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At least 19 recordsLinked to original sources

PubMed1989

Occurrence of mature B (IgM+, B220+) and T (CD3+) lymphocytes in scid mice.

Scid mice with and without detectable serum Ig (scid Ig+ and scid Ig- mice, respectively) were examined for the presence of mature "leaky" lymphocytes by flow microfluorimetry with the use of antibodies to B (IgM, B220) and T (CD3, CD4, CD8) lymphocyte surface Ag. The data showed that leaky scid mice are more frequent than is evident from serum Ig analysis and that the incidence of detectable B and T cells increases with age. IgM+ B220+ cells were not detectable in young adult mice (3 mo old), but in old mice (greater than or equal to 1 yr old) they were routinely present in the peritoneal cavity though not in the spleen. Striking differences in the representation of T cell subsets were seen in the thymus of these two age groups. Most young adult mice contained CD3- populations of CD4/CD8 double positive cells, and in some cases, CD4 or CD8 single positive cells as well. By contrast, identifiable T lineage cells in old mice were all CD3+ and predominantly single positive for CD4 or CD8. Detectable peripheral T cell populations numbered less than 10(5) cells, and the representation of T subset markers (CD4, CD8) varied widely among individual mice; further, Southern blot analysis of TCR gene rearrangements in the DNA of polyclonally stimulated lymphoid cultures from these mice showed very restricted heterogeneity relative to that of cultures from normal mice. We conclude that most leaky mice contain very few T cell clones.

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PubMed1991

CD3+ T cells in severe combined immunodeficiency (SCID) mice. V. Allogeneic T cells engrafted into SCID mice do not induce graft-versus-host disease in spite of the absence of host veto and natural suppressor cell activity.

Intravenous injection of 10(6) to 10(7) non-fractionated spleen cells (SC) from C57BL/6 (B6, H-2b) mice into completely allogeneic, immunodeficient H-2d severe combined immuno deficiency (scid) mice leads to engraftment of allogeneic donor T cells. Mice analysed in the tenth week posttransfer had engrafted donor-type CD4+ and CD8+ T cells in the spleens but showed no clinical evidence of graft-versus-host disease (GVHD). Transfer of allogeneic T cells engrafted in scid recipients did not induce GVHD upon i.v. injection into secondary scid recipients and lead in most recipients to engraftment of a pure CD4+ T-cell population. Experiments were carried out to investigate the reason(s) for the lack of GVHD in recipient scid mice, i.e. the presence of allotolerance in the engrafted donor T cells. Scid spleen cells (SC) efficiently stimulated alloreactive responses of B6 T cells: scid SC stimulated H-2d-specific cytotoxic responses in a B6 anti-scid mixed lymphocyte culture in vitro, and scid SC injected i.v. into B6 mice efficiently primed splenic cytotoxic lymphocyte precursors against H-2d alloantigens. Moreover when assayed in vitro, no veto activity or natural suppressor activity was detectable in scid SC. These data demonstrate that tolerizing mechanisms currently believed to operate in vivo can not explain the fact that allogeneic T cells injected i.v. into immunodeficient scid mice become tolerized against host-type alloantigens. Our results are discussed in the light of clinical experience of allogeneic T-cell transfer in scid infants.

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PubMed1991

CD3+ T cells in severe combined immunodeficiency (scid) mice. II. Transplantation of dm2 lymphoid cells into semi-allogeneic scid mice.

Intravenous injection of nonfractionated BALB/c-H-2dm2 (dm2) (Ld-) spleen cells into 4-week-old, semi-allogeneic (H-2d, Ld+) C.B-17 scid/scid severe combined immunodeficient (scid) mice (2 x 10(7) cells/mouse) reconstituted T lymphopoiesis in thymi and repopulated the lymphoid white pulp in spleens of these immunodeficient recipients. Transplantation of dm2 thymocytes into young scid mice (5 x 10(7) cells/mouse) established a donor-derived CD3+ T cell population in spleens of recipient scid mice, in which CD4+T cells predominated. This was demonstrated by marker analyses of thymocytes and splenocytes, and determinations of serum immunoglobulin levels in transplanted scid mice. Transfer of splenocytes from young primary scid recipients into young secondary or tertiary recipients (3 x 10(6) cells/mouse) engrafted preferentially dm2-derived CD3+CD4+CD8- T cells in spleens of scid mice despite the strong selective Ld-associated alloantigenic stimulus for CD8+ T cells. Intravenous injections of nonfractionated dm2 spleen cells (2 x 10(7) cells/mouse) or thymocytes 5 x 10(7) cells/mouse) into 10- to 12-month-old, "leaky" scid mice induced severe clinical signs of graft-vs.-host disease (GVHD) in all scid recipients. Lymphoid repopulation of spleen and thymus in old scid recipients was incomplete. This GVHD was not transferrable by injecting 3 x 10(6) spleen cells from old diseased primary scid recipients into secondary or tertiary young scid recipient mice. In these serial transfers, dm2-derived CD3+CD4+CD8- T cells were again preferentially engrafted in spleens of scid recipients. Transfer of purified CD4+ dm2 T cells into young scid mice (2 x 10(5) to 5 x 10(5) cells/mouse) engrafted this T cell subset into the spleen of semi-allogeneic scid recipients. This was revealed by histological examinations, surface marker analyses, in vitro isolation of donor-type CD3+CD4+ T cell lines from spleens of transplanted scid mice, and serial transfer experiments. These data indicated that the CD4+ T cell compartment of scid mice can be selectively repopulated by semi-allogeneic T cells. Injections of purified CD8+ dm2 T-cells into young scid mice (2 x 10(5) cells/mouse) did not establish a CD8+ T cell graft in spleens of recipients. It was necessary to inject transplanted scid mice biweekly with 10(4) units recombinant interleukin 2 to establish and/or maintain transferred dm2 CD8+ T cells in spleens of these recipients, dm2 CD8+ T cell-transplanted and interleukin 2-treated scid mice did not develop any evidence of GVHD over the 9-week observation period.

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PubMed1991

CD3+ T cells in severe combined immunodeficiency (scid) mice. IV. Graft-vs.-host resistance of H-2d scid mice to intravenous injection of allogeneic H-2b (C57BL/6) spleen cells.

Intraperitoneal injection of 2 x 10(7) nonfractionated spleen cells (SC) from C57BL/6 (B6, H-2b) mice into completely allogeneic immunodeficient H-2d scid mice induced clinical and histological signs of acute graft-vs.-host disease (GVHD), with all transplanted severe combined immunodeficiency (scid) mice dying in the 3rd week post-transfer. In contrast four out of five scid mice survived for greater than 7 weeks after intravenous (i.v.) injections of equal numbers of B6 SC. Intravenously allotransplanted scid mice analyzed in the 8th week post-transfer had engrafted donor-type CD4+ and CD8+ T cells in the spleens but showed no clinical or histological evidence of GVHD. i.v. injection of 10(7) or 10(6)O B6 SC engrafted allogeneic T cells in spleens of scid recipients; in contrast, i.v. injection of 10(5) nonfractionated B6 SC or 3 x 10(5) cell sorter-purified, naive or anti-H-2d-primed splenic CD4+ or CD8+ B6 T cells led to rejection by young scid recipient mice. B6 T cells engrafted into spleens of scid mice after i.v. injection showed proliferative anti-host alloreactivity in vitro. No cytotoxic reactivity against host-type alloantigens was found in standard 4-h 51Cr-release assays. These data demonstrate that allogeneic T cells injected i.v. into immunodeficient scid mice are partially tolerized against host-type alloantigens.

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PubMed1990

T-cell receptor gene rearrangements in functional T-cell clones from severe combined immune deficient (scid) mice: reversion of the scid phenotype in individual lymphocyte progenitors.

The severe combined immune deficient (scid) mouse mutant is characterized by a general absence of functional B and T lymphocytes. This deficiency appears to result from a defect in the variable-diversity-joining (VDJ) recombinase system, which is responsible for the assembly of V, D, and J gene segments that code for immunoglobulin and T-cell receptor (TCR) V regions. Most rearranged immunoglobulin or TCR genes in transformed scid lymphocytes contain abnormal J-associated deletions and are nonfunctional. A few functional lymphocyte clones do arise, however, in some young adult scid mice and in virtually all old scid mice; this phenomenon is referred to as leakiness. Alloreactive, CD3+ T-cell clones were isolated from leaky scid mice and the status of their TCR beta and gamma loci was examined in an effort to assess the nature of the recombinase activity that gives rise to functional scid lymphocytes. The recombination junctions of six gamma and two beta alleles were sequenced, representing four alloreactive T-cell clones. All of the junctions were indistinguishable from those seen in normal cells. These results cannot be attributed to selection by antigen because other rearranged TCR genes account for the TCR molecules expressed by these T-cell clones. We conclude that reversion of the scid phenotype can occur in rare lymphocyte progenitors and may account for most functional lymphocyte clones in leaky scid mice.

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PubMed1992

Comparative studies between nude and scid mice on the growth and metastatic behavior of xenografted human tumors.

The growth and metastatic behavior of three human tumor cell lines and a human colon carcinoma previously passaged in vivo were compared between nude mice and scid mice after xenotransplantation. The three human tumor lines included a bladder carcinoma (T24B), a melanoma (RPMI 7931) and a lacZ gene-transduced breast cancer (MDA-MB-435 BAG). The lacZ gene codes for beta-galactosidase, which can be stained blue with chromogenic substrate X-gal, thus allowing the highly sensitive detection and quantitative examination of human cancer metastasis in host mice. Adult (7-14 weeks) NMRI nude and C.B-17 SCID mice were inoculated with 0.5-5 x 10(6) tumor cells s.c. Comparable take rate, latent period and growth rate of implanted tumors were observed in nude and scid mice for each of the cell lines tested. At the time of autopsy, which varied from 6 to 11 weeks after inoculation, a significantly higher incidence of spontaneous lung metastasis was discovered in scid mice (96%) than in age-matched nude mice (27%, total P less than 0.001). In vitro assays for NK cell-mediated cytotoxicity revealed no significant differences between the two strains of mice. Our results suggest that nude and scid mice are equally suitable for propagating human tumors. However, the metastatic capacity of human tumor cells appears to be better expressed in scid mice. Scid mice may therefore provide an advantageous model for the study of human tumor metastasis.

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PubMed1988

Transcription of unrearranged antigen receptor genes in scid mice.

The scid mouse mutant is severely deficient in lymphocytes; cells of the B or T lymphocyte lineage cannot be detected by either serological or functional assays. However, as shown here, germ-line transcripts of B cell immunoglobulin (Ig) constant and variable region genes and of T cell receptor (TCR) genes are detectable in lymphopoietic tissues of scid mice, as well as B and T lineage-specific lambda 5 and T3 delta transcripts. We conclude that B and T lineage-committed cells do arise in scid mice and that their Ig and TCR genes are accessible to enzymes involved in their recombination. This suggests that scid impairs lymphopoiesis at the stage at which antigen receptor genes normally undergo rearrangement.

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PubMed1991

CD3+ T cells in severe combined immune deficiency (scid) mice. I. Transferred purified CD4+ T cells, but not CD8+ T cells are engrafted in the spleen of congenic scid mice.

Young (less than 3 months of age) and old (greater than 1 year of age) C.B-17 scid/scid mice were tested for the presence of immunoglobulin in serum and CD3+ T cells in spleen and peritoneal cavity. In all old severe combined immune deficiency (scid) mice tested we found detectable, but very variable levels of serum immunoglobulin as well as splenic and peritoneal CD3+ T cells comprising 3% to 10% of the nonfractionated cell populations of these organs (n = 10). In contrast, none of the analyzed young scid mice showed any evidence of peripheral lymphocytes. Low numbers (2 x 10(5) to 5 x 10(5) cells/mouse) of highly purified CD4+ cells from congenic C.B-17 or BALB/c donor mice were injected intravenously into young scid recipient mice. A CD4+ T cell population was clearly engrafted when transplanted scid mice were analyzed 8 to 13 weeks after T cell transfer: (a) a CD3+CD4+CD8- T cell population was detectable in the spleens of all recipient scid mice by flow microfluorometry analyses; (b) CD3+CD4+CD8 T cell lines could be grown out of these spleens in vitro; (c) the histological examination revealed evidence of lymphoid cell repopulation in the spleens of all transplanted scid mice and (d) transplanted CD4+ T cell populations could be serially transferred into secondary and tertiary recipient scid mice. These data indicate that scid mice can be constructed in which only the CD4+ T cell compartment is selectively reconstituted. In contrast to the successful engraftment of CD4+ T cell, highly purified congenic CD8+ T cells could not be engrafted into the spleen of scid mice.

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PubMed1992

CD4+CD8- thymocytes from neonatal mice induce IgM production in SCID mice.

Defective recombination of both the TCR and Ig genes results in the absence of mature lymphocytes in mice with the scid mutation. We have shown previously that the transfer of neonatal, but not adult, thymocytes results in high levels of Ig production in 100% of C.B-17-scid (SCID) mice, in contrast to the 10 to 25% of SCID mice spontaneously producing low levels of oligoclonal Ig. In this report we demonstrate that neonatal CD4+8- thymocytes were able to induce this response; the CD4+8+ and CD4-8+ subpopulations were totally inactive and CD4-8- T cells had only limited activity several weeks after transfer. The stimulation of IgM production in SCID mice was detectable by 1 wk posttransfer of CD4+8- thymocytes or splenic T cells, and could be achieved with as few as 300 cells. The ability of neonatal CD4+8- thymocytes to induce Ig diminished gradually to insignificant levels at 3 wk postbirth; this loss of function was not associated with differential survival of neonatal T cells. Neonatal CD4+8- thymocytes from C.B-17 and other H-2d strains rescued Ig production, whereas cells from H-2b, H-2a, and H-2k strains were much less effective. These results suggest that a CD4+8- subpopulation found in both neonatal thymus and peripheral lymphoid tissues is able to induce the expansion or differentiation of the small numbers of functional B lymphocytes in SCID mice, and that the inducing T cell disappears shortly after birth, perhaps during the acquisition of self-tolerance.

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PubMed1989

Analysis of lymphoid population in scid mice; detection of a potential B lymphocyte progenitor population present at normal levels in scid mice by three color flow cytometry with B220 and S7.

We have used 3 color FACS analysis (together with dead cell exclusion by propidium iodide) to ascertain the levels of lymphoid lineage cells present in typical young adult (2-5 month) SCID mice. Both mature and early B and T lineage cells are severely decreased (greater than 100X) in thymus, spleen and peritoneum of such mice. Analysis revealed a significant fraction of B220+ cells in bone marrow and, curiously, all such cells co-expressed a determinant recognized by the S7 antibody, likely lost early in B lineage differentiation. Thus, together with B220, expression of S7 may serve to mark the stage at which the SCID defect first becomes manifest, at least in the B lineage. This suggests that B220+/S7+ cells in bone marrow may be pro-B cells or even a lymphoid progenitor population.

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PubMedDate not supplied

Study on placental transmission of Pneumocystis carinii in mice using immunodeficient SCID mice as a new animal model.

Placental transmission of Pneumocystis carinii in mice was examined in 39 animals obtained by caesarean section from 17 pregnant SCID females experimentally infected with P. carinii. When examined with toluidine blue O, DAPI and immunofluorescent antibody stains, P. carinii was detected in the lungs of infected mothers but not in the lungs of caesarean section-derived neonates even after the neonates were treated with dexamethasone for 8 weeks. However, 13 neonates born to five infected females developed P. carinii pneumonia. These results indicate that P. carinii cannot be transmitted transplacentally in mice.

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PubMed1992

Multiplication of human-derived Pneumocystis carinii in severe combined immunodeficient (SCID) mice.

Clinically healthy SCID mice were infected intratracheally with Pneumocystis carinii (PC) of human origin. The data obtained provides unambiguous evidence that progressive multiplication of PC organisms of human origin takes place in the lungs of experimentally infected animals. SCID mice that were infected with human-derived PC also revealed a markedly greater number of mouse PC organisms in their lungs than the controls. All the SCID recipients of human PC died by day 65 post infection, whereas the controls, housed under identical conditions, started dying significantly later due to severe mouse pneumocystosis. This animal model could be used for the maintenance and propagation of human PC, and for evaluating strategies for treating human pneumocystosis.

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PubMed1992

CD3+ T cells in severe combined immunodeficiency (scid) mice. VI. Rescue of scid-derived, IgM-producing B cells by transfer of CD4+ CD8- T cells from various lymphoid organs.

Intravenous injection of purified CD4+ CD8- T cells from thymus, spleen or lymph nodes of adult dm2 donor mice (H-2d, Ld-, IgMa) into young C.B-17 scid/scid (scid) mice (H-2d, Ld+, IgMb) partially and selectively reconstituted the splenic CD4+ T-cell compartment of recipient scid mice. This was demonstrated by cytofluorographic analyses, histological examinations, growing donor-derived CD4+ T-cell lines in vitro from spleens of transplanted scid mice, and serial passage of Ld-, CD3+CD4+CD8- T-cell lines through young scid recipients for more than 1 year. Host-derived IgMb appeared in sera of all CD4+ T-cell-transplanted young scid mice, while none of the sex- and age-matched, non-transplanted control scid mice was Ig+. B-cell leakiness was most efficiently induced by transfer of low numbers of adult CD4+ CD8- thymocytes: transfer of 10(3) purified CD4+ CD8- thymocytes efficiently rescued scid-derived B cells, while transfer of 2 x 10(7) non-fractionated thymocytes from the same donor mouse was inefficient. Serum antibodies of scid mice with T-cell-induced B-cell leakiness stained congenic 'double-positive' (CD4+ CD8+) thymocytes and immunoprecipitated protein bands with an apparent MW of 14,000, 28,000, 43,000, 65,000 and 80,000 from 125I-labelled thymocytes. These data indicate that repopulation of peripheral lymphoid organs with CD4+ T cells is always accompanied by partial co-reconstitution of the B-cell system, and raises the question of the interdependence of these two lymphocyte subsets.

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PubMed1991

Human immunodeficiency virus infection of human-PBL-SCID mice.

Severe combined immunodeficient (SCID) mice reconstituted with human peripheral blood leukocytes (hu-PBL-SCID mice) have inducible human immune function and may be useful as a small animal model for acquired immunodeficiency syndrome (AIDS) research. Hu-PBL-SCID mice infected with human immunodeficiency virus-1 (HIV-1) contained virus that was recoverable by culture from the peritoneal cavity, spleen, peripheral blood, and lymph nodes for up to 16 weeks after infection; viral sequences were also detected by in situ hybridization and by amplification with the polymerase chain reaction (PCR). Mice could be infected with multiple strains of HIV-1, including LAV-1/Bru, IIIB, MN, SF2, and SF13. HIV-1 infection affected the concentration of human immunoglobulin and the number of CD4+ T cells in the mice. These results support the use of the hu-PBL-SCID mouse for studies of the pathogenesis and treatment of AIDS.

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PubMed1992

High yields of anti-HLA human monoclonal antibodies can be provided by SCID mice.

In an attempt to develop a suitable model for increasing the yield of human anti-HLA mAbs, we have used mice with SCID for i.p. injection of two human-mouse heterohybridomas. HMP1 hybridoma secretes a DQB1*0201 allele-specific human mAb whereas HMP12 secretes a human mAb recognizing the DRB1*1101, 1102, 1103, and 1104 alleles. Both hybridomas could be grown in SCID mice as localized tumors with no apparent alteration in the morphology of the cells or in the immunoglobulin secretion. Ascitic fluid was produced that showed a 600- to 1000-fold increase in monoclonal antibody cytotoxic titer as compared with that obtained in tissue culture. HLA-DQB1* and DRB1* alleles recognized by ascites and supernatants from SCID-derived cultures were analyzed by microlymphocytotoxicity assay on a small panel of B-lymphoblastoid cell lines. The results show that HLA specificity was retained after in vivo passage.

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PubMedDate not supplied

Introduction of Pneumocystis carinii in a colony of SCID mice.

Pneumocystis carinii-free SCID mice were housed closely exposed to corticosteroid-treated non-SCID mice in a conventional area of our laboratory animal facilities. A one-day exposure was sufficient for P. carinii transmission. The lung infection increased thereafter. Irradiation or splenectomy of SCID mice at the beginning of the exposure resulted in a marked increase of parasite multiplication. Extrapulmonary foci of pneumocystosis were detected in heart and spleen of SCID mice infected by P. carinii via air transmission.

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PubMed1992

Immune responses to Cryptosporidium muris and Cryptosporidium parvum in adult immunocompetent or immunocompromised (nude and SCID) mice.

Adult murine models of Cryptosporidium infection involving Cryptosporidium muris and C. parvum were used to study immunity to cryptosporidiosis in the mammalian host. Immunocompetent BALB/c or C57BL/6 mice developed a highly patent infection with the RN 66 strain of C. muris but overcame the infection and were immune to reinfection. In contrast, severe combined immunodeficiency (SCID) mice or nude mice had a chronic infection lasting at least 109 days. The development of the C. muris infection appeared to be confined to the gastric epithelium in immunocompetent and immunocompromised mice. SCID mice injected intraperitoneally with histocompatible spleen or mesenteric lymph node cells from uninfected BALB/c mice were able to recover from the C. muris infection. The protective effect of donor spleen cells was not reduced by depletion of the B cell population but was significantly reduced by depletion of Thy.1 cells. Treatment of C57BL/6 or BALB/c mice during infection with a gamma interferon-neutralizing monoclonal antibody, but not a tumor necrosis factor-neutralizing monoclonal antibody, resulted in a significant increase in oocyst production. In the C. parvum model, a severe and eventually fatal chronic infection with a cervine isolate was established in SCID mice, with parasitization occurring in the ileum, cecum, and colon. SCID mice injected with unprimed BALB/c spleen cells prior to inoculation of C. parvum oocysts were resistant to infection. These results suggested that the two animal models should be valuable in the study of immunity to cryptosporidial infection.

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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.

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