Human Peripheral Blood Leukocyte Engraftment into SCID Mice: Critical Role of CD4+ T Cells

Duchosal, Michel A.; Mauray, Sandrine; Rüegg, Marlies; Trouillet, Philippe; Vallet, Véronique; Aarden, Lucien A.; Tissot, Jean‐Daniel; Schapira, Marc

doi:10.1006/cimm.2001.1822

Cited by 6 publications

(4 citation statements)

References 48 publications

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“…Previous studies by others have established that human CD4 + T cells can recognize and become activated by xenoantigens presented via murine MHC class II molecules [60,61]. Since NOD/SCIDβ2m null mice have normal MHC class II function, they should retain their ability to present xenoantigens to human CD4 + T cells.…”

Section: Discussionmentioning

confidence: 99%

Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2mnull mice

Nervi

Rettig

Ritchey

et al. 2007

Experimental Hematology

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Objective-Graft-versus-host disease (GVHD) is the major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Models of immunodeficient mice that consistently and efficiently reconstitute with xenoreactive human T cells would be a valuable tool for the in vivo study of GVHD, as well as other human immune responses.Materials and Methods-We developed a consistent and sensitive model of human GVHD by retro-orbitally injecting purified human T cells into sublethally irradiated NOD/SCID-β2m null recipients. In addition, we characterized for the first time the trafficking patterns and expansion profiles of xenoreactive human T cells in NOD/SCID-β2m null recipients using in vivo bioluminescence imaging.Results-All NOD/SCID-β2m null mice conditioned with 300 cGy of total body irradiation and injected with 1 × 10 7 human T cells exhibited human T cell engraftment, activation, and expansion, with infiltration of multiple target tissues and a subsequent greater than 20% loss of pretransplant body weight. Importantly, histological examination of the GVHD target tissues revealed changes consistent with human GVHD. Furthermore, we also showed by in vivo bioluminescence imaging that the development of lethal GVHD in the NOD/SCID-β2m null recipients was dependent upon the initial retention and early expansion of human T cells in the retroorbital sinus cavity.Conclusion-Our NOD/SCID-β2m null mouse model provides a system to study the pathophysiology of acute GVHD induced by human T cells and aids in the development of more effective therapies for human GVHD.

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Section: Discussionmentioning

confidence: 99%

Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2mnull mice

Nervi

Rettig

Ritchey

et al. 2007

Experimental Hematology

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“…To test this hypothesis in vivo, we used the well established chimeric hu-SCID mouse model, in which human donor CD4 + T cells mediate GVHD in SCID mice ( 17,18 ). In our hands, conditioned SCID mice injected i.p.…”

Section: Human DC Are Required For Gvhd In the Chimeric Human Pbmc-transplanted Scid Mouse Model (Hu-scid)mentioning

confidence: 99%

“…To investigate the antihuman CD83 antibody in vivo, we used a chimeric human/mouse model of xenogeneic GVHD (17) in which SCID mice are engrafted with human PBMC. These hu-SCID mice develop a fatal human CD4 + T cell–dependent GVHD-like syndrome affecting multiple organs, which has histological features similar to those seen in allo human and mouse GVHD (18). We show in this paper that human DC were required to induce GVHD in this model.…”

mentioning

confidence: 98%

Antibody to the dendritic cell surface activation antigen CD83 prevents acute graft-versus-host disease

Wilson

Cullup

Lourie

et al. 2009

Journal of Experimental Medicine

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Allogeneic (allo) hematopoietic stem cell transplantation is an effective therapy for hematological malignancies but it is limited by acute graft-versus-host disease (GVHD). Dendritic cells (DC) play a major role in the allo T cell stimulation causing GVHD. Current immunosuppressive measures to control GVHD target T cells but compromise posttransplant immunity in the patient, particularly to cytomegalovirus (CMV) and residual malignant cells. We showed that treatment of allo mixed lymphocyte cultures with activated human DC-depleting CD83 antibody suppressed alloproliferation but preserved T cell numbers, including those specific for CMV. We also tested CD83 antibody in the human T cell–dependent peripheral blood mononuclear cell transplanted SCID (hu-SCID) mouse model of GVHD. We showed that this model requires human DC and that CD83 antibody treatment prevented GVHD but, unlike conventional immunosuppressants, did not prevent engraftment of human T cells, including cytotoxic T lymphocytes (CTL) responsive to viruses and malignant cells. Immunization of CD83 antibody-treated hu-SCID mice with irradiated human leukemic cell lines induced allo antileukemic CTL effectors in vivo that lysed 51Cr-labeled leukemic target cells in vitro without further stimulation. Antibodies that target activated DC are a promising new therapeutic approach to the control of GVHD.

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“…Among studies on cancer therapy of human tumors in athymic and SCID animal models, the research on the efficacy of immune modulators in cancers is limited due to the impaired immune system of these mice. Engraftment of lymphocytes or distinct lymphocyte populations into a SCID mouse was shown to overcome the recipient immune deficiencies, thus enabling studies on the effect of immune modulators in cancer therapy (1,2). The attempts to apply new therapeutics in cancer by immune modulators aim to modulate the immune system response in order to kill tumor cells.…”

Section: Introductionmentioning

confidence: 99%

BAT mAb induces lymphopoiesis in nude mice

Hardy¹,

Niv²,

Fadaeev³

et al. 2005

International Immunology

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The athymic nude mouse provides a powerful tool in the study of human tumors, as it enables growth of human tumors due to deficiencies in T cell functions. However, deficiencies in T cell functions might limit research on efficacy of immune modulators in cancer immunotherapy. BAT mAb mediates its anti-cancer activity through modulation of the immune system that involves both NK and T cells. We analyzed lymphocyte populations in blood 5 and 14 days following the injection of BAT antibody alone or following engraftment of human colon carcinoma cells. Our results demonstrate that BAT injection induced lymphopoiesis in the nude mouse. Percentage of CD3 cells increased up to 24%, CD4 cells up to 20% but no increase was found in CD8 T cells in BAT-injected nude mice. Injection of BAT 12 days post-tumor engraftment propagated CD3, CD4 and CD8 cells seen in the blood 5 days later but not seen in the blood 14 days post-BAT injection. It is possible that this decrease is associated with migration of the lymphocytes from the blood to the tumor sites in the livers. The percentage of CD56-positive NK cells increased (up to 18%) by BAT administration alone or post-tumor injection. The presence of tumors alone did not induce lymphopoiesis in the nude mice. Propagation and lymphopoiesis by BAT mAb might have future clinical implications.

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Human Peripheral Blood Leukocyte Engraftment into SCID Mice: Critical Role of CD4+ T Cells

Cited by 6 publications

References 48 publications

Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2mnull mice

Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2mnull mice

Antibody to the dendritic cell surface activation antigen CD83 prevents acute graft-versus-host disease

BAT mAb induces lymphopoiesis in nude mice

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