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

Nervi, Bruno; Rettig, Michael P.; Ritchey, Julie; Wang, Hanlin L.; Bauer, Gerhard; Walker, John T.; Bonyhadi, Mark; Berenson, Ronald J.; Prior, Julie L.; Piwnica‐Worms, David; Nolta, Jan A.; DiPersio, John F.

doi:10.1016/j.exphem.2007.06.007

Cited by 57 publications

(70 citation statements)

References 61 publications

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“…2,3 More recently, use of severely immune-deficient NOD/SCID/␥c Ϫ/Ϫ (NSG; NOD.Cg-Prkdc scid / IL2rg tm1Wjl /SzJ and NOG; NOD.Cg-Prkdc scid /Il2rgt m1Sug /Jic) mice, which lack functional B, T, and NK cells, has allowed for more consistent and reproducible engraftment of normal human cells and primary leukemias. [4][5][6] Primary acute lymphoblastic leukemia (ALL) xenografts in immune-deficient mice accurately represent human disease and gene expression and may have predictive value for clinical variables, such as drug resistance and time to relapse. [7][8][9][10][11] Although this model is a powerful and widely used tool for the ongoing development of new drugs and biologic therapeutics for ALL, [12][13][14][15][16][17][18][19] the kinetics of every primary patient sample are different, some engrafting in 4 weeks and others taking as long as one year, when measured by the appearance of human ALL blasts in peripheral blood.…”

Section: Introductionmentioning

confidence: 99%

Noninvasive bioluminescent imaging of primary patient acute lymphoblastic leukemia: a strategy for preclinical modeling

Barrett

Seif

Carpenito

et al. 2011

Blood

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The efficient engraftment in immunedeficient mice achieved with both acute lymphoblastic leukemia (ALL) cell lines and primary samples has facilitated identification of the antileukemia activity of a wide variety of agents. Despite widespread usage, however, little is known about the early ALL localization and engraftment kinetics in this model, limiting experimental read-outs primarily to survival and endpoint analysis at high disease burden. In this study, we report that bioluminescent imaging can be reproducibly achieved with primary human ALL samples. This approach provides a noninvasive, longitudinal measure of leukemia burden and localization that enhances the sensitivity of treatment response detection and provides greater insight into the mechanism of action of antileukemia agents. In addition, this study reveals significant cell line-and species-related differences in leukemia migration, especially early in expansion, which may confound observations between various leukemia models. Overall, this study demonstrates that the use of bioluminescent primary ALL allows the detection and quantitation of treatment effects at earlier, previously unquantifiable disease burdens and thus provides the means to standardize and expedite the evaluation of anti-ALL activity in preclinical xenograft studies. (Blood. 2011;118(15): e112-e117) IntroductionMurine leukemia models have been useful and versatile tools for identifying and targeting underlying disease mechanisms. 1 However, preclinical studies involving human samples are more immediately applicable when investigating new drugs or therapies. Initial studies with human leukemia in immune-deficient mice, such as the NOD/SCID (NOD.CB17-Prkdc scid /J), were a great step forward and remain valuable for rapid iterations in the study of novel therapies at the preclinical level. 2,3 More recently, use of severely immune-deficient NOD/SCID/␥c Ϫ/Ϫ (NSG; NOD.Cg-Prkdc scid / IL2rg tm1Wjl /SzJ and NOG; NOD.Cg-Prkdc scid /Il2rgt m1Sug /Jic) mice, which lack functional B, T, and NK cells, has allowed for more consistent and reproducible engraftment of normal human cells and primary leukemias. [4][5][6] Primary acute lymphoblastic leukemia (ALL) xenografts in immune-deficient mice accurately represent human disease and gene expression and may have predictive value for clinical variables, such as drug resistance and time to relapse. [7][8][9][10][11] Although this model is a powerful and widely used tool for the ongoing development of new drugs and biologic therapeutics for ALL, [12][13][14][15][16][17][18][19] the kinetics of every primary patient sample are different, some engrafting in 4 weeks and others taking as long as one year, when measured by the appearance of human ALL blasts in peripheral blood. 5,10,20 The endpoints of these studies are typically limited to survival analysis and time to grossly detectable disease. Monitoring the peripheral blood compartment for blasts is the primary method of disease detection, leaving the early engraftment kinetics and localization, t...

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Section: Introductionmentioning

confidence: 99%

Noninvasive bioluminescent imaging of primary patient acute lymphoblastic leukemia: a strategy for preclinical modeling

Barrett

Seif

Carpenito

et al. 2011

Blood

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“…As previously reported, a semiquantitative scoring system was used to assess abnormalities associated with GVHD or allograft rejection. 28 The scoring system designated 0 as normal, 0.5 as focal and rare, 1.0 as focal and mild, 2.0 as diffuse and mild, 3.0 as diffuse and moderate, and 4.0 as diffuse and severe. Scores were added to provide a total score for each specimen.…”

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confidence: 99%

Granzyme B is not required for regulatory T cell–mediated suppression of graft-versus-host disease

Cai

Cao

Hassan

et al. 2010

Blood

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Regulatory T (T reg ) cells can suppress a wide variety of immune responses, including antitumor and alloimmune responses.The mechanisms by which T reg cells mediate their suppressive effects depend on the context of their activation. We previously reported that granzyme B is important for T reg cell-mediated suppression of antitumor immune responses. We therefore hypothesized that granzyme B may likewise be important for suppression of graft-versus-host disease (GVHD). We found that allogeneic mismatch induces the expression of granzyme B in mixed lymphocyte reactions and in a model of graft-versus-host disease (GVHD). However, wild-type and granzyme B-deficient T reg cells were equally able to suppress effector T (T eff ) cell proliferation driven by multiple stimuli, including allogeneic antigen-presenting cells. Surprisingly, adoptive transfer of granzyme B-deficient T reg cells prevented GVHD lethality, suppressed serum cytokine production in vivo, and prevented target organ damage. These data contrast strikingly with our previous study, which demonstrated that granzyme B plays a nonredundant role in T reg cell-mediated suppression of antitumor responses. Taken together, these findings suggest that targeting specific T reg cell-suppressive mechanisms, such as granzyme B, may be therapeutically beneficial for segregating GVHD and graft-versus-tumor immune responses. (Blood. 2010;115: 1669-1677) IntroductionCD4 ϩ Foxp3 ϩ regulatory T (T reg ) cells play an indispensable role in maintaining peripheral tolerance to self-antigens by suppressing effector immune responses. Mice or humans with a deficiency of T reg cells, induced by antibody-mediated 1,2 or toxin-mediated 3,4 depletion or by mutations 5 and deletions 6,7 of the lineage specification factor Foxp3, manifest severe autoimmune disease. In addition to preventing autoimmunity, T reg cells can also suppress immune responses generated against tumor cells, 8,9 alloantigens, 10 allergens, [11][12][13] and microbial antigens. 14,15 Several mechanisms have been proposed to explain how T reg cellmediated suppression of effector immune responses occurs. In certain model systems, T reg -cell secretion of anti-inflammatory cytokines, such as transforming growth factor-␤ and interleukin-10 (IL-10), has been shown to be required for suppressive function. [16][17][18] In other experimental settings, contact-dependent mechanisms, such as interactions between CTLA-4 on T reg cells and CD80/CD86 on antigen-presenting cells (APCs), have also been reported. [19][20][21] Because of the variety of animal models, in vitro activation methods, and readouts for suppression, rigorously defining nonredundant T reg -suppressive mechanisms has been challenging and controversial. It is probable that T reg cells use multiple mechanisms depending on the context in which they are activated in vivo. 22 Our group previously demonstrated that human regulatory T cells can use the perforin/granzyme pathway to suppress effector T (T eff )-cell proliferation and kill autologous immune cells. ...

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“…transfer. Although little data are available on differences between the techniques, in one study in which human T cells transduced with a luciferase-containing retrovirus were transferred into NOD severe-combined immunodeficient mice, retro-orbital injection resulted in improved engraftment compared with tail vein injection, with decreased cell trapping in the lungs and increased xenogeneic graft-versus-host disease development (30).…”

Section: Eae Induction and Adoptive Immunotherapymentioning

confidence: 99%

Redirecting Therapeutic T Cells against Myelin-Specific T Lymphocytes Using a Humanized Myelin Basic Protein-HLA-DR2-ζ Chimeric Receptor

Moisini

Nguyen

Fugger

et al. 2008

The Journal of Immunology

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Therapies that Ag-specifically target pathologic T lymphocytes responsible for multiple sclerosis (MS) and other autoimmune diseases would be expected to have improved therapeutic indices compared with Ag-nonspecific therapies. We have developed a cellular immunotherapy that uses chimeric receptors to selectively redirect therapeutic T cells against myelin basic protein (MBP)-specific T lymphocytes implicated in MS. We generated two heterodimeric receptors that genetically link the human MBP84–102 epitope to HLA-DR2 and either incorporate or lack a TCRζ signaling domain. The Ag-MHC domain serves as a bait, binding the TCR of MBP-specific target cells. The ζ signaling region stimulates the therapeutic cell after cognate T cell engagement. Both receptors were well expressed on primary T cells or T hybridomas using a tricistronic (α, β, green fluorescent protein) retroviral expression system. MBP-DR2-ζ-, but not MBP-DR2, modified CTL were specifically stimulated by cognate MBP-specific T cells, proliferating, producing cytokine, and killing the MBP-specific target cells. The receptor-modified therapeutic cells were active in vivo as well, eliminating Ag-specific T cells in a humanized mouse model system. Finally, the chimeric receptor-modified CTL ameliorated or blocked experimental allergic encephalomyelitis (EAE) disease mediated by MBP84–102/DR2-specific T lymphocytes. These results provide support for the further development of redirected therapeutic T cells able to counteract pathologic, self-specific T lymphocytes, and specifically validate humanized MBP-DR2-ζ chimeric receptors as a potential therapeutic in MS.

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

Cited by 57 publications

References 61 publications

Noninvasive bioluminescent imaging of primary patient acute lymphoblastic leukemia: a strategy for preclinical modeling

Noninvasive bioluminescent imaging of primary patient acute lymphoblastic leukemia: a strategy for preclinical modeling

Granzyme B is not required for regulatory T cell–mediated suppression of graft-versus-host disease

Redirecting Therapeutic T Cells against Myelin-Specific T Lymphocytes Using a Humanized Myelin Basic Protein-HLA-DR2-ζ Chimeric Receptor

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