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PubMed1992

Theileria sergenti proliferates in SCID mice with bovine erythrocyte transfusion.

The unavailability of in vitro or in vivo experimental systems has been the major factor hampering the progress of research studies on Theileria sergenti, causative agent of theileriosis, a major disease of cattle in Japan. We report the first successful propagation of T. sergenti in SCID mice into which uninfected bovine erythrocytes (Bo-RBC) were supplied periodically. The infectivity of T. sergenti proliferated in an SCID mouse was ascertained by successful transfer of infection into another SCID mouse into which uninfected Bo-RBC were supplied periodically.

Animals↗

PubMed1994

Human hematolymphoid cells in SCID mice.

The severe combined immunodeficient C.B.-17 scid/scid (SCID) mouse has been widely used to study the normal processes of murine lymphoid differentiation. To create an in vivo model of the human hematolymphoid system, this mouse strain has been engrafted with human organ systems (the SCID-hu mouse) or with human peripheral blood mononuclear cells (the hu-PBL-SCID mouse). These mouse models have now been characterized and used to analyze human infectious diseases, hematopoiesis, malignancies and vaccines.

Animals↗

PubMed1994

Low-dose interleukin 2 prevents the development of Epstein-Barr virus (EBV)-associated lymphoproliferative disease in scid/scid mice reconstituted i.p. with EBV-seropositive human peripheral blood lymphocytes.

When severe combined immune deficient (SCID) mice undergo i.p. injection with peripheral blood lymphocytes from normal human donors seropositive for EBV, a majority of these mice (hu-PBL-SCID mouse model) subsequently develop a fatal EBV+ lymphoproliferative disease (EBV-LPD) of human B-cell origin. Because T cells normally are critical in the control of EBV infection, we hypothesized that human T-cell dysfunction accounts for EBV-LPD in the hu-PBL-SCID mouse and that systemic administration of T-cell-derived cytokines would reestablish protective immunity against EBV-LPD. We show that the daily s.c. administration of a very low dose (500 international units) of polyethylene glycol-modified recombinant human interleukin 2 (PEG-IL-2) to hu-PBL-SCID mice can prevent the development of fatal EBV-LPD and significantly improves survival (78%), compared with the survival of hu-PBL-SCID mice treated with placebo (20%, P = 0.0008). Additional lymphocyte-depletion experiments showed that mouse natural killer cells and human CD8+ T cells provided cellular immunity necessary for the PEG-IL-2-mediated protective effect, whereas i.p. injection of human peripheral blood lymphocytes depleted of CD4+ T cells had no adverse effect when combined with PEG-IL-2 therapy and may have been beneficial. These data establish that very low-dose PEG-IL-2 therapy can overcome the immune deficiencies that lead to EBV-LPD in the hu-PBL-SCID mouse and point to the usefulness of this model for evaluating cytokine therapies in EBV-LPD. The use of low-dose IL-2 as a preventative immune therapy has potential application in immunocompromised individuals at high risk for EBV-LPD.

Animals↗

PubMed1999

Administration of Flk2/Flt3 ligand induces expansion of human high-proliferative potential colony-forming cells in the SCID-hu mouse.

The effects of Flk2/Flt3 ligand (FL) administration on human hematopoiesis were investigated using SCID-hu mice transplanted with human fetal bone fragments. Treatment with recombinant human FL induced significant increases in the frequencies of the high-proliferative potential colony-forming cells and low-proliferative potential colony-forming cells in steady-state human bone marrow. FL also promoted the expansion of high-proliferative potential colony-forming cells and low-proliferative potential colony-forming cells in the human bone marrow during the recovery phase after irradiation, which was evident in increases in the frequencies as well as in the absolute numbers of colony-forming cells. Furthermore, higher percentages of CD33+ CD15- cells were found in the marrows treated with FL as compared to that of controls, indicating that FL hastened the recovery of at least some aspect of myelopoiesis after irradiation. These results indicate that FL induces the expansion of primitive hematopoietic progenitor cells in vivo and, therefore, may be useful in treating patients to promote an early hematopoietic recovery after cytoablative therapies.

Animals↗

PubMed2002

Differential long-term and multilineage engraftment potential from subfractions of human CD34+ cord blood cells transplanted into NOD/SCID mice.

Over the past decade xenotransplantation systems have been used with increasing success to gain a better understanding of human cells that are able to initiate and maintain the hematopoietic system in vivo. The nonobese diabetic/severe combined immunodeficiency (SCID) mouse has been a particularly useful model. Human cells capable of hematopoietic repopulation in this mouse, termed SCID-repopulating cells, have been assumed to represent the most primitive elements of the hematopoietic system, responsible for long-term maintenance of hematopoiesis. However, we demonstrate that SCID-repopulating cells present in the CD34(+) cell fraction of cord blood can be segregated into subpopulations with distinct repopulation characteristics. CD34(+)/CD38(+) progenitors can repopulate recipients rapidly, but can only maintain the graft for 12 weeks or less and have no secondary repopulation potential. Conversely, the more primitive CD34(+)/CD38(-) subpopulation repopulates recipients more gradually, can maintain the graft for at least 20 weeks, and contains cells with serial repopulation potential throughout the engraftment period. Additionally, a much higher frequency of T cell precursors are found among SCID-repopulating cells in the CD34(+)/CD38(-) subpopulation. These findings demonstrate that cells with variable repopulation potential comprise the human CD34(+) population and that short- and long-term potential of human precursors can be evaluated in the mouse model.

ADP-ribosyl Cyclase↗

PubMedDate not supplied

In vivo models for Epstein-Barr virus (EBV)-associated B cell lymphoproliferative disease (BLPD).

EBV infects B lymphocytes in vivo and establishes a life-long persistent infection in the host. The latent infection is controlled by EBV-specific MHC class 1-restricted CTL. Immunosuppression reduces CTL activity, and this facilitates outgrowth of EBV+ve B cell lymphoproliferative disease (BLPD). BLPD are aggressive lesions with high mortality. This review presents some key facets in the development of EBV-associated BLPD and in vivo studies on its pathogenesis. The animal models used to date include the common marmoset (Callithrix jacchus), the cottontop tamarin (Saguinus oedipus oedipus), rhesus monkey, murine herpesvirus 68 (MHV68), and the severe combined immunodeficient (scid) mouse, each of which has been used to address particular aspects of EBV biology and BLPD development. Scid mice inoculated i.p. with PBMC from EBV-seropositive individuals develop EBV+ve BLPD-like tumours. Thus this small animal model (hu-PBMC-scid) is currently used by many laboratories to investigate EBV-associated diseases. We and others have studied BLPD pathogenesis in the hu-PBMC-scid model and shown that EBV+ve B cells on their own do not give rise to tumours in this model without inclusion of autologous T cell subsets in the inoculum. Based on the findings that (1) established tumours do not contain T cells and (2) tumour cells express a variety of B cell growth factors, a stepwise model of lymphomagenesis in the scid mouse model can be defined. Additionally, the hu-PBMC-scid model can be used to assess novel therapeutic regimes against BLPD before introduction into a clinical setting.

Animals↗

PubMed1994

Interferon-gamma- and interleukin-4-producing T cells can be primed on dendritic cells in vivo and do not require the presence of B cells.

The antigen-presenting cell (APC) requirements for the in vivo induction of Th1- and Th2-type responses were investigated using a severe combined immunodeficiency (SCID)mouse chimera model. SCID mice adoptively transferred with either T cells [SCID(T)] or T+B cells [SCID(T+B)] and immunized with antigen in adjuvant were able to generate antigen-specific T cells which could produce both interferon (IFN)-gamma and interleukin (IL)-4 upon in vitro restimulation. This suggests that B cell APC are not necessary for the priming of either IFN-gamma- or IL-4-producing T cells in vivo. The ability of different APC to activate Th2-dependent effector mechanisms was also investigated. SCID(T) and SCID(T + B) mice were infected with the nematode parasite Nippostrongylus brasiliensis and analyzed for the development of IL-5-dependent peripheral blood eosinophilia. Following infection both SCID(T) and SCID(T+B) mice generated similar numbers of peripheral blood eosinophils, suggesting that similar amounts of IL-5 had been produced. Therefore, B cell APC are also not required for the in vivo activation of Th2 cells to lymphokine production. To establish more precisely which APC prime T cells to produce IFN-gamma and IL-4, normal mice were immunized by injection of syngeneic splenic dendritic cells which had been pulsed with antigen in vitro. T cells from these immunized mice were able to produce good IFN-gamma and IL-4 responses upon in vitro restimulation with specific antigen; therefore, dendritic cells appear to be sufficient APC for the in vivo priming of both IFN-gamma- and IL-4-producing T cells.

Animals↗

PubMed2001

CD8+ T lymphocytes protect SCID mice against Encephalitozoon cuniculi infection.

Microsporidia are obligate intracellular parasites that cause opportunistic infections in immunocompromised patients. The role of two main T cell subsets in anti-microsporidial immunity has been studied using an Encephalitozoon cuniculi-severe combined immunodeficient (SCID) mouse model. Whereas SCID mice reconstituted with CD4+ T lymphocyte-depleted naive BALB/c splenocytes resolved the infection, adoptive transfer of CD8+ T cell-depleted splenocytes failed to protect the animals against a lethal E. cuniculi infection. Splenocytes from E. cuniculi-immune mice specifically killed syngeneic infected macrophages in a short-term 51Cr-release assay. These results suggest the crucial role of cytotoxic T lymphocytes in the protection against E. cuniculi infection.

Adoptive Transfer↗

PubMed1990

Development of B-lineage cells in the bone marrow of scid/scid mice following the introduction of functionally rearranged immunoglobulin transgenes.

Mice homozygous for the mutation scid (scid mice) are severely immunodeficient and generally lack detectable numbers of pre-B, B, and T cells. This condition is believed to result from a defect in the mechanism responsible for rearrangement of immunoglobulin and T-cell receptor genes in developing B and T lymphocytes. To test this hypothesis and evaluate whether scid affects only the process of gene recombination, we introduced functionally rearranged immunoglobulin genes into the scid mouse genome. As scid mice appear to contain early lymphoid cells committed to the B lineage (pro-B cells), we asked whether the introduction of an IgM heavy-chain gene alone (mu-transgenic scid mice) or both IgM heavy- and kappa light-chain genes (mu kappa-transgenic scid mice) would allow further differentiation of scid pro-B cells into pre-B and B cells. We found that normal numbers of pre-B cells appeared in the bone marrow of mu-transgenic scid mice and that both pre-B and B cells appeared in the bone marrow of mu kappa-transgenic scid mice. However, in the latter case, the number of pre-B and B cells was 2- to 3-fold less than in the controls (mu kappa-transgenic scid heterozygotes) and few, if any, B cells were detectable in the peripheral lymphoid tissues. The implications of these results for the above hypothesis are discussed.

Animals↗

PubMed2003

Brain slice culture for analysis of developmental brain disorders with special reference to congenital cytomegalovirus infection.

Cytomegalovirus (CMV) is the most significant infectious cause of congenital abnormalities of the central nervous system (CNS) with variation from the fatal cytomegalic inclusion disease to functional brain disorder. The phenotype and degree of the brain disorder depends on infection time during the developing stage, virulence, route of infection and the viral susceptibility of the cells. The pathogenesis of the CMV infection to the CNS seems to be strongly related to neural migration, neural death, cellular compositions and the immune system of the brain. To understand the complex mechanism of this disorder, we used organotypic brain slice cultures. In the brain slice culture system, migration of CMV-infected neuronal cells was observed, which reflects infectious dynamics in vivo. Neural progenitor cells or glial immature cells in the subventricular zone and marginal area are most susceptible to murine cytomegalovirus (MCMV) infection in this system. The susceptibility declined as the number of immature glial cells decreased with age. The immature glial cells proliferated in brain slice cultures during prolonged incubation, and the susceptibility to MCMV infection also increased in association with the proliferation of these cells. The brain slice from an immunocompromised mouse (Beige-SCID mouse) unexpectedly showed lower susceptibility than that of an immunocompetent mouse during any prolonged incubation. These results suggest that the number of immature glial cells might determine the susceptibility of CMV infection to the brain, independent of the immune system. We reviewed recent findings of CMV infection to the brain from the perspective of brain slice cultures and the possibility that this system could be a useful method to investigate mechanisms of congenital anomaly of the brain.

Animals↗

PubMed2001

Antibacterial effect of human V gamma 2V delta 2 T cells in vivo.

V gamma 2V delta 2 cells, a class of T cells found only in primates, are reactive to nonpeptide organophosphate and alkylamine antigens secreted by bacteria and parasites. These cells make up 2-5% percent of human peripheral blood T cells but expand to make up 8-60% of peripheral blood T cells during bacterial and parasitic infections. We show here, using a chimeric severe combined immunodeficiency (SCID) mouse (hu-SCID) model, that human V gamma 2V delta 2 T cells mediate resistance to extracellular gram-positive (Staphylococcus aureus) and gram-negative (Escherichia coli and Morganella morganii) bacteria, as assessed by survival, body weight, bacterial loads, and histopathology. Surprisingly, this bacterial resistance was evident 1 day after infection, and bacteria were cleared well before gamma delta T cell expansion was detected 6 days after infection. Decreased resistance in V delta 2 T cell-depleted hu-SCID mice correlated with decreased serum IFN-gamma titers. Intravenous treatment of infected, reconstituted hu-SCID mice with pamidronate, a human V gamma 2V delta 2 T cell-specific aminobisphosphonate antigen, markedly increased the in vivo antibacterial effect of V gamma 2V delta 2 T cells. Therefore, this large pool of antigen-specific, yet immediately reactive memory human V gamma 2V delta 2 T cells is likely to be an important mediator of resistance against extracellular bacterial infection and may bridge the gap between innate and acquired immunity.

Animals↗

PubMed2002

Ex vivo development of functional human lymph node and bronchus-associated lymphoid tissue.

We introduce a novel in vivo model of human mucosal immunity, based on the implantation of human fetal bronchial mucosa and autologous peribronchial lymph node (PLN) in the severe combined immunodeficiency (SCID) mouse. In the SCID host, human fetal bronchi implanted alone retain macrophages and mast cells but lose T cells. In contrast, fetal bronchi co-implanted with PLN contain, in addition to macrophages and mast cells, numerous T cells and B cells, often clustered in intramucosal bronchus-associated lymphoid tissue (BALT). Functionally, bronchus-PLN cografts are able to mount robust alphabeta and gammadelta T-cell-mediated immune responses to Pseudomonas aeruginosa and 3,4-epoxy-3-methyl-1-butyl-diphosphate challenges. No other autologous lymphoid organ (bone marrow, thymus, liver) allows for BALT development in co-implanted bronchi, which suggests special ontogenetic and functional relations between extramucosal PLN and intramucosal BALT. Overall, the bronchus-PLN cograft appears as a promising model for human bronchial immune development and function. Our study is the first to document long-term ex vivo maintenance of functional human lymph nodes as native appendices to mucosal tissue. Our results, therefore, suggest a simple strategy for developing similar experimental models of human immune function in other mucosae.

Abortion, Spontaneous↗

PubMed1993

HIV induces thymus depletion in vivo.

Human immunodeficiency virus (HIV) disease is typified by declining CD4+ T lymphocyte counts in the peripheral circulation, a loss which may be secondary to accelerated destruction, to suppressed differentiation, and/or to sequestration of circulating cells into tissue spaces. As it is hard to distinguish between these possibilities in human subjects, the pathogenic mechanisms associated with HIV infection are unclear. In particular, little is known about the events that occur within infected lymphoid organs in which most CD4 T lymphocytes mature and function. To obtain a better description of HIV pathogenesis in vivo, we have implanted human haematolymphoid organs into the immunodeficient SCID mouse to create the SCID-hu mouse. We have previously shown that these organ systems promote long-term multilineage human haematopoiesis and are permissive for infection with HIV. Here we report that human thymopoiesis is suppressed by HIV infection, thereby precluding regeneration of the peripheral T-cell compartment.

Animals↗

PubMed1992

Human hematopoietic cells and thymic epithelial cells induce tolerance via different mechanisms in the SCID-hu mouse thymus.

To study the role of thymic education on the development of the human T cell repertoire, SCID-hu mice were constructed with fetal liver and fetal thymus obtained from the same or two different donors. These animals were studied between 7 and 12 mo after transplantation, at which times all thymocytes and peripheral T cells were derived from stem cells of the fetal liver graft. Immunohistology of the thymus grafts demonstrated that thymic epithelial cells were of fetal thymus donor (FTD) origin. Dendritic cells and macrophages of fetal liver donor (FLD) origin were abundantly present in the medullary and cortico-medullary areas. Thymocytes of SCID-hu mice transplanted with liver and thymus of two different donors (FLDA/FTDB animals) were nonresponsive to Epstein-Barr virus-transformed B cell lines (B-LCL) established from both the FLDA and FTDB, but proliferated vigorously when stimulated with third-party allogeneic B-LCL. Mixing experiments showed that the nonresponsiveness to FTDB was not due to suppression. Limiting dilution analysis revealed that T cells reacting with the human histocompatibility leukocyte antigens (HLA) of the FLD were undetectable in the CD8+ T cell population and barely measurable in the CD4+ subset. On the other hand, CD4+ and CD8+ T cells reactive to the HLA antigens of the FTD were readily detectable. These results indicate that FLD-reactive cells were clonally deleted, whereas FTD-reactive cells were not. However, the frequencies of FTD-reactive T cells were consistently twofold lower than those of T cells specific for any third-party B-LCL. In addition, the cytotoxic activity and interleukin 2 production by FTD-specific T cells were lower compared with that of third-party-reactive T cell clones, suggesting that FTD-specific cells are anergic. These data demonstrate that T cells become tolerant to autologous and allogeneic HLA antigens expressed in the thymus via two different mechanisms: hematopoietic cells present in the thymus induce tolerance to "self"-antigens by clonal deletion, whereas thymic epithelial cells induce tolerance by clonal energy and possibly deletion of high affinity clones.

Animals↗

PubMedDate not supplied

Interferon gamma increases the antitumor activity of mitomycin C against human colon cancer cells in vitro and in vivo.

A combined antitumor activity of mitomycin C (MMC) and interferon gamma-1a (IFN-gamma) was evaluated to be synergistic by the 3-(4, 5-dimethylthiazol-2yl)-2,5-diphenyl-2H tetrazolium bromide assay and human tumor xenografts/severe combined immunodeficient (SCID) mouse system using colon cancer cell lines. The experimental metastasis of WiDr cells in SCID mouse was inhibited by MMC and IFN-gamma with their synergism. Intracellular uptake of MMC in WiDr cells in vitro was significantly increased by IFN-gamma, suggesting the mode of synergism of these agents. This model may also partly explain the antitumor activity of combined MMC, 5-fluorouracil and interleukin-2 treatment on hepatic metastasis of colon cancer.

Animals↗

PubMed1993

B-lineage cells in mu-transgenic scid mice proliferate in response to IL-7 but fail to show evidence of immunoglobulin light chain gene rearrangement.

The severe combined immunodeficiency (scid) mouse mutation impairs the recombination of Ig and TCR genes. Mice homozygous for this mutation (scid mice) lack pre-B, B, and T lymphocytes. Earlier we introduced a functionally rearranged mu-heavy chain gene into the scid mouse genome and found that this resulted in the development of pre-B cells in the bone marrow of these mice; however, sIgM+ B cells were not detected. We have now investigated the growth properties and rearrangement status of Ig genes in early B-lineage cells arising in mu-transgenic scid mice. We find that the presence of a functional mu-transgene allows pro-B cells from these mice to proliferate in short-term culture with IL-7. Nevertheless, rearrangements of Ig light chain genes are not detected in the bone marrow of such mice. Furthermore, the frequency of rearrangement detected at the endogenous Ig heavy chain locus in scid pro-B and pre-B cells is reduced relative to that in wild-type cells.

Animals↗

PubMed1994

Engraftment of human peripheral blood lymphocytes in normal strains of mice.

Transplantation of bone marrow from SCID mice into lethally irradiated normal mice can potentially endow the normal recipients with characteristics typical of the immune-deficient SCID mouse. In the present study, we investigated whether intraperitoneal grafting of human peripheral blood lymphocytes (PBLs), which has been documented in the SCID mouse, can also be achieved in irradiated BALB/c mice radioprotected with SCID bone marrow. Evaluation of different radiation protocols suggested that, considering the quality of engraftment and rate of survival, optimal results were obtained with split dose total body irradiation (TBI; 4 Gy followed 3 days later by 10 Gy). Monitoring of mouse T cells in peripheral blood indicated an inverse correlation between the presence of such cells and the engraftment of human CD45+ cells in the peritoneum. Also, engraftment of human PBLs in nude BALB/c mice, conditioned with the same radiation protocol, was significantly higher than that achieved in their normal counterparts. Further improvement of human PBL engraftment was found when the mice were thymectomized 2 weeks before conditioning with split TBI. After transplantation of 80 x 10(6) human PBLs in such recipients, a marked engraftment of human T cells and B cells in the peritoneum cavity could be detected for at least 2 months, whereas significant amounts of human Ig could be detected for more than 3 months. Migration of human PBLs into internal organs such as spleen, liver, kidney, and lungs (and into thymus in nonthymectomized mice) was found within a few days of grafting and also persisted for 2 to 3 months. The majority of the engrafted lymphocytes were single-positive CD4+ and CD8+ T lymphocytes, about 50% of which were activated, as judged by their expression of HLA-DR. Staining with anti-CD25 antibody was lower compared with that found with anti-HLA-DR. CD20+ B cells were detected in all of the above-mentioned internal organs, but were mainly concentrated in the spleen. CD14+ monocytes could be detected only during the first week posttransplant of PBLs. Total human Ig in peripheral blood reached an average of 2.8 mg/mL 14 days posttransplant, and continued to be significant for several months. In vitro transformation by Epstein-Barr virus of human B cells from different tissues could be established 30 days after transplantation and led to outgrowth of two IgG+ cell lines, two IgM+ cell lines, and one IgA+ cell line producing 0.6 to 4.2 micrograms/mL human Ig in the supernatant.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2001

The citrus flavonoid, nobiletin, inhibits peritoneal dissemination of human gastric carcinoma in SCID mice.

The flavonoid nobiletin (5,6,7,8,3',4'-hexamethoxyflavone), found in Citrus depressa Rutaceae, a popular citrus fruit in Okinawa, Japan, reportedly inhibits the production of pro-matrix metalloproteinase (proMMP)-1, 3, and 9 in rabbit synovial fibroblasts in vitro. In the present study, we demonstrated the inhibitory effects of nobiletin on the proliferation of the cancer cell line, TMK- 1, and its production of MMPs. In the SCID mouse model, we found that nobiletin inhibited the formation of peritoneal dissemination nodules from TMK-1. The enzymatic activity of MMP-9 expressed in culture medium obtained from a co-culture of TMK-1 and mouse fibroblastic cells was inhibited by nobiletin in a concentration-dependent manner. In the SCID mouse model, total weight of dissemination nodules was significantly lower in the treated group compared with the vehicle control group (0.07 g vs. 0.78 g, P = 0.0059). The total number of dissemination nodules was also significantly lower than in the vehicle control group (7.5 vs. 69.3 / body, P = 0.0001). These results suggest that nobiletin may be a candidate anti-metastatic drug for prevention of peritoneal dissemination of gastric cancer.

Animals↗