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PubMed1996

Development and applications of the SCID-hu mouse model.

The SCID-hu mouse was designed to serve as a preclinical model for the analysis of human physiology and pathophysiology. In distinction to other immunodeficient mouse models, SCID-hu mice are made upon implantation of intact human organ systems rather than dispersed cell populations. Two constructs, the SCID-hu Thy/Liv and the SCID-hu Bone models, have been developed to reproduce the differentiation and function of human hematopoietic progenitor cells within the human thymus and bone marrow microenvironments, respectively. This review focuses on several applications of these models: definition of multilineage and lineage-restricted human hematopoietic progenitor cells and evaluation of HIV disease and its treatment.

Animals↗

PubMed2001

[Clinical effectiveness of m-THPC-PEG in a new xenogenic animal tumor model for human squamous epithelial carcinomas].

BACKGROUND: Animal tumor models are still essential for the development of new medication and therapy concepts. For the field of oropharyngeal cancer only few reliable xenogeneic tumor models are available. In a two-part experiment a new xenogeneic tumor model was established. PART 1 OF THE STUDY: The growth rates of two different tumor cell lines were compared in the RAG-2 mouse, the SCID mouse and the Swiss nude mouse. Cells from a lymph-node metastasis of an oral squamous cell carcinoma (XF-354) showed a better growth rate and clearer histology than cells from a primary squamous cell carcinoma of the floor of the mouth (UM-SCC-14C). The tumor growth rate was highest on the RAG-2 mouse, followed by the SCID mouse. The Swiss nude mouse showed no tumor growth at all. The combination of the XF-354 tumor cell line and the RAG-2 mouse was the most successful, with a tumor growth rate of 95%. The animal model is very reliable and robust and enables manipulations under anaesthesia outside the sterile barrier for up to 30 min. The single steps for cell cultivation and tumor implantation are described and discussed in detail. PART 2 OF THE STUDY: The second part of this study investigated the clinical efficacy of the macromolecular linked photosensitizer--mTHPC-PEG compared with the free photosensitizer mTHPC. Macromolecular linked photosensitizers have theoretical advantages owing to their pharmacokinetics and tumor selectivity. For the animal experiment, the photosensitizer mTHPC showed significantly better results than the macromolecular linked photosensitizer mTHPC-PEG. The reasons for these in vivo results are discussed in detail.

Animals↗

PubMed1996

A new approach to analysis of human sweating.

In human skin transplanted to the back of 3 strains of immuno-deficient mice the function of the eccrine sweat glands of the human transplant was tested by topical intradermal application of pilocarpine, adrenaline and atropine + pilocarpine. Sweat responses were observed in pre-selected fields of observation by means of video macroscope. The iodine starch reaction served as an indicator for the appearance of sweat sport and permitted the evaluation of areas wetted by sweat in the field of observation. Among 9 animals tested, the hybrids between the CB-17-scid mouse and the BALB/cA-nu mouse (BALB/cA-nu,scid) seemed to exhibit the most consistent sweating response to local pharmacological stimulation. According to histological examination, eccrine sweat glands were preserved in human skin transplanted into the back skin of the BALB/cA-nu,scid mouse strain. The heterologous, human skin graft provides a novel model permitting, independent of the normal sweat gland innervation, the analysis of molecular receptors of sweat gland cells by which the actions of natural transmitters and pharmacological agents are transduced.

Animals↗

PubMed1991

Clonal analysis of the peripheral T cell compartment of the SCID-hu mouse.

Severe combined immunodeficiency (SCID) mice can be transplanted successfully with human fetal liver and thymus (SCID-hu mice). Precursor cells derived from the fetal liver differentiate in the thymus and migrate into the blood as mature T cells. In the present paper, the peripheral T cell compartment of such mice was studied. Peripheral WBC were activated by PHA and cultured in the presence of irradiated human feeder cells. The resultant cell population consisted exclusively of human CD1- CD2+ CD3+ CD7+ T lymphocytes; up to 4% of the T cells expressed the TCR gamma delta, whereas 95 to 100% were TCR alpha beta +. The CD4bright (42 to 66%) and CD8bright (30 to 54%) populations coexpressed variable but low levels of CD8 and CD4, respectively. The T cell cultures from the SCID-hu mice did not display reactivity towards the autologous human EBV-transformed B cell lines (B-LCL). On the other hand, these human T cells proliferated and were cytotoxic against allogeneic human B-LCL. T cell clones were established from cultured SCID-hu T cells. All T cell clones were TCR alpha beta + CD3+ CD2+; 61% of the clones were CD4+ CD8-, 27% were CD8+ CD4-, 11% were CD8+ CD4lo, and 2% were CD4+ CD8lo. None of these clones recognized the autologous B-LCL established from the fetal human donor. Fourteen of 100 T cell clones had specific alloreactivity, as tested on a panel of five B-LCL. Of these 14, two CD8+ CD4lo and two CD8+ CD4- clones were cytotoxic and did not proliferate in response to specific stimulator cells. Furthermore, two CD4+ CD8lo and eight CD4+ CD8- clones proliferated specifically in response to alloantigens. In conclusion, the peripheral human T cells of SCID-hu animals are functional and their TCR repertoire is polyclonal, alloreactive, and devoid of self-reactive cells. Therefore, the SCID-hu mouse can be a suitable model for the study of alloreactivity and allotolerance in vivo, as well as for the study of negative selection in the human thymus.

Animals↗

PubMed1993

Preclinical analysis of cytokine therapy in the SCID-hu mouse.

A severe combined immunodeficient (SCID)-hu mouse model implanted with human fetal bone was used to assess the effects of various recombinant human (rh) hematopoietic growth factors, administered either alone or in combination, on human hematopoiesis in vivo. Treatment with rh granulocyte colony-stimulating factor (G-CSF) elicited the expansion of mature neutrophilic granulocyte populations in human marrow. Administration of rh interleukin-3 (IL-3) induced significant increases of eosinophilic granulocyte and burst-forming unit, erythrocyte (BFU-E) activity. The rhIL-6 did not cause significant changes in the subpopulations of human hematopoietic cells within the grafts, but did increase the number of colony-forming unit, granulocyte-macrophage and BFU-E. Pretreatment with rhIL-3 followed by rh erythropoietin (Epo) administration enhanced Epo-induced human erythropoiesis significantly. No synergistic effects on myelopoiesis were observed using sequential treatment with rhIL-3 followed by rhG-CSF. Instead, these factors seemed to work independently, with rhG-CSF increasing the percentage of neutrophils and rhIL-3 increasing the percentage of eosinophils. When administered simultaneously with rhEpo, rhIL-6 showed dose-dependent inhibitory effects on in vivo Epo-induced human erythropoiesis. The rhIL-6 also caused a reduction in the percentage of human neutrophils induced by rhG-CSF. These results suggest that the SCID-hu mouse provides a useful small animal model to assess the in vivo effects of hematopoietic growth factors on human hematopoiesis.

Animals↗

PubMed1993

The use of the severe combined immunodeficient mouse and the athymic "nude" mouse as models for the study of human autoimmune thyroid disease.

The athymic "nude" mouse and the severe combined immunodeficient (SCID) mouse have differing immunological properties which permit complementary studies of autoimmune thyroid disease (AITD). The nude mouse accepts human thyroid xenografts, but lyses the passenger lymphocytes, whereas in the SCID mouse both the xenograft and its lymphocytes survive. Human AITD thyroid xenografts manifest a worsening of the pathological picture in the SCID mouse, but show a return to normal morphology and function in the nude mouse at the time of sacrifice 6-8 weeks after engraftment. Such tissue which has been grafted into the nude mouse can be retrieved and then can be re-xenografted into the SCID mouse. Normalized AITD thyroid tissue (from the nude mouse xenograft) will remain normal in the SCID mouse, but if xenografted into a SCID mouse which already has a primary autologous AITD thyroid xenograft, or if autologous PBMC are added, the AITD lesion will be reproduced. This demonstrates the primacy of the immune system in AITD and constitutes a useful model for the study of this human disorder.

Animals↗

PubMed1991

The SCID-hu mouse: a small animal model for HIV infection and pathogenesis.

The SCID-hu mouse is a heterochimeric small animal model designed to support hematopoietic differentiation and function in vivo. Multiple organs of the human hematolymphoid system have been successfully engrafted into the immunodeficient C.B-17 scid scid mouse, including fetal liver, thymus, lymph node, and skin. Co-implantation of human fetal liver and human fetal thymus results in long-term, multilineage human hematopoiesis in vivo. Mature human lymphocytes within the SCID-hu mouse are phenotypically and functionally normal. HIV infection of the SCID-hu mouse reflects a tropism similar to that found in humans: only human organs with CD4+ cells are infected. Viral replication can thereafter be monitored with assays that are safe, reproducible, and quantitative. Given this small animal model, it is now possible to study systematically the infective process of HIV and to address questions about the efficacy of novel antiviral compounds or vaccines in vivo.

Animals↗

PubMed2006

Development of vaccines and passive immunotherapy against SARS coronavirus using mouse and SCID-PBL/hu mouse models.

We have investigated novel vaccines strategies against severe acute respiratory syndrome (SARS) CoV infection using cDNA constructs encoding the structural antigens; spike (S), membrane (M), envelope (E), or nucleocapsid (N) protein, derived from SARS CoV (strain HKU39849, TW1, or FFM-1). As SARS-CoV is thought to infect the alveolar epithelial cell of the lung,in the present study, a type II alveolar epithelial cell clone, T7, was used to analyze the mechanism of CTL against SARS CoV membrane antigens. Mice vaccinated with SARS CoV (N) DNA or (M) DNA using pcDNA 3.1 (+) plasmid vector showed T-cell immune responses (CTL induction and proliferation) against type II alveolar epithelial cells (T7) transfected with SARS (N) or (M) DNA, respectively. To determine whether these DNA vaccines could induce T-cell immune responses in humans as well as in mice, SCID-PBL/hu mice were immunized with these DNA vaccines. PBL from healthy human volunteers were administered i.p. into IL-2 receptor gamma-chain-disrupted NOD-SCID mice [IL-2R(-/-) NOD-SCID]. SCID-PBL/hu mice thus constructed can be used to analyze the human immune response in vivo. The SCID-PBL/hu mice were immunized with SARS (N) DNA or (M) DNA and analyzed for a human T-cell immune response. The M DNA vaccine enhanced CTL activity and proliferation in the presence of M peptide in SCID-PBL/hu mice. Furthermore, the SARS N DNA vaccine induced CTL activity (IFN-gamma production by recombinant N protein or N protein-pulsed autologous B blast cells) and proliferation of spleen cells in SCID-PBL/hu mice. These results, demonstrate that SARS M and N DNA vaccines induced human CTL and human T-cell proliferative responses. On the other hand, we have developed SARS DNA vaccines that induce human neutralizing antibodies and human monoclonal antibodies against SARS CoV. Transgenic mice expressing SARS-CoV receptor (angiotensin converting enzyme 2) are also under development. These vaccines are expected to induce immune responses specific for SARS CoV in human and should provide useful tool for development of protective vaccines.

Animals↗

PubMed1988

Infection of the SCID-hu mouse by HIV-1.

SCID-hu mice with human fetal thymic or lymph node implants were inoculated with the cloned human immunodeficiency virus-1 isolate, HIV-1JR-CSF. In a time- and dose-dependent fashion, viral replication spread within the human lymphoid organs. Combination immunohistochemistry and in situ hybridization revealed only viral RNA transcripts in most infected cells, but some cells had both detectable viral transcripts and viral protein. Infected cells were always more apparent in the medulla than in the cortex of the thymus. These studies demonstrate that an acute infection of human lymphoid organs with HIV-1 can be followed in the SCID-hu mouse.

Acquired Immunodeficiency Syndrome↗

PubMed1999

Immunohistochemical and ultrastructural evidence for myelopoiesis in the scid/scid mouse thymus.

The ultrastructure of scid mouse thymus (a small encapsulated epithelial mass within the precardial fat pad) is described. The epithelium did not form cortex or medulla and hence remained relatively undifferentiated. Small unmyelinated nerves innervated the capsule, the major blood vessels and were distributed between the epithelial cells. Fenestrated blood vessels were common. Thymocytes were not identified but numerous granulocytes, mast cells and some fibroblasts, macrophages and interdigitating cells were present. All stages of granulopoiesis were observed in scid thymus. A very small number of immunoreactive ER-MP58 cells indicated bone marrow derived myeloid precursor cells, and low numbers of ER-MP12+ and ER-MP20+ mononuclear cells indicated stages of myeloid cells committed to the granulocyte/macrophage lineage. Cells containing proliferating nuclear cell antigen (cells in G1, S and G2-M stage) were present throughout the thymic mass. BALB/c thymuses contained cortical foci of p53+ cells whereas in scid mice, p53 positive cells were scattered singly throughout the thymus. This study indicates that the presence of moderately extensive myelopoiesis within the scid mouse thymus has potential for the study of extramedullary haematopoiesis, and also that it is important to bear this function in mind when using the scid mouse as an immunological model for thymus reconstitution and for creating 'organoid' cultures.

Animals↗

PubMed2002

The RAG 2 mouse model for xenografted human oral squamous cell carcinoma.

Animal tumor models are still essential for the development of new medication and therapy concepts. In the field of human oral squamous cell cancer, there are few reliable xenografted tumor models available. Therefore, during a two-course experiment, we established a new xenografted tumor model of human oral squamous cell cancer. The tumor growth rates of two different tumor cell lines were compared in the inbred immunodeficient CD-17-RAG 2 mouse, NMRI-SCID mouse (scid/scid), and Swiss nude mouse (nu/nu). The tumor cell line from a lymphnode metastasis of an oral squamous cell carcinoma (XF 354) had a faster growth rate and a more characteristic histology than did the cell line from the primary tumor of a squamous cell carcinoma of the floor of the mouth (UM-SCC-14C). The highest tumor growth rate was observed in the RAG 2 mouse, followed by the SCID mouse. The Swiss nude mouse showed no tumor growth. The combination of the XF 354 tumor cell line and the RAG 2 mouse was most successful, with a tumor growth rate of 95%. Our animal model is very reliable and allows manipulations for as long as 30 min under anesthesia outside of microbiologic safety cabinets, where the handling of animals is much more comfortable and less time-consuming. The tumor histology was easily interpreted by using light microscopy. Steps for cell cultivation and tumor implantation are described and discussed. Therefore we strongly recommend the use of the model comprising the RAG 2 mouse with the xenografted cell line XF 354 for research in the field of human oral squamous cell carcinoma.

Animals↗

PubMed1996

Development of an orthotopic SCID mouse-human tumor xenograft model displaying the multidrug-resistant phenotype.

Multiple myeloma is a plasma cell malignancy which is generally incurable in spite of a high initial response to chemotherapy. While animal models of myeloma are known, the recent developments of human xenografts in nude and SCID mice suggests a promising experimental model. The SCID model, in particular, holds promise because these animals readily accept hematopoietic and lymphoid transplantation and do not generally develop graft versus host reaction. We have developed two drug-resistant variants of the human multiple myeloma cell line ARH-77 by in vitro exposure to gradually increasing concentrations of doxorubicin (ARH-D60) or mitoxantrone (ARM-80). When injected into irradiated SCID mice, the ARH-D60 cell line grew in an orthotopic pattern with the development of osteolytic lesions. This is in contrast to the 8226/C1N human myeloma cell line which grows in a disseminated but nonorthotopic manner in the SCID mouse. Both the ARH-D60 and ARM-80 cell lines are resistant to doxorubicin and cross-resistant to mitoxantrone, vinca alkaloids, taxol and m-AMSA while maintaining sensitivity to antimetabolites and alkylating agents. Growth characteristics and cell cycle kinetics, including S-phase, were not altered in the resistant sublines. The ARH-D60 and ARM-80 cell lines both displayed a classic multidrug-resistance (MDR) phenotype which was partially reversed by the addition of verapamil. These two cell lines represent the first MDR human myeloma cell lines which have demonstrated an orthotopic growth pattern in the SCID mouse and thus may be of value in studying the pathophysiology of this disease.

Animals↗

PubMed1997

The SCID-hu mouse: an in vivo model for HIV-1 infection in humans.

The lack of suitable animal models for the in vivo study of HIV-1 infection has prompted investigators to take advantage of the graft-rejection deficit in severe combined immunodeficient (SCID) mice. Two separate approaches have been used to transplant human lymphoid and/or hemolymphoid tissues into SCID mice to generate chimeric animals in which distinct elements of the human immune system could be maintained and studied in vivo. The two models that arose from this work were the SCID-hu mouse and hu-PBL-SCID mouse. The goal of producing these distinct models is to provide an easily manipulable model for the in vivo analysis of HIV-1 infection and its ensuing pathophysiology. Both models support HIV-1 replication and display potential as models for studying antiviral strategies and mechanisms of viral pathogenesis. This review focuses on the SCID-hu mouse.

Acquired Immunodeficiency Syndrome↗

PubMed1992

Preliminary report: growth of Hodgkin's lymphoma derived cells in immune compromised mice.

Until now there has been no satisfactory animal host for the in vivo growth of Hodgkin lymphoma cells. With the exception of one mutant subline (L540Cy) none of the other Hodgkin derived cell lines nor Hodgkin's disease (HD) derived lymphatic tissue could be propagated in suitable animal systems such as the T-cell deficient nude mouse. Recently, the severe combined immunodeficient (SCID-) mouse has been demonstrated as a possible recipient for human lymphatic tissue. In the present study, we have evaluated the SCID mouse as a possible in vivo model for Hodgkin's lymphoma. I) We demonstrate that seven permanent cell lines derived from patients with Hodgkin's disease grow progressively in SCID mice after subcutaneous and intraperitoneal inoculation. II) In addition, after intravenous injection, two of these lines (L540, L540Cy) show a disseminated growth pattern resembling the distribution of HD cells in man (involvement of lymph nodes, liver and bone marrow but not of spleen). The observed reproducible disseminated tumor growth establishes the SCID mouse as a new animal model for experimental treatment strategies in Hodgkin's lymphoma. III) We present preliminary results of the transplantation of primary material from 13 patients with Hodgkin's disease. Material from two patients induced human tumors in the SCID mice recipients, whereas material from two others led to the induction of mouse lymphomas. The human tumors showed three distinct histological patterns: 1) Lymphoproliferative disease (LPD); 2) anaplastic large cell lymphomas (ALCL); 3) Hodgkin like lesions (HLL). In vitro cell lines established from human SCID mouse tumors were of B-lymphoid origin, were EBV-positive and showed numerical and some structural chromosomal aberrations of varying degree.

Animals↗

PubMed1998

Prognostic significance of B-lineage leukemic cell growth in SCID mice: a Children's Cancer Group Study.

Primary leukemic cells isolated from children (N = 681 ) with newly diagnosed B-lineage ALL enrolled on risk-adjusted treatment protocols of the Children's Cancer Group (CCG) were injected via the tail vein into 7-10 week old SCID mice. Leukemic cells from 104 of 681 patients (15.3%) were able to engraft and proliferate in one or more SCID mouse organs. These SCID+ patients were somewhat more likely than SCID patients to be older than 10 years of age (p = 0.03) and have WBC counts >20,000/microL (p = 0.04), but the groups were similar with respect to all other presenting features. Event-free survival (EFS) outcome at 3 years of follow-up was similar for SCID+ patients compared with SCID- patients (79.2%, SD = 5. 1% vs. 84.8%, SD = 2.8%; p = 0.20). Overall survival also was similar between the two groups (p = 0.93). This result was maintained within the subgroups of lower risk (N = 448) and higher risk (N = 233) patients. However, there were trends for poorer outcome among patients whose cells caused overt leukemia in SCID mice and infiltrated either 6 or more organs (p = 0.03), skeletal muscle (p = 0.0003), kidney (p = 0.05), or spleen (p = 0.06). Thus, engraftment of primary leukemic cells in SCID mice was not a significant predictor of outcome for the aggregate population of B-lineage ALL patients, the majority of whom were low risk, treated according to contemporary intensive chemotherapy programs of the CCG. However, development of disseminated overt leukemia and infiltration of SCID mouse skeletal muscle by primary leukemic cells from adjacent bone marrow may reflect a biologically more aggressive disease and identify patients at higher risk for treatment failure.

Adolescent↗

PubMed2003

[Application of SCID mouse-human leukemia model for leukemia research].

SCID mouse-human leukemia model is an important and useful tool for study on proliferation, differentiation and modulation of leukemic cells. In this article, the establishment of the model, advances in research and application in studies of pathogenesis, cell biology, clinical diagnosis, therapy and assessment of prognosis of leukemia patients are reviewed. The limitations of the model are also commented.

Animals↗

PubMed1995

IL-1 beta is required for IL-12 to induce production of IFN-gamma by NK cells. A role for IL-1 beta in the T cell-independent mechanism of resistance against intracellular pathogens.

Mice with the severe combined immunodeficiency (SCID) possess an IFN-gamma-dependent mechanism of resistance to the intracellular pathogens Toxoplasma gondii and Listeria monocytogenes that is dependent on IL-12-induced production of IFN-gamma by NK cells. In this report we demonstrate that IL-1 beta is required for IL-12 to stimulate production of IFN-gamma by NK cells, and that IL-1 is important in IL-12-mediated resistance to T. gondii in vivo. Stimulation of SCID mouse splenocytes with tachyzoites of T. gondii resulted in production of IFN-gamma. Addition of neutralizing Ab specific for IL-1 beta to these cultures inhibited completely the production of IFN-gamma. Similar results were obtained when LPS or L. monocytogenes were used to stimulate production of IFN-gamma by SCID mouse splenocytes. Addition of a neutralizing Ab to IL-1 alpha did not affect production of IFN-gamma by SCID mouse splenocytes stimulated with T. gondii, L. monocytogenes, or LPS. Stimulation of SCID mouse splenocytes with IL-1 beta or IL-1 alpha did not result in production of IFN-gamma but enhanced remarkably the ability of T. gondii or IL-12 to stimulate production of IFN-gamma. Furthermore, production of IFN-gamma by SCID mouse splenocytes stimulated with IL-12 plus TNF-alpha was completely ablated by anti-IL-1 beta, but not by anti-IL-1 alpha. Analysis of the culture supernatants of spleen cells from SCID mice stimulated with T. gondii or IL-12 plus TNF-alpha detected low levels of IL-1 beta; addition of a neutralizing Ab to IFN-gamma resulted in a 5- to 10-fold increase in levels of IL-1 beta. Furthermore, stimulation of SCID mouse splenocytes with IL-12, in the presence of anti-IFN-gamma, resulted in an increase in detectable levels of IL-1 beta. To determine the in vivo relevance of our in vitro data, SCID mice were infected with T. gondii and treated with IL-12 alone or IL-12 in combination with an Ab specific for the type I IL-1 receptor. This Ab reduced production of IFN-gamma by SCID mouse splenocytes stimulated with either T. gondii, LPS, L. monocytogenes, or IL-12 plus IL-1 beta. In vivo administration of this Ab antagonized significantly the ability of exogenous IL-12 to delay the time to death of SCID mice infected with T. gondii.(ABSTRACT TRUNCATED AT 400 WORDS)

Adjuvants, Immunologic↗

PubMed2001

GM-CSF and IL-2 induce specific cellular immunity and provide protection against Epstein-Barr virus lymphoproliferative disorder.

Epstein-Barr virus-associated lymphoproliferative disease (EBV-LPD) is a potentially life-threatening complication in immune-deficient patients. We have used the severe combined immune deficient (SCID) mouse engrafted with human leukocytes (hu-PBL-SCID) to evaluate the use of human cytokines in the prevention of EBV-LPD in vivo. Daily low-dose IL-2 therapy can prevent EBV-LPD in the hu-PBL-SCID mouse, but protection is lost if murine natural killer (NK) cells are depleted. Here we demonstrate that combined therapy with human GM-CSF and low-dose IL-2 is capable of preventing EBV-LPD in the hu-PBL-SCID mouse in the absence of murine NK cells. Lymphocyte depletion experiments showed that human NK cells, CD8(+) T cells, and monocytes were each required for the protective effects of GM-CSF and IL-2 combination therapy. This treatment resulted in a marked expansion of human CD3(+)CD8(+) lymphocytes in vivo. Using HLA tetramers complexed with EBV immunodominant peptides, a subset of these lymphocytes was found to be EBV-specific. These data establish that combined GM-CSF and low-dose IL-2 therapy can prevent the immune deficiencies that lead to fatal EBV-LPD in the hu-PBL-SCID mouse depleted of murine NK cells, and they point to a critical role for several human cellular subsets in mediating this protective effect.

Animals↗