I)F1fC3H hybrid female mice were determined. When hybrid females were neonatally thymectomized by controlled suction, a procedure that removes thymic lobes completely, a large proportion of animals developed stigmas of a fulminant wasting disease and died before tumors developed. However, when hybrid females were subjected to neonatal thymectomy by continuous suction, a procedure that resulted in retention of thymic remnants, they survived and manifested a significant prolongation of latent period before tumorigenesis.

Stimulation of immune mechanisms against mammary tumors by incomplete T cell depletion.

When BALB/cfC3H females are subjected to continous suction thymectomy, a procedure that results in retention of thymic remnants, the latent period before tumor development is significantly prolonged. However, when BALB/cfC3H females are thymectomized by control suction, a procedure which removes thymic lobes completely, there is no effect on mammary tumorigenesis. Our results show that incomplete T cell depletion causes premature onset of non-T cell cytotoxicity, an augmentation of T cell cytotoxicity, and an alteration in a serum-blocking activity to mammary tumor target cells as tested in microcytotoxicity assay.

Characterization of cytotoxic effector cells in the mouse mammary tumor system.

Cell types involved in the immune response in vitro to MTV-induced BALB/cfC3H mammary tumors have been studied with techniques designed to inactivate or deplete different cytotoxic effector cells from spleen cells populations. The minimal activity of spleen cells from neonatally MTV-infected virgin BALB/cfC3H females is dependent upon the presence of T cells. Spleens from multiparous BALB/cfC3H females bearing small tumors are similar to those of tumor-free multiparous females.