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PubMed1999

Development of intraepithelial T lymphocytes in the intestine of irradiated SCID mice by adult liver hematopoietic stem cells from normal mice.

BACKGROUND/AIMS: We recently reported the adult mouse liver to contain c-kit+ stem cells that can give rise to multilineage leukocytes. This study was designed to determine whether or not adult mouse liver stem cells can generate intraepithelial T cells in the intestine as well as to examine the possibility that adult liver c-kit+ stem cells originate from the fetal liver. METHODS: Adult liver mononuclear cells, bone marrow (BM) cells, liver c-kit+ cells or bone BM c-kit+ cells of BALB/c mice were i.v. transferred into 4 Gy irradiated CB17/-SCID mice. In other experiments, fetal liver cells from Ly5.1 C57BL/6 mice and T cell depleted adult BM cells from Ly5.2 C57BL/6 mice were simultaneously transferred into irradiated C57BL/6 SCID mice (Ly5.2). At 1 to 8 weeks after cell transfer, the SCID mice were examined. RESULTS: Not only BM cells and BM c-kit+ cells but also liver mononuclear cells and liver c-kit+ cells reconstituted gamma delta T cells, CD4+ CD8+ double-positive T cells and CD8 alpha+beta- T cells of intestinal intraepithelial lymphocytes of SCID mice. Injection of a mixture of fetal liver cells from Ly5.1 C57BL/6 mice and adult BM cells from Ly5.2 C57BL/6 mice into Ly5.2 C57BL/6 SCID mice induced both Ly5.1 and Ly5.2 T cells, while also generating c-kit+ cells of both Ly5.1 and Ly5.2 origins in the liver. CONCLUSIONS: Adult mouse liver stem cells were able to generate intestinal intraepithelial T cells of the SCID mice, and it is thus suggested that some adult liver stem cells may indeed be derived from the fetal liver.

Animals↗

PubMed1991

Selective reconstitution of T lymphocyte subsets in scid mice.

The 'empty' splenic T-cell compartment of young scid mice was partially and selectively reconstituted by low numbers of adoptively transferred congenic (C.B-17, BALB/c) or semi-allogeneic (dm2), but not completely allogeneic (C57BL/6) CD4+ T cells from adult donor mice. Under the same experimental conditions, the CD8+ T-cell compartment of young scid mice could only be reconstituted in scid mice continuously substituted with IL-2. CD4+ T cells engrafted in the spleen of H-2d scid recipients displayed specific, anti-Ad-associated proliferative reactivity. (Semi)allogeneic CD8+ T cells engrafted in spleens of scid recipients showed no anti-host H-2 class I-associated cytotoxic reactivity, i.e., this T-cell compartment was specifically tolerized against host (allo)antigens. Reconstitution of lymph nodes was not observed following transplantation of purified CD4+ or CD8+ T cells. Antigen-specific, cellular immune responses could not be induced in scid mice selectively reconstituted with either CD4+ T cells or CD8+ T cells. Partial reconstitution of the CD4+ T-cell compartment was always associated with the appearance of scid-derived, 'endogenous' IgM-producing B cells. Serum antibodies of scid mice with this T cell-induced B-cell leakiness stained an immature subset of congenic thymocytes.

Animals↗

PubMed2004

Human prolactin improves engraftment and reconstitution of human peripheral blood lymphocytes in SCID mice.

Recombinant human prolactin (rhPRL) was administered to huPBL-SCID mice to determine its effects on human immunologic reconstitution and function. The huPBL-SCID mice were given 10 microg i.p. injection of rhPRL every other day for a total of 10 injections after huPBL were transferred. The results demonstrated that rhPRL improved the engraftment of lymphocytes into thymus, lymph nodes and spleens, showing that the cellularities of these organs increased although the cellularities tended to vary depending on the donor. The amounts of human T cells (HLA-ABC+/CD3+) increased greatly in thymus (14.2 folds), spleen (4.16 folds) and lymph nodes (40.18 folds) after rhPRL injections. The amounts of human B cells (HLA-ABC+/CD19+) also increased greatly in lymph nodes (42.5 folds) and spleen (5.78 folds). The lymph node cells from the rhPRL-treated huPBL-SCID mice were more sensitive to PHA stimulation ([3H] thymidine incorporation). The supernatant of PHA-stimulated PBL from rhPRL-treated huPBL/SCID chimerism contained more cytokines (IFN-gamma and IL-2). The natural cytotoxicity against human sensitive target cells, K562 cells, from spleen and bone marrow of hPBL/SCID chimerism was significantly enhanced by rhPRL administration. The lymph node cells were stimulated with LPS in vitro for 3 days and the lymphocytes from the rhPRL-treated huPBL-SCID mice were more sensitive to mitogen stimulation. Both serum total IgG level and IgM level of rhPRL-treated huPBL/SCID chimerism were increased, and even without DT-rechallenge the base line of DT-specific IgG was elevated after rhPRL treatment in huPBL-SCID mice. Thus, rhPRL stimulation promotes reconstitution of human immune system in huPBL-SCID mice.

Animals↗

PubMed1995

The human immune system in hu-PBL-SCID mice.

Severe combined immunodeficiency (SCID) mice can be stably grafted with human peripheral blood lymphocytes, creating hu-PBL-SCID chimeras; essentially, these are mice with a human immune system. Here, Magdalena Tary-Lehmann, Andrew Saxon and Paul Lehmann discuss the immunobiology of these chimeras. The authors propose that hu-PBL-SCID chimerism evolves in two phases. During the first three weeks after grafting, many of the injected cells survive and the human immune system is functional. Subsequently, anti-mouse-reactive clones are selected and the immune system becomes nonfunctional. The implications of this scenario for the utilization of the hu-PBL-SCID model are discussed.

Animals↗

PubMed1991

Strong priming of T cells adoptively transferred into scid mice.

We have examined the requirements for activating unprimed T cells in vivo by transferring T cells into scid mice, which lack mature B and T cells. Purified adult thymocytes and a protein antigen, keyhole limpet hemocyanin (KLH), were injected into scid mice. scid mice injected with T cells and KLH developed cellular lymph nodes containing CD4+ and CD8+ T cells. Cells recovered from the lymph nodes of injected scid mice proliferated and secreted interleukin 2 in response to KLH in vitro. The results indicate that T cells can be primed to KLH in the scid mouse in the absence of B cells.

Animals↗

PubMed1992

Human peripheral blood leukocytes transplanted on CB17 scid-scid mice are transferred to their offspring.

Severe combined immunodeficient (scid) mice are deficient in functional T cells and B cells. Hence, scid mice reconstituted with human peripheral blood leukocytes (scid-huPBL) provide an excellent model for analysis of the human immune response under in vivo conditions. We have investigated this model further by analyzing human immune responses in the progeny of scid-huPBL (termed scid-humo). We find markedly elevated levels of human immunoglobulins (Ig) in the serum of scid-humo for more than 12 weeks indicating materno-fetal transfer of human B lymphocytes. Consistent with this finding we obtained evidence for the existence of human lymphocytes in scid-humo. Murine Ig levels in scid-humo were also elevated and surface Ig-expressing cells (probably B cells) were demonstrable. In this respect scid-humo resembled "leaky" scid. In contrast to "leaky" scid, scid-humo accepted transfer of human blood leukocytes. Not only leukocytes from autologous but also those from heterologous donors were accepted. Human Ig levels in scid-humo increased more rapidly as compared to normal scid mice. Thus, despite these increased B cell activities in scid-humo, transferred human leukocytes were not affected indicating that materno-fetal transfer of human cells had caused tolerization or conditioning. This is in contrast to scid mice in which elevated Ig levels correlate with increased failure rates of reconstitution with human blood leukocytes. We propose that scid-humo provide an improved model for studying the human immune responses in an in vivo setting.

Animals↗

PubMed1996

The anti-Dextran response of scid mice transgenic for the heavy chain of a Dextran specific IgM antibody.

Mice homozygous for the scid mutation bear a severe defect in their ability to rearrange V(D)J gene segments to yield active genes for immunoglobulin and T cell receptor molecules. In older animals few clones of B and T cells can arise at random, a phenomenon called leakyness of the scid mutation. We established scid mice carrying as a transgene the rearranged heavy chain of the IgM/lambda1 antibody MOPC 104E with specificity for the alpha(1,3) glucosidic linkages in Dextran. Despite the scid defect one-third of these mice immunized with the thymus independent antigen Dextran at 2 weeks of age, and all of those immunized at 6 weeks responded with anti-Dextran antibodies bearing the lambda light chain. This indicates that despite the scid mutation these animals had at least once successfully rearranged their endogenous lambda1 light chain gene segments and harbor Dextran specific B cells. These mice thus provided for the first time the opportunity to study the immune response of B cells of a single specificity in an environment that should, as we shall argue, be devoid of regulatory B and T cells able to recognize the idiotype of the responding cells. One week after immunization the anti-Dextran response of 5- to 6-week-old mu-transgenic scid mice amounted to 30% of the response of mu-transgenic non-scid mice but in essence both responses followed the same kinetics, reaching antibody concentrations indistinguishable from each other 8 weeks after a single dose of Dextran. Furthermore, the ready response of young mu-transgenic scid mice to this antigen by employment of endogenously rearranged lambda1 light chains allowed experiments to be done to compare the frequency of lambda1 light chain rearrangements in mu-transgenic scid mice to that in mu-transgenic non-scid mice. This was done in limiting dilution assays counting B cell precursors responsive to mitogen and differentiating in vitro to produce antibodies toward Dextran. Specific precursors were reduced to about 1% in the spleen of mu-transgenic scid mice when compared to the spleen of mu-transgenic non-scid mice; those in the peritoneal cavity lymphocyte population were reduced to about 12%.

Animals↗

PubMed1999

Decreased growth of human prostate LNCaP tumors in SCID mice fed a low-fat, soy protein diet with isoflavones.

Epidemiological studies suggest that high intake of dietary fat is a risk factor for the development of clinical prostate cancer. Soy protein has also been proposed to play a role in the prevention of prostate cancer, and one of the isoflavones in soy protein, genistein, inhibits the growth of human prostate cancer cell lines in vitro. This study was designed to evaluate whether altering dietary fat, soy protein, and isoflavone content affects the growth rate of a human androgen-sensitive prostate cancer cell line (LNCaP) grown in severe-combined immunodeficient (SCID) mice. SCID mice were randomized into four dietary groups: high-fat (42.0 kcal%) + casein, high-fat (42.0 kcal%) + soy protein + isoflavone extract, low-fat (12.0 kcal%) + casein, and low-fat (12.0 kcal%) + soy protein + isoflavone extract. After two weeks on these diets, the mice were injected subcutaneously with 1 x 10(5) LNCaP tumor cells and placed in separate cages (1 mouse/cage) to strictly control caloric intake. Isocaloric diets were given 3 days/wk, and tumor sizes were measured once per week. The tumor growth rates were slightly reduced in the group that received the low-fat + soy protein + isoflavone extract diet compared with the other groups combined (p < 0.05). In addition, the final tumor weights were reduced by 15% in the group that received the low-fat + soy protein + isoflavone extract diet compared with the other groups combined (p < 0.05). In this xenograft model for prostate cancer, there were statistically significant effects on tumor growth rate and final tumor weight attributable to a low-fat + soy protein + isoflavone extract diet.

Animals↗

PubMed1993

Exacerbation of Pneumocystis carinii pneumonia in immunodeficient (scid) mice by concurrent infection with a pneumovirus.

scid mice naturally infected with Pneumocystis carinii and inoculated with a normally apathogenic pneumovirus had significantly higher P. carinii cyst counts and developed significantly more severe P. carinii-related disease than did sham-inoculated, P. carinii-infected scid mice. P. carinii-free, virus-infected scid mice survived for 2 months despite high pulmonary virus titers. These results show that a respiratory virus infection can exacerbate P. carinii disease in an immunocompromised-rodent model.

Animals↗

PubMed1998

Induction of oral tolerance in splenocyte-reconstituted SCID mice.

The participation of each lymphocyte compartment in the induction of oral tolerance for antibody response was investigated by means of a new cell-transfer experimental system, using severe combined immunodeficiency (SCID) mice. Various lymphocyte compartments from BALB/c mice were transferred into SCID mice and these mice were evaluated for oral tolerance induction. First, whole splenocytes from BALB/c mice were transferred into SCID mice and these mice were orally administered bovine alpha s1-casein. The specific antibody response in these mice after subsequent immunization with antigen was greatly reduced compared to controls which were not fed the antigen, and it was demonstrated that oral tolerance was induced in SCID mice bearing donor splenocytes. Oral tolerance was induced in SCID mice that were reconstituted with only T cells, revealing that B cells were not required for the induction of oral tolerance. Further, oral tolerance was induced in SCID mice reconstituted with CD8-depleted splenocytes but not in mice reconstituted with only CD8+ T cells. These results demonstrate that oral tolerance could be induced in SCID mice bearing normal splenocytes and that interaction of CD4+ T cells with antigen-presenting cells other than B cells are responsible for the induction of oral tolerance. Our experimental system may be useful for investigations with human lymphocytes.

Administration, Oral↗

PubMed1994

T cells and natural killer cells regulate human IgG subclass concentrations in SCID mice.

Cytokine regulation of human IgG subclass production is not well understood. Since T cells and natural killer (NK) cells produce IL-4 and/or IFN-gamma, we examined the effect of these cells on human IgG subclass concentration in reconstituted severe combined immunodeficient (SCID) mice. SCID mice receiving only B-cell-enriched splenocyte preparations had significantly decreased IgG concentrations and significantly decreased IgG1/IgG2 ratios compared to mice receiving B cells plus T cells (P = 0.02). IgG2 represented 58% of the total IgG at 28 days in mice receiving B-cell-enriched preparations compared to 19% of the total for the group receiving both B cells and T cells (P = 0.013). The effect of natural killer cells (CD16+) on IgG subclass was also studied in this model. IgG2 concentrations were twofold higher in mice receiving CD16-depleted cells compared to controls (P = 0.004). No significant differences were noted for IgG1, IgG3, or IgG4 subclass concentrations. In conclusion, T cells and natural killer cells influence human IgG subclass regulation in the SCID mouse model. We propose that the regulation of human IgG subclass production can be further examined in the SCID model.

Animals↗

PubMed1993

Regulation of human IgE response in hu-PBL-SCID mice.

The human IgE response was investigated in hu-PBL-SCID mice created by ip injection of human PBL into C.B.17 scid/scid (scid) mice. With 30-100 x 10(6) PBL/mouse, 80 to 90% of the animals responded with human IgE serum levels of 3-1000 ng/ml after 2 weeks. PBL from all donors analyzed (total number > 20) responded with IgE production. The half-lives of human IgE, IgM, and IgG in scid mice were determined to test the possibility of a passive transfer of the immunoglobulins in contrast to de novo synthesis. The values found were 88, 128, and 126 hr, respectively. In general, immunoglobulin production of all isotypes continuously increased over a period of 7-9 weeks after PBL injection, indicating de novo synthesis had taken place. The kinetics of the IgE response exhibited two phases: An initial burst of IgE production occurred between Days 12 and 22. This burst reached levels of 25-70 ng/ml IgE. After a rapid decline to about 50% of the peak value there was a sustained, slow, increase of IgE production for several weeks, excluding a passive transfer for IgE. About half of the donors lacked the initial burst of IgE production and only exhibited a slowly rising IgE production that is indistinguishable from the slow phase of the former donor population. The levels reached in this second phase of IgE production were 20-40 ng/ml after 6-7 weeks. This kinetics may reflect the presence of two different B cell populations, of which only one is present in all donors. The initial IgE burst was only partially dependent on the presence of human IL-4, reflected by a partial inhibition of this response by a neutralizing monoclonal anti-IL-4 antibody. The IgE response in scid mice seems to consist therefore of an IL-4-independent and an IL-4-dependent part, indicating the response to be partially driven by preswitched B cells. Injection of exogenous recombinant human IL-4 (rhIL-4) was not suitable due to the short half-life of rhIL-4 in scid mice of 12 min. Attempts to supply a constant source of rhIL-4 by injection of IL-4-producing Chinese hamster ovary cells failed because of toxic effects produced by these cells. The human IgE production in the scid mice was suppressed by interferon-alpha (BD) to 60-80% compared to that of untreated mice. The suppression was not isotype specific, however, because production of IgG and IgM was inhibited to similar extents.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1994

Xenotransplantation of canine tumors into severe combined immunodeficient (SCID) mice.

Canine tumors resected at surgery or autopsy were subcutaneously xenotransplanted into SCID mice. Thirty of the seventy-three tumors (41.1%) grew primarily in SCID mice. The primary take rate of mammary tumors and skin and subcutaneous tumors was 55.9% (19/34) and 28.6% (8/28), respectively. One thyroid carcinoma, one oral leiomyosarcoma and one osteosarcoma also underwent successful primary growth. Thirteen of the forty-one benign tumors (31.7%) and 17 of the thirty-two malignant ones (53.1%) were successfully transplantable. The histological features of the primary xenografts and their original tumors were similar to each other in all the cases. Three xenografts of the four malignant tumors with metastasis in the canine patients were shown to grow also in SCID mice and two mammary tumor xenografts out of the three metastasized to the lungs of SCID mice as well. All the 30 primary tumor xenografts grown in the first recipient were successfully transplantable to the second generation of the SCID mice. Xenotransplantation using SCID mice appears to be a valuable tool for investigating the biological characteristics of canine neoplasmas.

Animals↗

PubMed1994

Effect of spleen cell populations on resolution of Cryptosporidium parvum infection in SCID mice.

Persistent infection was established in SCID mice given 10(7) Cryptosporidium parvum oocysts. Nine groups of infected SCID mice were inoculated with 10(6), 10(5), or 10(4) total spleen cells, CD8-depleted spleen cells, or CD4-depleted spleen cells from naive BALB/c donors. Infection was significantly reduced in all treatment groups. The most profound effect occurred with spleen cell preparations containing CD4 T lymphocytes but depleted of CD8 T lymphocytes.

Animals↗

PubMed1994

Human primary immune response in SCID mice engrafted with human peripheral blood lymphocytes.

Severe combined immune deficient (SCID) mice were engrafted with human peripheral blood lymphocytes (Hu-PBLs) after treatment with anti-asialo GM-1 antiserum and radiation. This pretreatment facilitates high level of Hu-PBL engraftment in the SCID mice spleen. The next day, the Hu-PBL-SCID mice were immunized with either keyhole limpet hemocyanin (KLH), or carbohydrate Ag STn (AcNeu-alpha 2-alpha 6-Gal NAc-0) conjugated to KLH or protein of circumsporozoite malaria parasite (CSP), in a mixture of complete and incomplete Freund's adjuvant (1:10 v/v). The mice were bled 14 to 16 days after immunization, and the sera analyzed for STn-, KLH-, and CSP-specific human IgG and IgM Abs. The results showed that the immunized animals had a significantly higher titer of Ag-specific human IgG and IgM Abs compared to the control Hu-PBL-SCID mice. No significant Ab cross-reactions were detected between sera from KLH-, STn-, and CSP-vaccinated Hu-PBL-SCID mice. Depletion of either human CD4+ or CD8+ cells, in Hu-PBL-SCID mice, showed that CD4+ cells were essential for the primary immune response, but depletion of CD8+ cells had no influence on the titer of Ag-specific human IgG and IgM Abs.

Animals↗

PubMed1994

Human IgE in SCID mice reconstituted with peripheral blood mononuclear cells from Dermatophagoides pteronyssinus-sensitive patients.

SCID mice were reconstituted with purified peripheral blood mononuclear cells from patients sensitive to Dermatophagoides pteronyssinus (Dpt). After immunization with a low dose of the related allergen, these human (Hu)-SCID mice may develop a specific IgE response. By using an IgE-dependent platelet assay and the related allergen Dpt, the human IgE was demonstrated to be functional. Indeed a high correlation was obtained between both parameters. No rise in human IgE level was detected within 3 wk after the immunization with an unrelated Ag. When mice were reconstituted with peripheral blood cells from nonallergic donors and immunized with the Dpt allergen, no human IgE production was evidenced in the serum of SCID mice. However, in both allergic Hu-SCID mice (reconstituted with cells from allergic patients) or in nonallergic Hu-SCID mice (reconstituted with cells from healthy donors), an IgG response was detectable. Finally by radioallergosorbent test, a specific IgE Ab response was detected after the first allergen challenge only in allergic Hu-SCID mice. Thus, without ethical constraints, SCID mice represent a useful model for analyzing the IgE response occurring in allergic patients.

Allergens↗

PubMed1992

Interleukin 1 participates in the development of anti-Listeria responses in normal and SCID mice.

Using T- and B-cell deficient C.B-17 mice with the scid mutation, we have previously documented the existence of a T-cell-independent but interferon gamma-dependent pathway of macrophage activation that confers upon the host partial resistance to the facultative intracellular bacterium Listeria monocytogenes. This pathway is operative in both normal and SCID mice and consists of at least four components: interferon gamma, tumor necrosis factor, macrophages, and natural killer cells. Here we demonstrate that interleukin 1 also participates in this pathway but at a different site of action. Using monoclonal antibodies that neutralize the biologic activities of interleukin 1 alpha and interleukin 1 beta, we document that interleukin 1 participates neither directly in the induction of interferon gamma from isolated SCID natural killer cells nor in the antigen-specific activation of CD4+ T cells derived from Listeria-immune C.B-17 mice. In contrast, injection of a mixture of anti-interleukin 1 alpha, anti-interleukin 1 beta, and a newly derived monoclonal antibody specific for the murine type I interleukin-1 receptor into either SCID or normal C.B-17 mice blocked the in vivo elaboration of class II major histocompatibility complex-positive macrophages after infection of the animals with Listeria. Moreover, SCID mice treated with the anti-interleukin-1 mixture failed to control the growth of Listeria in vivo and eventually succumbed to the infection. These results document that endogenously produced interleukin 1 plays an obligate role in the Listeria-dependent induction of activated macrophages in vivo and demonstrate that the action of interleukin 1 is distinct from the generation of natural killer cell-derived interferon gamma.

Animals↗

PubMed1993

Selective engraftment of memory CD4+ T cells with an unusual recirculation pattern and a diverse T cell receptor-V beta repertoire into scid mice.

Young (H-2d, Ld+) severe combined immunodeficiency (scid) mice were injected intravenously with 10(5) CD4+CD8- T cells purified from spleen, thymus or lymph nodes (LN) of dm2 (H-2d, Ld-) donor mice. In the immunodeficient recipients, the lymphoid compartment in the splenic white pulp was repopulated with donor-type T cells and cellularity in the red pulp was increased. In addition, donor-type CD4+ T cells repopulated the peritoneal cavity, mesenteric LN and the lamina propria of the small intestine of scid mice, but were undetectable in thymus and peripheral (inguinal, axillary) LN. Histological examination of repopulated mesenteric LN showed expanded subcapsular sinuses, repopulated cortical areas, but poorly developed high endothelial venules (HEV) indicating deficient blood-LN lymphocyte recirculation. The engrafted CD4+ T cell population had the surface phenotype of memory T cells (CD44/Pgp-1high CD45RB(low) and expressed the Peyer's patch HEV-specific homing receptor CD49d (LPAM-1), but not the LN HEV-specific homing receptor LECAM-1. The CD4+ T cell population in spleen and mesenteric LN of transplanted scid mice displayed a diverse T cell receptor-V beta repertoire. Transfer of titrated numbers (10(3), 10(4), 10(5) cells per mouse) of CD4+ T cells into scid mice established donor-type T cell populations with this unusual homing pattern in all recipients. Repeated serial transfers of dm2 CD4+ T cells through young scid mice revealed an extensive in vivo expansion potential of transferred cells for > 18 months. The experimental system described represents an in vivo model to study the functional competence and the differentiation potential of a murine memory CD4+ T cell subset.

Animals↗