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PubMed1999

Elongated telomeres in scid mice.

Severe combined immunodeficiency (scid) mice are deficient in the enzyme DNA-PK (DNA-dependent protein kinase) as a result of the mutation in the gene encoding the catalytic subunit (DNA-PKcs) of this enzyme. DNA-PKcs is a member of the phosphatidylinositol 3-kinase superfamily, which includes the human protein ATM (ataxia telangiectasia mutated) and the yeast protein Tel1. Using Q-FISH (quantitative fluorescence in situ hybridization), we show here that scid mice from four different genetic backgrounds have, on average, 1.5-2 times longer telomeres than those of corresponding wild-type mice. Our results point to the possibility that DNA-PKcs may, directly or indirectly, be involved in telomere length regulation in mammalian cells.

Animals↗

PubMed1994

Host defense mechanisms against murine cytomegalovirus infection induced by poly I:C in severe combined immune deficient (SCID) mice.

The role of host defense mechanism against murine cytomegalovirus (MCMV) infection in mice with severe combined immunodeficiency (SCID) was investigated using polyinosinic:polycytidylic acid (poly I:C) as a nonspecific stimulator of the immune system. When administered ip at doses of 3.7 or 15 mg/kg 18 hr prior to infection of SCID mice with 10(3) or 10(4) plaque-forming units of MCMV, poly I:C significantly increased the animals' life span. Poly I:C enhanced, in a dose-dependent manner (0.01-1 mg/kg), the peritoneal natural killer (NK)-cell activity and macrophage activity of SCID mice. When SCID mice were pretreated with anti-asialo GM1 antibody (against NK cells) or anti-Mac1 antibody (against macrophages), poly I:C failed to stimulate the activity of NK cells and macrophages. Intraperitoneal administration of poly I:C also induced both early (2 hr) and late (18 hr) type interferon (IFN) in the peritoneal fluid and blood. The IFN-inducing activity of polyl:C was not affected by pretreatment of the mice with anti-asialo GM1 or anti-Mac1 antibody. Poly I:C also caused a significant but less pronounced increase in the life span of MCMV-infected SCID mice in which the NK cells or macrophages had been depleted by treatment with anti-asialo GM1 or anti-Mac1 antibody, respectively. These results suggest that poly I:C-induced interferon as well as activation of NK cell and macrophages contribute to the host defense mechanism against MCMV infection in SCID mice.

Animals↗

PubMed1997

Preventive effect of IgG from EBV-seropositive donors on the development of human lympho-proliferative disease in SCID mice.

The effect of weekly treatments with various gammaglobulin preparations on the development of human B-cell tumors was studied in severe combined immunodeficient (SCID) mice. SCID mice were injected i.p. with human peripheral blood mononuclear cells (PBMCs) from an Epstein-Barr virus (EBV)-seropositive healthy blood donor. Repopulated SCID mice were divided into 7 treatment groups receiving either PBS, 2 commercial gammaglobulin preparations, purified IgG prepared from pooled plasma from EBV-seronegative or -seropositive blood donors, a rabbit anti-serum against EBV envelope glycoprotein gp340 or interferon (IFN)-alpha. All treatments started 1 day after injection of PBMC and continued for 8 weeks. In the PBS-treated control group, 85% of mice developed tumors in the abdominal cavity, mostly with liver metastasis within 150 days. Tumor formation was prevented by treatment with the 2 commercial gammaglobulin preparations as well as by purified IgG from EBV-seropositive donors. In contrast, purified IgG from EBV-seronegative donors, rabbit anti-gp340 anti-serum or IFN-alpha had no effect. Our results indicate that the effect of gammaglobulin is due to the presence of specific antibodies against EBV antigens. Further experiments showed that both the time of onset and the duration of treatment, as well as the dose of Ig, are important factors for prevention of tumor formation. Studies aiming at identification of target antigens for antibodies which prevent lymphoma development may be clinically relevant for prevention and possibly treatment of lympho-proliferative disease in severely immuno-compromised patients.

Abdominal Neoplasms↗

PubMed1993

Lymphocyte engraftment conveys immunity and alters parasite development in scid mice infected with Echinococcus multilocularis.

Severe combined immune-deficient (scid) mice, which lack functional B- and T-lymphocytes, were infected with Echinococcus multilocularis larval tissue before or after reconstitution with lymphoid cells from immunocompetent donor mice. Untreated scid mice were highly susceptible to E. multilocularis infection, while scid mice reconstituted with purified lymphocytes derived from either infected or uninfected normal donor mice were capable of almost totally suppressing the growth of the larval cyst mass. The somatic development of the larval parasite varied according to the infection status of the cell donor, with protoscolices forming in scid mice reconstituted with cells from uninfected normal mice but not in those receiving cells from infected normal mice. These results confirm earlier findings that lymphocytes are important in suppressing the growth of E. multilocularis cysts in the intermediate host and also indicate that protoscolex development is influenced by lymphocytes or their products.

Animals↗

PubMed1997

N-acetyl-cysteine and L-2-oxothiazolidine-4-carboxylic acid enhance contact-dependent growth of HIV in resting peripheral blood mononuclear cells (PBMC) in vitro and increase recovery of HIV from human-PBMC SCID mice.

OBJECTIVES: To ascertain the effects of N-acetyl-cysteine (NAC) and L-2-oxothiazolidine-4-carboxylic acid (OTC) on HIV replication in resting T lymphocytes mixed with chronically infected U1 promonocytic cells; examine the phenotypes of NAC- and OTC-treated cells; and monitor HIV recovery from hu-PBMC SCID mice (SCID mice infected with HIV-1BaL reconstituted with human peripheral blood mononuclear cells) treated with oral OTC. DESIGN AND METHODS: Unstimulated PBMC from uninfected donors preincubated for 2 days with pH-adjusted NAC or OTC were cultured at a concentration of 1 x 10(6) cells/ml with 100 U1 cells that were chronically infected with HIV-1IIIB. HI-1 production in the presence or absence of zidovudine was measured by p24 assay at 1-3 weeks, and results were compared with values from the same cell cultures maintained without NAC or OTC exposure. In some experiments U1 cells were separated from PBMC by a 0.4 micron membrane. NAC-treated and -untreated cells were subjected to FACS analysis of multiple-cell-surface adhesion and activation molecules and the results were compared. Hu-PBMC SCID mice were fed OTC for 3 days prior to infection with HIV-1BaL and for the next 3 weeks. Mice were then sacrificed and peritoneal lavage cells were cultured for virus analysis. RESULTS: Unstimulated, non-dividing PBMC supported high levels of HIV replication when in direct contact with U1 cells in the presence of NAC or OTC; CD2 and CD54 (I-CAM1) were down-regulated on NAC-treated PBMC; and OTC-treated mice produced significantly higher yields of HIV-1 from peritoneal cells than did untreated mice. CONCLUSIONS: At concentrations < or = 5 mM, NAC and OTC potentiate HIV growth in unstimulated PBMC in vitro and in SCID mice. Caution in the use of these agents as antiviral monotherapies is advisable.

Acetylcysteine↗

PubMed1999

Antibody-mediated inhibition of the human alloimmune response to platelet transfusion in Hu-PBL-SCID mice.

Severe combined immune deficient (SCID) mice were engrafted with human (Hu) peripheral blood lymphocytes (PBL) from a previously alloimmunized donor and transfused with HLA-mismatched platelets. We have previously shown this to be a useful model for platelet transfusion. These engrafted mice (Hu-PBL-SCID mice) produced high levels of alloantibody in response to standard platelet preparations. However, when the first platelet challenge was presensitized with anti-HLA antibody and then transfused there was a marked reduction in the amount of alloantibody produced to five subsequent untreated platelet transfusions. Platelets pretreated with platelet-specific anti-HPA-1a (PL(A1)) sera did not induce a decrease in the anti-HLA alloantibody response. This demonstrated that platelet-induced HLA alloimmunization can be blocked by anti-HLA antibody-sensitized cells.

Animals↗

PubMed1999

Mycobacterium avium infection in BALB/c and SCID mice.

BALB/c and severe combined immunodeficient (SCID) mice were inoculated intraperitoneally with Mycobacterium avium and the numbers of cfu were monitored for 70 days in spleen, liver, lung, kidney, brain and peritoneum. While BALB/c mice formed typical granulomas and controlled bacterial growth in organs, a delay in development of lesions and a modest containment of infection were observed in SCID mice. In the spleen of BALB/c mice, in which bacterial growth was contained, macrophages (Mo) and natural killer (NK) cell numbers increased > or = 4.2 times and T- and B-cell numbers increased > or = 1.8 times after 42 days of infection; conversely, a low recruitment of mononuclear cells was observed in the spleen of SCID mice, where M. avium proliferated efficiently. Unlike visceral organs, a pronounced decrease in the number of cfu was observed in the peritoneum of BALB/c mice, concomitantly with a > or = 31.7-fold increase in Mo and NK cells and a > or = 9.1-fold increase in T and B cells. In the peritoneum of SCID mice only a bacteriostatic effect was observed despite a > or = 56.7-fold increase in Mo and NK cells and a > or = 22.3-fold increase in T and B cells. These results suggest that while an intact immune response can efficiently control M. avium infection in the spleen and peritoneum of BALB/c mice, cells of the innate immune system such as Mo and NK cells play a role in the containment of bacterial growth in the peritoneum, but not spleen, of SCID mice.

AIDS-Related Opportunistic Infections↗

PubMed2002

Effects of sex and age on the susceptibility of C57BL/6J mice to infection with Brachylaima cribbi and the course of infection in NOD SCID mice.

The C57BL/6J strain of Mus musculus is susceptible to the terrestrial trematode Brachylaima cribbi. The duration of infection in these mice is generally 9-12 weeks with a peak excretion of eggs at 4 weeks post-infection (wpi). The effects of age and sex on the course of infection were investigated by comparing infections in male and female mice aged 8 or 28 weeks at the time of infection. There were no significant differences in the susceptibility of the adolescent mice of either sex or older male mice. However, older, mature female mice were significantly more resistant to B. cribbi infection than older mature males and adolescent females with reduced worm burden, fecundity and egg fertility. In comparison with young males, all three parameters were again reduced but this was only significant statistically for reduced egg fertility. It is likely that mature female sex hormones influence resistance to B. cribbi infection. The susceptibility of immunodeficient NOD SCID mice was evaluated and compared with C57BL/6J mice. NOD SCID mice were susceptible to B. cribbi infection with the infection persisting with a relatively unchanged worm burden for the life of the mouse with the longest surviving mice being 31 wpi. The life-span of B. cribbi is therefore at least 31 weeks. There were no significant differences in egg excretion, worm burden or fecundity among NOD SCID mice at 4, 8 or 18 wpi. As the infection progressed in NOD SCID mice, the location of worms in the small intestine moved from the anterior third in the early stages of the infection to the mid- to posterior intestine in the later stages. Comparison of the infection in NOD SCID mice with C57BL/6J mice indicates that the expulsion of worms in the latter is mediated by an immune response.

Aging↗

PubMed1993

Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine for the treatment of lethal vaccinia virus infections in severe combined immune deficiency (SCID) mice.

Severe combined immune deficient (SCID) mice inoculated intravenously with vaccinia virus (VV) became sick within 6-8 days and died 10-12 days after infection. Tail lesions developed and the number depended on the virus inoculum. Age-matched immunocompetent NMRI mice similarly infected also developed tail lesions but did not become sick. When the infected SCID mice were treated with the acyclic nucleoside phosphonate HPMPC [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine], either for 5 consecutive days starting on the day of infection or for 5 consecutive days starting on day 2, 4, or 6 post infection, or as a single dose at 7 days or 1 day before infection, VV-associated death was significantly delayed. VV-infected SCID mice that received two doses of 20 mg/kg of HPMPC every week survived the infection for about 130 days. The period during which the mice remained disease-free following HPMPC treatment correlated with the absence of detectable virus in their organs. The VV/SCID mouse model employed here may be useful for determining whether (attenuated) recombinant VV (carrying HIV genes) may have detrimental effects in the immunodeficient host. HPMPC may be considered as a drug candidate for the treatment and prophylaxis of such complications.

Animals↗

PubMed1997

Features of Schistosoma mansoni infection in SCID mice.

Features of Schistosoma mansoni infection in SCID mice, which lack functional T- and B-lymphocytes, were investigated. The retarded development of parasites as well as reduction of liver egg recovery in SCID mice was significantly lower than those in congenic counterpart C.B-17 mice. Furthermore, the rate of parasite recovery from SCID mice with primary infection was always lower than that from C.B-17 mice by 20%, showing the innate resistance to S. mansoni infection. SCID mice vaccinated with UV-attenuated S. mansoni cercariae did not show protective immunity against a homologous challenge infection. The present innate resistance exhibited in SCID mice is discussed in relation to cell mediated immunity of macrophage activation by IFN-gamma which would not involve T-lymphocytes but is initiated by IL-12 and TNF-alpha cytokines. SCID mice may provide novel information on the host-parasite relationship in schistosome infections.

Animals↗

PubMed1994

Effect of total body irradiation, busulfan-cyclophosphamide, or cyclophosphamide conditioning on inflammatory cytokine release and development of acute and chronic graft-versus-host disease in H-2-incompatible transplanted SCID mice.

In a previous study, we found that total body irradiation (TBI) was essential to induce acute graft-versus-host disease (GVHD) after allogeneic H-2-incompatible splenocyte (SP) transplantation in SCID mice. SCID mice (H-2d) conditioned with cyclophosphamide and transplanted intravenously (IV) with 5 x 10(7) C57BL/6 (H-2b) SP developed chronic GVHD within 3 months posttransplant without any evidence of preceding acute GVHD. In this study, SCID mice were conditioned with 4 Gy TBI or non-TBI regimens, either BuCy2 (busulfan 4 mg/kg/d + cyclophosphamide 100 mg/kg/d for 2 days) or Cy5 (cyclophosphamide 100 mg/kg/d for 5 days), and then transplanted IV with 5 x 10(7) SP. The TBI-conditioned mice were further divided into tree transplant groups: (1) TBI and SP administered the same day (TBI + D0 SP), (2) SP administered 4 days post-TBI (TBI + D4 SP), and (3) SP administered 7 days post-TBI (TBI + D7 SP). The severity of GVHD was compared among these groups by clinical and histologic grading. Twenty-eight of 28 mice treated with TBI + D0 SP died of acute GVHD, with overwhelming diarrhea by day 15 posttransplantation. Sixteen mice treated with either TBI + D4 SP or TBI + D7 SP developed acute GVHD, but none of them died of this disorder during 30 days posttransplantation. The mice conditioned with non-TBI regimens developed chronic GVHD within 3 months without showing any detectable signs of acute GVHD. Serum and in situ colonic cytokines were determined by enzyme-linked immunosorbent assay and immunohistology respectively. TBI itself significantly increased both serum and colonic tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), and IL-6 when compared with non-TBI regimens and normal controls. TNF-alpha appeared in the serum and colon 4 hours post-TBI and peaked in 24 hours, followed by increasing IL-1 alpha and then IL-6 levels. TNF-alpha and IL-1 alpha decreased rapidly within 3 to 5 days post-TBI if no allogeneic cells were transplanted. Histoincompatible transplantation augmented cytokine release, which remained elevated on day 10 in these animals. Mice treated with TBI + D0 SP developed the most severe acute GVHD and had the highest levels of TNF-alpha, IL-1 alpha, and IL-6. The BuCy2-conditioned mice had the lowest cytokine levels and developed no acute GVHD. When the mice transplanted with TBI + D0 SP were treated immediately with recombinant soluble human TNF receptor (rhuTNFR:Fc) 100 micrograms/d intraperitoneally and for the subsequent 15 days acute GVHD mortality was significantly reduced from 100% to 50% (P < .001).(ABSTRACT TRUNCATED AT 400 WORDS)

Acute Disease↗

PubMed2001

Evaluation of recombinant interleukin-2 immunotherapy for human hemangiosarcoma in a SCID mice model (WB-SCID).

We treated the patients with cutaneous hemangiosarcoma with recombinant interleukin-2 (rIL-2) immunotherapy that showed clear therapeutic effects. This immunotherapy is popular for the treatment of hemangiosarcoma in Japan. The purpose of this study is to clarify the clinical effects in an animal experiment. After establishing a SCID mouse model of human hemangiosarcoma WB-SCID, we used this model to investigate anti-tumor effects of rIL-2 and LAK cells. We demonstrated that hemangiosarcoma cells are LAK-sensitive, and LAK cells induced by rIL-2 suppress the growth of hemangiosarcoma. Our results may assure the clinical effects of rIL-2 immunotherapy on hemangiosarcoma.

Aged↗

PubMed1993

Single and combined humoral and cell-mediated immunotherapy of Pneumocystis carinii pneumonia in immunodeficient scid mice.

Homozygous mutant scid/scid (severe combined immunodeficiency) mice (referred to as scid mice) lack both specific humoral and cell-mediated immune functions and are exemplary in vivo models for analysis of host-parasite relationships. In our colony, scid mice routinely and predictably develop spontaneous Pneumocystis carinii pneumonia (PCP) with high morbidity. Previous studies have identified both T cells (specifically, CD4+ cells) and antibody as independent mechanisms of effective anti-P. carinii resistance; however, CD4+ T cells also cause an often fatal hyperinflammatory reaction. The current study has explored the optimal application of these immune components for conferring protection against P. carinii. Anti-P. carinii hyperimmune serum was highly effective at reducing the number of P. carinii organisms in early, intermediate, and advanced stages of PCP and was capable of increasing the mean life expectancy of P. carinii-infected scid mice by more than threefold if provided on a continuing basis. When a short course of hyperimmune-serum therapy was provided prior to transfer of P. carinii-sensitized normal lymphocytes, scid mice were rendered permanently free of P. carinii without the pathological sequelae of the hyperinflammatory reaction. These findings are discussed in the contexts of mechanism and clinical relevance.

Age Factors↗

PubMed1997

Innervation of the thymus in normal and bone marrow reconstituted severe combined immunodeficient (SCID) mice.

The innervation of the thymus was studied in SCID mice: There was a relatively more dense innervation pattern in SCID mice as compared to normal BALB/c mice (from which SCID mice are derived), including nerve fibres immunoreactive for protein gene product 9.5 (PGP 9.5), tyrosine hydroxylase (TH), neuropeptide tyrosine (NPY) and vasoactive intestinal peptide (VIP), although there was no reactivity to substance P (SP) or leucine enkephalin (ENK). Only a few acetylcholinesterase (AChE)-positive nerve fibres were observed in the SCID thymus. Ten weeks after the transfer of bone marrow from normal BALB/c mice into SCID mice no immunoreactivity to the above markers was found, nor was there any AChE reaction, although histologically the thymus appeared normal and dot-blot assays demonstrated the presence of immunoglobulin indicating a return to normal bone marrow function in SCID mice. Both innervation and morphology were restored 6 months after bone marrow transfer. In conclusion, the thymus of SCID mice lacking thymocytes has visible neurotransmitter levels in the nerves, but after thymocyte repopulation by bone marrow transplantation the transmitters are generally not demonstrable. This indicates that the innervation may be more important for the establishment of the microenvironment rather than the maintenance of thymocyte differentiation.

Animals↗

PubMed1992

T-cell-dependent production of IgG by human cord blood B cells in reconstituted SCID mice.

Reconstitution of severe combined immunodeficient (SCID) mice with human lymphocytes has recently allowed the elucidation of abnormalities of immune responses in various immunological disorders. In the present study, mononuclear cells (MNC) from neonatal cord blood and adult peripheral blood were intraperitoneally injected into SCID mice to examine induction of human Ig in respective mice recipients. Human IgG was consistently detected in the serum of SCID transferred with adult MNC, but only a few SCID recipients of cord blood MNC showed detectable but low levels of IgG in the serum. The combination experiments of isolated B and T cells disclosed that some interactions between B and T cells might be necessary for IgG production in transferred SCID mice. Notably, transfer of cord blood B cells with adult but not cord blood T cells resulted in efficient induction of IgG, associated with a change in subclass distribution. The results suggest that inability of neonatal B cells to produce IgG can be overcome by transfer with adult mature T cells into SCID mice.

Animals↗

PubMed1993

Prophylactic and therapeutic immune reconstitution of SCID mice infected with Encephalitozoon cuniculi.

Severe combined immunodeficient (SCID) mice develop lethal infections, resembling opportunistic microsporidiosis of immunocompromised patients, after intraperitoneal (i.p.) inoculations of spores of Encephalitozoon cuniculi. In the present study, SCID mice reconstituted i.p. with 5 x 10(7) spleen cells from naive adult BALB/c mice 14 days prior to the i.p. injection of 10(7) spores were completely resistant to the infection, whereas control infected SCID mice developed clinical disease and died within 17 days post infection (DPI). In another experiment, SCID mice infected i.p. with 10(7) spores of E. cuniculi and after that (on DPI 7) injected i.p. with 5 x 10(7) spleen lymphocytes isolated from immune adult BALB/c mice were partially protected against the parasite (40% of the reconstituted mice survived). In both experiments, high levels of parasite-specific serum antibodies (mostly of the IgG-isotype) were detected in the infected immunocompetent BALB/c mice, whereas virtually no antibodies were found in the infected SCID mice. However, SCID mice reconstituted with either naive spleen cells or immune lymphocytes revealed humoral immune responses comparable with those of immunocompetent mice.

Animals↗

PubMed1992

Cytokine stimulation of multilineage hematopoiesis from immature human cells engrafted in SCID mice.

Severe combined immunodeficient (SCID) mice transplanted with human bone marrow were treated with human mast cell growth factor, a fusion of interleukin-3 and granulocyte-macrophage colony-stimulating factor (PIXY321), or both, starting immediately or 1 month later. Immature human cells repopulated the mouse bone marrow with differentiated human cells of multiple myeloid and lymphoid lineages; inclusion of erythropoietin resulted in human red cells in the peripheral blood. The bone marrow of growth factor-treated mice contained both multipotential and committed myeloid and erythroid progenitors, whereas mice not given growth factors had few human cells and only granulocyte-macrophage progenitors. Thus, this system allows the detection of immature human cells, identification of the growth factors that regulate them, and the establishment of animal models of human hematopoietic diseases.

Animals↗

PubMed1997

Interleukin-12 modulates the protective immune response in SCID mice infected with Histoplasma capsulatum.

Infection with Histoplasma capsulatum results in a subclinical infection in immunocompetent hosts due to an effective cellular immune response. By contrast, immunodeficient individuals can have a severe disseminated and potentially fatal disease. In a previous study, it was demonstrated that normal mice infected intravenously with H. capsulatum and treated with interleukin-12 (IL-12) at the time of infection were protected from a fatal outcome. In this study, we examined the immunomodulatory effects of IL-12 on disseminated histoplasmosis in immunodeficient SCID mice. SCID mice infected with H. capsulatum and treated with IL-12 showed an increase in survival and a reduction in the colony counts of H. capsulatum in internal organs at 14 days after infection. The protective effect of IL-12 was abrogated if animals were also treated with a neutralizing antibody to gamma interferon (IFN-gamma). IL-12 treatment also resulted in an increase in mRNA expression and protein production for IFN-gamma, tumor necrosis factor alpha (TNF-alpha), and nitric oxide from spleen cells. When IL-12 was combined with amphotericin B (AmB) treatment, there was a significant increase in survival compared with either modality alone. Moreover, combined treatment resulted in an increase in both IFN-gamma and TNF-alpha production, as well as in a substantial reduction in H. capsulatum burden at 35 and 90 days postinfection. This study demonstrates that IL-12 modulates the protective immune response to histoplasmosis in SCID mice and also suggests that IL-12 in combination with AmB may be useful as a treatment for H. capsulatum in immunodeficient hosts.

Amphotericin B↗