key: cord-0772379-r7ehkau9
authors: Zhang, Baojun; Duan, Ziyuan; Zhao, Yong
title: Mouse models with human immunity and their application in biomedical research
date: 2008-04-15
journal: J Cell Mol Med
DOI: 10.1111/j.1582-4934.2008.00347.x
sha: eb25ca46c7e411e952c63ded8455c9df1006bbd4
doc_id: 772379
cord_uid: r7ehkau9

Biomedical research in human beings is largely restricted to in vitro studies that lack complexity of a living organism. To overcome this limitation, humanized mouse models are developed based on immunodeficient characteristics of severe combined immunodeficiency (SCID) or recombination activating gene (Rag)(null) mice, which can accept xenografts. Peripheral constitution of human immunity in SCID or Rag(null) mice has been achieved by transplantation of mature human immune cells, foetal human thymus, bone marrow, liver tissues, lymph nodes or a combination of these, although efficiency needs to be improved. These mouse models with constituted human immunity (defined as humanized mice in the present text) have been widely used to investigate the basic principles of human immunobiology as well as complex pathomechanisms and potential therapies of human diseases. Here, elements of an ideal humanized mouse model are highlighted including genetic and non-genetic modification of recipient mice, transplantation strategies and proposals to improve engraftments. The applications of the humanized mice to study the development and response of human immune cells, human autoimmune diseases, virus infections, transplantation biology and tumour biology are reviewed as well.

The study of human immunobiology in vivo is limited by technical and ethical constraints. Animal models with humanized immune systems would significantly advance our understanding on human immunobiology and immune-related diseases such as autoimmune diseases, virus infections, as well as tumour and graft rejections. Immunodeficient mice with constituted human immunity have been developed to overcome these constraints and are now important research tools for the in vivo study of human haematolymphopoiesis and immune responses. Severe combined immunodeficiency (SCID) or recombination activating gene (Rag) null mice, lacking T and B cells, were originally used as recipients to re-build human immunity [1] . Recently, more and more genetically modified SCID or Rag null mice including SCID/beige [2] , non-obese diabetic/severe combined immunodeficiency (NOD/SCID) [3] , NOD/SCID/␤2M null [4] and NOD/SCID/␥c null 

SCID mice are defective in DNA repair because of a mutation in DNA-dependent protein kinase (DNA-PK) in the CB-17 inbred mouse strain [25, 26] , therefore they lack productive rearrangement of T cell receptor and immunoglobulin genes, which subsequently results in the deficiency of T and B cells [27] . The lack of functional T and B cells in SCID mice contributes to the acceptance of allogeneic or xenogeneic grafts without severe rejection [1, 28, 29] . However, SCID mice have a radiation repair deficiency and an uncomplete block of VDJ recombination, so some old SCID mice may become 'leaky' mice depending on antigen stimulation (Fig. 1 ). In addition, residual innate immunity including complement, natural killer (NK) cells, macrophages and granulocytes remains somewhat intact in SCID mice, which may limit the grafting efficiency of xenogeneic cells and tissues ( [47, 48] . NOD/SCID/␥c null mice were created by impairing ␥c chain in NOD/SCID mice, and these mice are completely defective in T, B and NK activity [5] . Moreover, CD11c + dendritic cells (DCs) become functionally defective in NOD/SCID/␥c null mice, resulting in the reduction of IFN-␥ production. Therefore, NOD/SCID/␥c null mice are currently considered as the optimal recipients of human HSCs [5] because of their complete deficiency in adaptive immunity and more impaired innate immunity (Fig. 2) .

The Rag1 or Rag2 are responsible for the initiation of TCR and immunoglobulin genes' VDJ rearrangement through the generation of a DNA double strand break, therefore homozygous mutants in mice result in the inability to produce mature T and B cells, leading to a SCID-like phenotype [6] [7] [8] . These mice do not become leaky with age due to their complete inability to initiate VDJ recombination and display a longer life span than NOD/LtSz-SCID mice. This is due to a delay or prevention of thymic lymphomas associated with the DNA repair defect (Fig. 1) [49]. However, they could not support efficient human engraftment because of the functional innate immunity (Fig. 2) (Fig. 2) [10]. Thus, the frequency of leakiness in immunodeficient mice is as follows (in descending order): NOD/SCID/␥c null mice, Rag2 null ␥c null mice, NOD/LtSz-Rag1 null Pfp null mice, NOD/LtSz-Rag1 null mice< Rag null mice < NOD/SCID mice < SCID mice (Fig. 1) . Until now, the favoured mouse recipients for grafting human haematopoietic or immune cells were generally as follows: NOD/SCID/␥c null mice, Rag2 null ␥c null mice or NOD/LtSz-Rag1 null Pfp null mice > NOD/SCID mice or NOD/LtSz-Rag1 null mice> SCID mice > Rag null mice (Fig. 2 ). [77, 78] [80] or a combination of these [81] . All these protocols showed only marginal effects if both the function and distribution of transferred human PBLs in lymph organs of these models were considered.

Another weakness of this model was the weak primary immune response [82] [83] [84] . However, it induced substantial immune responses against recipient mouse xenoantigens, which 'skew' the human lymphoid repertoire [85] . This xeno-response mediated by human T and B cells not only caused potentially fatal GVHD [79, 84, 86] , but also severely limited the ability of human PBLs to respond to exogenous antigens [70, 87] . Thus, the application of this approach in biomedical research is currently somewhat limited. 

Human bone marrow grafts in SCID mice were histologically comparable to normal foetal bone marrow when fragments of foetal human femur and tibia were implanted into SCID mice [88] . In this model, the human cell populations presenting in the circulation, consisted mostly of B cells and a few of cells belonging to the monocytic-granulocytic lineages. Human IgM, IgG and occasionally IgE were detected in the sera, but no mature human T cells could be observed in the bones or the circulation of these mice [88, 89] . The multi-lineage reconstitution of functional T, B and NK cells was achieved in irradiated NOD/SCID/␥c null mice after transplantation of human CD34 + HSCs without co-transplantation of human immune tissues [90] [91] [92] . Human T cells developing in the thymus of these mice migrated into peripheral lymphoid organs. These T cells beared polyclonal TCR-␣␤ and responded not only to mitogenic stimuli, such as PHA and IL-2, but also to allogeneic human cells. These results indicated that functional human T cells could be reconstituted in NOD/SCID␥c null mice by grafting human CD34 + cells [93] .

When human cord blood CD34 + cells were injected into NOD/SCID foetuses, human immune cells could not efficiently self-renew and differentiate in the foetal mouse environment [94] .

Although multilineage engraftment occurred in these foetal recipients, both the frequency and the levels of engraftment were lower than those previously reported when human immune cells were transplanted into adult NOD/SCID recipients [95] .

Like NOD/SCID/␥c null mice, Rag2 null ␥c null mice engrafted with human cord blood CD34 + cells led to multilineage of human haematopoiesis with the production of T cells, B cells and DCs [96] . Primary and secondary lymphoid organs (thymus, bone marrow, spleen and lymph nodes) were reconstituted in these mice with human immune cells. Human immune responses were demonstrated when these mice were immunized with tetanus toxoid or infected with Epstein-Barr virus (EBV) [96] . Low levels of antigen-specific human IgG productions upon immunization indicate that an inefficient class switching is present in this model [90, 92] . In addition, the levels of human T cells in these mice are much lower compared to humanized mice that receive human foetal thymus tissue, suggesting that poor efficacy of human thymopoiesis in xenogeneic mouse thymus may exist [90, 92] .

Another important approach to establish a humanized mouse model is transplanting foetal human thymus and liver tissue beneath the kidney capsules of SCID mice, which results in the development of a well vascularized human thymus-like organ [97] . [101] .

Despite the large numbers of human T cells present in the thymus, the levels of peripheral circulating human T cells were relatively low in this model. These human T cells were responsive to mitogenic stimuli and alloantigens, and produced the types and amounts of cytokines similar to compartment of human beings [100, 102] . However, no detectable mature human B cells were generated in these mice [89, 97] . Increasing the quantity of implanted foetal human thymus and liver tissues somehow enhanced the percentages of human CD4 + and CD8 + T cells in the peripheral blood, spleen and lymph nodes [103] . [104] . These structures of bone and thymus were indistinguishable from age-matched human counterparts. These mice produced human IgM and IgG at levels that were consistently higher than those observed in SCID mice grafted with human thymus and liver tissues from the same donor [89] . Furthermore, all four human IgG subclasses, IgA and IgE were detectable [104] . These results showed that human antibody production and isotype switching occured in these mice, indicating that human APCs, T and B cells interacted physiologically in response to environmental antigens.

Importantly, co-transplantation of human foetal thymus/liver tissues and CD34 + HSCs led to the efficient establishment of human haematopoiesis and functional immune systems in NOD/SCID mice, which showed repopulation with multilineage of human haematopoietic cells, including T cells, B cells and DCs in secondary lymphoid tissues [13] . These mice produced high levels of human IgM and IgG antibodies and mediated strong immune responses in vivo as demonstrated by skin xenograft rejection [13] . These humanized mice provided a more powerful model to study human immune function in vivo.

The optimal experimental humanized mouse model, in which all human immune cell lineages can develop and home to specific sites to perform optimal immune response, should be explored. 

Therefore, a combination of modified recipients (immunodeficiency, athymic, available 'space', and proper microenvironments including growth factors and homing molecules) and transplantation strategies (human immune tissues and stem cells) would create an optimal humanized mouse model with an approximation of a complete human immune system ( Table 2) . [108] 97] . The V␤ repertoire in thymocytes from grafts was comparable to those of the foetal thymus before transplantation, demonstrating generation of human T cell diversity in human thymus grafts [101] . Human T cells maturing in human thymus grafts responded to toxic shock syndrome toxin1 superantigens, EBV infection and mitogens, indicating they were functional [111, 113] . [96] . Our recent studies also showed human CD4 + CD25 + Foxp3 + T cells could efficiently devel- 90, 112] . These human antigen-specific immunoglobulins were produced after immunization with a T cell-independent antigen [90] [91] [92] 112] . Human DCs in humanized mice were developmentally, phenotypically, and functionally similar to the DC subsets found in human beings [114] . Human NK cells mainly repopulated in BM and spleen, and showed cytotoxicity against K562 cells in this model [91] .

Human PBLs obtained from patients with organ-specific and multi-system autoimmune diseases survived in SCID mice for several months and produced IgG and autoantibodies with the same specificities found in the donor [115] . Therefore, this provides a possible way to investigate the pathogenesis and effector phases of human autoimmune diseases in in vivo models.

into SCID mice, circulating anti-pemphigus antibodies were found in these mice, and human IgG deposited in their traumatized skin. Allogeneic human skin grafted to SCID mice before reconstitution with patients' PBLs developed PV-like lesions containing human IgG deposits [116] . These results indicate that humanized mice may serve as models of antibody-mediated human autoimmune skin diseases. [117, 118] . In SCID mice grafted with human PBLs, HIV infections were limited to a short period because CD4 + T cells were rapidly depleted and lacked replenishment sources [119] . After intrasplenic transfer of PBLs from untreated HIV-infected patients into NOD/SCID mice, a strong HIV-specific antibody response was observed [120] . This, therefore, is feasible for the study of HIVspecific human humoural immune responses and for the isolation of human mAbs against HIV. In humanized mice grafted with human thymus and liver tissues, HIV infection showed preferential tropism for a population of intrathymic CD3 Ϫ CD4 + CD8 Ϫ T progenitor cells [121] , while other thymocytes were normally generated [122, 123] . After transplantation of human CD34 + CB cells, the long-lasting viremia after infection with both CCR5-and CXCR4-tropic HIV-1 isolates was detected in spleen, bone marrow or thymi of NOD/SCID/IL-2␥c null mice. Also, this high rate of viral infection was accompanied by production of anti-HIV-1 Env gp120 and Gag p24 antibodies [90] . In humanized Rag2 null ␥c null mice constructed with cord blood CD34 + cells, CXCR4 and CCR5 expression on human CD4 + , T cells in lymphoid organs closely resembled HIV coreceptor expression in human beings [124, 125] .

Humanized mouse models have been developed for pre-clinical evaluation of antiviral compounds against HIV including azidothymidine [126] , dideoxyinosine, dideoxycytosine, nevirapine, protease inhibitors [127] , non-immunosuppressive cyclosporine derivatives, peptide inhibitors of env-CD4 interactions and 'zincfinger' inhibitors [128] . Humanized mice constructed by human thymus, liver tissues and lymph nodes were permissive for HIV replication [78] and antiviral compounds such as azidothymidine would partially suppress replication in a time-and dose-dependent manner [126] . Exposure to cocaine can enhance HIV infection in vivo by activating sigma-1 receptors and modulating the expression of HIV coreceptors. A selective sigma-1 antagonist, BD1047, blocked the effects of cocaine on HIV replication in SCID mice grafted with human PBLs [129] . In addition, humanized mouse models have also been proven useful in evaluating gene therapeutic approaches. Transferring human CD4 + T cells containing the IFN-␤ retroviral vector drastically reduced the pre-existing HIV infection and enhanced CD4 + T cells survival as well as Th1 cytokine expression [130] .

SARS, a kind of corona virus, caused a deadly epidemic in Asia [131] . The humanized mice constructed by human PBLs were used to study novel vaccine candidates against SARS CoV. SARS DNA vaccines induced human cytotoxic T lymphocytes specific for SARS antigens and human neutralizing antibodies against SARS CoV [132] . It was demonstrated that Angiotensin-converting enzyme 2 was a functional receptor for the SARS CoV [133] .

VZV appeared to cause viremia by infecting human lymphocytes [134] . Humanized mouse models were used to examine VZV pathogenesis and immunobiology in vivo [135] [136] [137] . These experiments provided evidence in support of a critical role for T cell tropism in VZV pathogenesis. Eliminating ORF47 kinase activity impaired virus production and envelopment, which would block VZV infectivity for T cells [134] .

Dengue virus is an important mosquito-borne flavivirus and it infects human beings causing a range of illnesses from subclinical infection to acute dengue fever to the severe dengue haemorrhagic fever/dengue shock syndrome [138] . A major limitation to the understanding of dengue virus pathogenesis and immunity has been the lack of an ideal humanized animal model. Irradiated NOD/SCID or Rag2 null ␥c null mice grafted with human cord blood haematopoietic progenitor cells or foetal liver-derived CD34 + cells achieved replication of dengue viral infection in a physiological setting. These models were found to be susceptible to dengue virus infection, showed signs typical of fever and thrombocytopenia, and were used to evaluate dengue virus pathogenesis [138, 139] . Also, humanized mice were used to investigate pathogenesis and therapeutics of EBV [140] , cytomegalovirus (CMV) [135] and influenza infections [141] .

Pigs may be suitable donors for human xenotransplantation. The potential transmission of PERVs to human cells was investigated in humanized mice, and some tissues were positive for PERVs' DNA [142, 143] . However, the infection was non-productive as PERV transcripts were not detectable in those tissues [144] , and might be due to microchimerism or pseudotyping with murine viruses [145] . Importantly, it was shown that human cells and porcine cells could co-exist for many weeks without any evidence for infection of human cells by PERVs in NOD/SCID mice transgenic for certain porcine cytokines and transplanted by porcine BMCs, human foetal thymus and liver tissues [146] . However, it remains to be seen whether immunosuppressive therapy would facilitate retroviral infection of human cells.

Transplantation of allogeneic HLA-mismatched foetal pancreases in SCID mice grafted with human thymus and liver tissues or PBLs resulted in infiltration of human mononuclear cells in the pancreas and subsequent rejection [89, 147] . Human T cells were responsible for the rejection of skin transplants from allogeneic donors in SCID mice [148, 149] . Like skin grafts performed among human beings, the dermal microvessels were destroyed and the skin became necrotic [150] .

SCID mice grafted with human PBLs were established models for delayed-type hypersensitivity (DTH) [151] . Human skin was grafted onto the backs and autologous human immune cells were injected into the peritoneal cavity of SCID mice. Injection of tetanus toxoid into the human skin grafts not adjacent mouse skin caused perivascular human T cell infiltrate, which indicates that human T cells specifically recognize human but not mouse skin as homing sites, and that human T cell responses depends on the human microenvironments. Recently, it was found that adaptive CD4 + CD25 + Treg cells isolated from kidney transplant recipients who are tolerant to the donor, mediated the suppression of donorspecific DTH in humanized SCID mice [152] . SCID mice transplanted with human foetal liver from donor A and foetal thymus from donor B developed a mixed chimeric human thymus [153] . In this model, human T cells reactive to donor A were clonally deleted by selection in the thymus, while T cells potentially responding to donor B were rendered anergic upon interaction with the allogeneic thymic epithelial cells of donor B [154] .

and CD69 were demonstrated in spleen, liver, lung, kidney and bone marrow of the recipients. [155] . Depletion of CD4 + CD25 + Treg cells from human PBMCs significantly exacerbated xenogeneic GVHD, whereas co-administration of this subset of Treg cells significantly inhibited the expansion of effector T cells and reduced the lethality of xenogeneic GVHD. Interestingly, the protective role was associated with a significant increase in plasma levels of IL-10 and IFN-␥, indicating the de novo development of Tr1 cells [155] .

Humanized mouse models were used to study the immune response to xenogeneic porcine grafts in vivo [156] [157] [158] . Circulating human T cells in these mice did not infiltrate pig skin or artery grafts in contrast to the robust immune responses against allogeneic human cells in vitro. However, TNF-treated pig tissue permitted human T cells to infiltrate and injure both pig skin and artery grafts because the actions of this proinflammatory cytokine were not species-restricted and could activate pig endothelial cells to express cell surface molecules that were necessary to recruit a local infiltrate of leucocytes [156, 158] . Thus, by addition of TNF, the humanized mice might be used to study primary human T cellmediated anti-porcine xenogeneic responses in vivo.

Porcine thymus grafts in SCID mice grafted with foetal porcine thymus and human liver tissues support normal development of polyclonal, functional human T cells from haematopoietic precursors provided by human foetal liver cells [159] . These human T cells were specifically tolerant to donor porcine antigens but normally responded to non-donor porcine xenoantigens and alloantigens. Exogenous IL-2 did not abolish tolerance, suggesting that central clonal deletion rather than anergy was the possible tolerance mechanism [159] . Recently [160] . Human T cells developed in this chimerism showed specific non-responsiveness to the porcine donor because it lacked rejection of porcine haematopoietic cells and anti-donor pig MLR responses, as well as the acceptance of donor swine leucocyte antigen (SLA)-matched skin grafts, whereas human T cells in the mixed chimeric mice rejected the third party porcine skin grafts and responded to the third party pig and allogeneic human antigens in MLR assays [160] . The capacity of haematopoietic chimerism to induce T cell tolerance to donor cells largely resulted from intrathymic clonal deletion of maturing donor-reactive thymocytes [161, 162] .

Malignant tumours can unlimitedly grow, escaping from human immune surveillance. Athymic nude mice, SCID or Rag Ϫ/Ϫ mice could be successfully engrafted with xenogeneic human tumours including a wide variety of solid human tumours and haematological neoplasms [163, 164] , in which human tumour biology, growth, angiogenesis and metastasis have been evaluated.

The ability to engraft human tumours and human immunocompetent cells successfully in immunodeficient mice has spawned the development and use of humanized mouse models to evaluate anti-tumour therapies, because the study of tumour biology in human beings was impeded by access to tissues and to the site of tumour growth as well as ethical concerns. Indeed, an ideal model was humanized mice with a complete human immune system, which will permit evaluating the mechanism of tumour immunobiology in the context of an intact human immune microenvironment. Humanized mice can be used for the evaluation of therapeutic approaches for the inhibition of human tumour growth, including the use of angiogenesis inhibitors [165] , cell-based therapies [166] , humanized antibodies [167] , traditional immunosuppressive and immunotherapeutic protocols [168] and tumour-growth inhibitors [169] [170] [171] .

Humanized mice provide an opportunity to evaluate human cytokines and chemokines that augment both innate and adaptive anti-tumour immune responses of human leucocytes, thus providing a model that is more clinically relevant. This model has been utilized to test the anti-tumour efficacy of a wide spectrum of human cytokines [172] [173] [174] and cytokine-delivery strategies including the direct injection of soluble cytokines [175] , cytokine gene transfer [173, 174] and the use of slow-release polymer particles [175] .

Humanized mouse models have made tremendous progress in modification of recipient mice and transplantation strategies in recent years. These models are becoming powerful and versatile tools to investigate human haematolymphoid differentiation, autoimmunity, virus infections, transplantation rejection and tolerance induction. However, much effort should be directed in minimizing innate immunity mediated by NK cells and macrophages in SCID or Rag null mouse recipients. Some incompatibility of cytokines and adhesive molecules between mice and human beings could descend the human immune cell levels in immunodeficient recipients. Immunodeficient mice with some important human growth factors will be ideal recipients to establish humanized mice. Optimized humanized mouse models will offer a powerful approach for us to study human immunity in vivo, which will significantly advance biomedical research. 

Human CD4+ T cells mediate rejection of porcine xenografts

Human immunodeficiency virus infection of human lymph nodes in the SCID-hu mouse

Infection of the SCID-hu mouse by HIV-1

Immunohistology and immunocytology of human T-cell chimerism and graft-versus-host disease in SCID mice

High level functional engraftment of severe combined immunodeficient mice with human peripheral blood lymphocytes following pretreatment with radiation and anti-asialo GM1

Successful engraftment of human postnatal thymus in severe combined immune deficient (SCID) mice: differential engraftment of thymic components with irradiation versus anti-asialo GM-1 immunosuppressive regimens

Primary Th1 cell immunization against HIVgp160 in SCIDhu mice coengrafted with peripheral blood lymphocytes and skin

Obtention of a human primary humoral response against schistosome protective antigens in severe combined immunodeficiency mice after the transfer of human peripheral blood mononuclear cells

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

Anti-SCID mouse reactivity shapes the human CD4+ T cell repertoire in hu-PBL-SCID chimeras

Human-mouse lymphoid chimeras: host-vs.-graft and graft-vs.-host reactions

Human lung tumors, patients' peripheral blood lymphocytes and tumor infiltrating lymphocytes propagated in SCID mice

Implantation and maintenance of functional human bone marrow in SCID-hu mice

Human Tand B-cell functions in SCID-hu mice

Hematopoietic stem cell-engrafted NOD/SCID/IL2R gamma null mice develop human lymphoid systems and induce long-lasting HIV-1 infection with specific humoral immune responses

Complete reconstitution of human lymphocytes from cord blood CD34+ cells using the NOD/SCID/gammacnull mice model

Functional CD5+ B cells develop predominantly in the spleen of NOD/SCID/gammac(null) (NOG) mice transplanted either with human umbilical cord blood, bone marrow, or mobilized peripheral blood CD34+ cells

Functional human T lymphocyte development from cord blood CD34+ cells in nonobese diabetic/Shi-scid, IL-2 receptor gamma null mice

Engraftment kinetics of human cord blood and murine fetal liver stem cells following in utero transplantation into immunodeficient mice

In utero transplantation of human fetal haemopoietic cells in NOD/SCID mice

Development of a human adaptive immune system in cord blood celltransplanted mice

Longterm human hematopoiesis in the SCID-hu mouse

The biology of hematopoietic stem cells

Isolation of a candidate human hematopoietic stem-cell population

Human T cells in the SCID-hu mouse are phenotypically normal and functionally competent

Thymic selection of the human T cell receptor V beta repertoire in SCID-hu mice

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

Disseminated human immunodeficiency virus 1 (HIV-1) infection in SCID-hu mice after peripheral inoculation with HIV-1

IL-4 induces human B cell maturation and IgE synthesis in SCID-hu mice. Inhibition of ongoing IgE production by in vivo treatment with an IL-4/IL-13 receptor antagonist

Shigella infection in a SCID mouse-human intestinal xenograft model: role for neutrophils in containing bacterial dissemination in human intestine

Neutrophil-mediated suppression of virus replication after herpes simplex virus type 1 infection of the murine cornea

Toxoplasma gondii triggers granulocyte-dependent cytokine-mediated lethal shock in D-galactosamine-sensitized mice

Similar myeloid recovery despite superior overall engraftment in NOD/SCID mice after transplantation of human CD34(+) cells from umbilical cord blood as compared to adult sources

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

Human T, B, natural killer, and dendritic cells arise from a common bone marrow progenitor cell subset

Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1

Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice

In vivo cytokine expression in the thymus. CD3high human thymocytes are activated and already functionally differentiated in helper and cytotoxic cells

Development and activation of human dendritic cells in vivo in a xenograft model of human hematopoiesis

Autoimmunity versus allo-and xeno-reactivity in SCID mice

Development of pemphigus vulgaris-like lesions in severe combined immunodeficiency disease mice reconstituted with lymphocytes from patients

Inhibition of acute in vivo human immunodeficiency virus infection by human interleukin 10 treatment of SCID mice implanted with human fetal thymus and liver

Transient renewal of thymopoiesis in HIV-infected human thymic implants following antiviral therapy

Rapid loss of CD4+ T cells in human-PBL-SCID mice by noncytopathic HIV isolates

The intraspleen huPBL NOD/SCID model to study the human HIVspecific antibody response selected in the course of natural infection

HIV-1-induced thymocyte depletion is associated with indirect cytopathogenicity and infection of progenitor cells in vivo

Differentiation of CD3-4-8-human fetal thymocytes in vivo: characterization of a CD3-4+8-intermediate

Precursors of CD3+CD4+CD8+ cells in the human thymus are defined by expression of CD34. Delineation of early events in human thymic development

Disseminated and sustained HIV infection in CD34+ cord blood cell-transplanted Rag2-/-gamma c-/-mice

HIV-1 infection and pathogenesis in a novel humanized mouse model

Suppression of HIV infection in AZT-treated SCID-hu mice

Liv mouse model for preclinical efficacy testing of anti-human immunodeficiency virus type 1 compounds

Antiviral efficacy in vivo of the anti-human immunodeficiency virus bicyclam SDZ SID 791 (JM 3100), an inhibitor of infectious cell entry

Cocaine and sigma-1 receptors modulate HIV infection, chemokine receptors, and the HPA axis in the huPBL-SCID model

Transfer of human CD4(+) T lymphocytes producing beta interferon in Hu-PBL-SCID mice controls human immunodeficiency virus infection

Identification of a novel coronavirus in patients with severe acute respiratory syndrome

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

Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

Varicella-Zoster virus pathogenesis and immunobiology: new concepts emerging from investigations with the SCIDhu mouse model

Tropism of varicella-zoster virus for human CD4+ and CD8+ T lymphocytes and epidermal cells in SCID-hu mice

The immediate-early 63 protein of Varicella-Zoster virus: analysis of functional domains required for replication in vitro and for T-cell and skin tropism in the SCIDhu model in vivo

Mutational analysis of open reading frames 62 and 71, encoding the varicella-zoster virus immediateearly transactivating protein, IE62, and effects on replication in vitro and in skin xenografts in the SCID-hu mouse in vivo

Dengue virus infection and immune response in humanized RAG2(-/-) gamma(c)(-/-) (RAG-hu) mice

Dengue fever in humanized NOD/SCID mice

Human plasmacytoid dendritic cells regulate immune responses to Epstein-Barr virus (EBV) infection and delay EBV-related mortality in humanized NOD-SCID mice

Human dendritic cell subsets in NOD/SCID mice engrafted with CD34+ hematopoietic progenitors

Xenoreactive anti-Galalpha(1, 3)Gal antibodies prevent porcine endogenous retrovirus infection of human in vivo

Porcine cell microchimerism but lack of productive porcine endogenous retrovirus (PERV) infection in naive and humanized SCIDbeige mice treated with porcine peripheral blood mononuclear cells

Porcine endogenous retroviruses PERV-A and PERV-B infect neither mouse cells in vitro nor SCID mice in vivo

Mouse retrovirus mediates porcine endogenous retrovirus transmission into human cells in long-term human-porcine chimeric mice

Rejection of human islets and human HLA-A2.1 transgenic mouse islets by alloreactive human lymphocytes in immunodeficient NOD-scid and NOD-Rag1(null)Prf1(null) mice

Immunopathology of human T cell responses to skin, artery and endothelial cell grafts in the human peripheral blood lymphocyte/severe combined immunodeficient mouse

Noncytolytic human lymphocytes injure dermal microvessels in the huPBL-SCID skin graft model

Human Tcell-mediated destruction of allogeneic dermal microvessels in a severe combined immunodeficient mouse

Human delayedtype hypersensitivity reaction in a SCID mouse engrafted with human T cells and autologous skin

Human CD4+CD25low adaptive T regulatory cells suppress delayed-type hypersensitivity during transplant tolerance

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

IL-2 reverses human T cell unresponsiveness induced by thymic epithelium in SCID-hu mice

Human regulatory T cells control xenogeneic graft-versus-host disease induced by autologous T cells in RAG2-/-gammac-/-immunodeficient mice

Human TNF can induce nonspecific inflammatory and human immune-mediated microvascular injury of pig skin xenografts in immunodeficient mouse hosts

Pig but not human interferon-gamma initiates human cell-mediated rejection of pig tissue in vivo

Human T cells infiltrate and injure pig coronary artery grafts with activated but not quiescent endothelium in immunodeficient mouse hosts

Normal development in porcine thymus grafts and specific tolerance of human T cells to porcine donor MHC

Induction of human T-cell tolerance to porcine xenoantigens through mixed hematopoietic chimerism

The complementary roles of deletion and regulation in transplantation tolerance

Mixed chimerism and transplant tolerance

Human lung tumor growth established in the lung and subcutaneous tissue of mice with severe combined immunodeficiency

Xenotransplantation of human lymphoid malignancies is optimized in mice with multiple immunologic defects

Angiostatin induces and sustains dormancy of human primary tumors in mice

Activated natural killer cells from patients with acute myeloid leukemia are cytotoxic against autologous leukemic blasts in NOD/SCID mice

The anti-CD20 antibody rituximab augments the immunospecific therapeutic effectiveness of an anti-CD19 immunotoxin directed against human B-cell lymphoma

Soluble interleukin-13Ralpha2 decoy receptor inhibits Hodgkin's lymphoma growth in vitro and in vivo

A novel NF-kappaB inhibitor DHMEQ selectively targets constitutive NF-kappaB activity and induces apoptosis of multiple myeloma cells in vitro and in vivo

Rapid tumor formation of human T-cell leukemia virus type 1-infected cell lines in novel NOD-SCID/gammac(null) mice: suppression by an inhibitor against NF-kappaB

Expression of the antiangiogenic factor 16K hPRL in human HCT116 colon cancer cells inhibits tumor growth in Rag1(-/-) mice

Antitumor immune response of human peripheral blood lymphocytes coengrafted with tumor into severe combined immunodeficient mice

The anti-human tumor effect and generation of human cytotoxic T cells in SCID mice given human peripheral blood lymphocytes by the in vivo transfer of the Interleukin-6 gene using adenovirus vector

Granulocytemacrophage colony-stimulating factor and B7-2 combination immunogene therapy in an allogeneic Hu-PBL-SCID/beige mousehuman glioblastoma multiforme model

Cytokines delivered by biodegradable microspheres promote effective suppression of human tumors by human peripheral blood lymphocytes in the SCID-Winn model

Murine granulocytes control human tumor growth in SCID mice

Human recombinant interleukin-4 (HurIL-4) improves SCID mouse reconstitution with human peripheral blood lymphocytes