Human Lymphoid and Myeloid Cell Development in NOD/LtSz-<i>scid IL2R</i>γ<i>null</i> Mice Engrafted with Mobilized Human Hemopoietic Stem Cells

Shultz, Leonard D.; Lyons, Bonnie L.; Burzenski, Lisa M.; Gott, Bruce; Chen, Xiaohua; Chaleff, Stanley; Kotb, Malak; Gillies, Stephen D.; King, Marie; Mangada, Julie; Greiner, Dale L.; Handgretinger, Rupert

doi:10.4049/jimmunol.174.10.6477

Cited by 1,515 publications

(1,484 citation statements)

References 73 publications

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“…It is reasonable to assume that similar distributions of V-J combinations in humans and humanized mice may translate into similar distributions of CDR3 sequences as well. However, previous work assessing CDR3 repertoire diversity by PCR spectratyping reported poor repertoire diversity in reconstituted NSG mice [4], in apparent disagreement with our hypothesis. A major difference, however, is that the whole spleen was subjected to CDR3 spectratyping in the former study whereas we sorted human CD3 1 cells before analysis for semi-quantitative PCR.…”

Section: Discussioncontrasting

confidence: 99%

“…The extent of the human T-cell repertoire diversity generated in mice may represent an important functional indicator [3], useful for immunological studies in the models. However, although some studies have reported on the TCR repertoire diversity of humanized mice [4,5], a comprehensive analysis of T-cell repertoire combinatorial diversity in humanized mice is lacking. We believe that this analysis is relevant since it may provide new information about the rules governing V-J combinations distribution in humans.…”

Section: Introductionmentioning

confidence: 99%

“…We therefore believe that the poor CDR3 spectratyping complexity score reported in this study reflected a limiting number of targets rather than a poor CDR3 diversity. This idea is further supported by the fact that IL-7 adjunction greatly improved both T-cell reconstitution and repertoire diversity [4]. Using pyrosequencing, Warren et al recently described limited conservation of CDR3 sequences among human individuals (around 1%) [8].…”

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confidence: 99%

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Half of the T‐cell repertoire combinatorial diversity is genetically determined in humans and humanized mice

Pham

Manuel²,

Petit

et al. 2011

Eur J Immunol

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In humanized mice, the T-cell repertoire is derived from genetically identical human progenitors in distinct animals. Thus, careful comparison of the T-cell repertoires of humanized mice with those of humans may reveal the contribution of genetic determinism on T-cell repertoire formation. Here, we performed a comprehensive assessment of the distribution of V-J combinations of the human b chain of the T-cell receptor (hTRBV) in NOD.SCID.cc À/À (NSG) humanized mice. We observed that numerous V-J combinations were equally distributed in the thymus and in the periphery of humanized mice compared with human references. A global analysis of the data, comparing repertoire perturbation indices in humanized NSG mice and unrelated human PBMCs, reveals that 50% of the hTRBV families significantly overlapped. Using multivariate ranking and bootstrap analyses, we found that 18% of all possible V-J combinations contributed close to 50% of the expressed diversity, with significant over-representation of BV5-J1.111.2 and BV6-J1.111.2 rearrangements. Finally, comparison of CD3 À and CD3 1 thymocyte repertoires indicated that the observed V-J combination overlap was already present before TCR-MHC selection in the thymus. Altogether, our results show that half of the T-cell repertoire combinatorial diversity in humans is genetically determined.Key words: Humanized mice . ISEApeaks . Multivariate score . T-cell repertoire . V-J rearrangements Supporting Information available online Introduction T-cell repertoire diversity is based upon tightly ordered genetic rearrangements of the T-cell receptor V, D and J genes. The available numbers of these genes in the genome constitutes a first level of diversity: to date, 33 and 65 genes encoding variable elements of the human T-cell receptor b chain (hTRBV) from 30 hTRBV families have been characterized in mice and humans respectively (according to the ImMunoGeneTics (IMGT) database (http://www.imgt.org)). An additional level of diversity comes from the association of single V, (D) and J elements together. The major determinant of repertoire diversity is then random addition of nucleotides at the junction of these V(D)J gene segments, constituting the CDR3 of the TCR. Finally, a fourth level of complexity originates from the association of the rearranged a and b chains of the TCR. In theory, these sequential processes occurring during T-cell differentiation in the thymus could Eur. J. Immunol. 2012. 42: 760-770 760 generate up to 10 15 different TCRs, a number far in excess of the number of T-cells in the body. The 'real' size of the repertoire is probably much lower though, with recent estimations of unique TCR b chains ranging from 10 6 to 4.10 6 in humans [1,2]. Mice reconstituted with a human immune system generated from hematopoietic precursors represent a new animal model for human immunology studies. The extent of the human T-cell repertoire diversity generated in mice may represent an important functional indicator [3], useful for immunological studies in the models. However, a...

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Half of the T‐cell repertoire combinatorial diversity is genetically determined in humans and humanized mice

Pham

Manuel²,

Petit

et al. 2011

Eur J Immunol

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“…The initial limitations of the SCID and NOD-SCID mice for the implantation and long term survival of human normal and neoplastic tissues have now been overcome by the generation of a new generation of NOD-SCID mouse with a null mutation of the IL-2 common γ chain receptor [130][131][132]. These NOD-SCID IL2Rγ null mice are called NOG mice, and the IL-2R mutation results in a defect of the high affinity receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 that blocks the development of NK cells and further impairs innate immunity [130,133].…”

Section: Mouse/human Xenograft Models To Study In Vivo Dynamic Interamentioning

confidence: 99%

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Barnas

Simpson-Abelson

Yokota

et al. 2010

Cancer Microenvironment

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The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments.

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“…22 Aside from obviating the need for frequent injections of the NK mAb, these animals also support engraftment of other human cell lineages, in addition to T cells. 23 Identical adoptive transfers of PBMNCs (from the same healthy human donor as for the previous studies) into the NOD/SCID IL-2R␥ null resulted in enhanced engraftment and propagation of activated human T cells ( Figure 5, A and B), compared with the original NOD/ SCID animals ( Figure 1B). Donor human B cells (CD19 ϩ ), monocytes (CD14 ϩ ), and some macrophages (CD68 ϩ ) were also evident in the spleens of the NOD/SCID IL-2R␥ null recipients.…”

Section: Studies In Nod/scid Il-2r␥ Null Micementioning

confidence: 79%

A Human-Mouse Chimeric Model of Obliterative Bronchiolitis after Lung Transplantation

Xue

Zhu

George

et al. 2011

The American Journal of Pathology

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Obliterative bronchiolitis is a frequent, morbid, and usually refractory complication of lung transplantation. Mechanistic study of obliterative bronchiolitis would be aided by development of a relevant model that uses human immune effector cells and airway targets. Our objective was to develop a murine chimera model that mimics obliterative bronchiolitis of lung allograft recipients in human airways in vivo. Human peripheral blood mononuclear cells were adoptively transferred to immunodeficient mice lacking activity of T, B, and NK cells, with and without concurrent transplantations of human small airways dissected from allogeneic cadaveric lungs. Chimerism with human T cells occurred in the majority of recipient animals. The chimeric T cells became highly activated, rapidly infiltrated into the small human airway grafts, and caused obliterative bronchiolitis. In contrast, airways implanted into control mice that did not also receive human peripheral blood mononuclear cell transfers remained intact. In vitro proliferation assays indicated that the chimeric T cells had enhanced specific proliferative responses to donor airway alloantigens. This model confirms the critical role of T cells in development of obliterative bronchiolitis among human lung allograft recipients and provides a novel and easily implemented mechanism for detailed, reductionist in vivo studies of human T-cell responses to allogeneic human small airways. Chronic lung allograft rejection typically manifests with obliterative bronchiolitis (OB), a small airway fibroproliferative disease process characterized by varying degrees of airway luminal obliteration with fibrinous granulation tissue. 1 Lung transplant recipients with OB develop expiratory airflow obstruction, which is often inexorably progressive, and have increased predilection for infection. 2 Despite extensive investigation, as well as incremental advances in donor organ preservation, surgical techniques, immunosuppressive regimens, and infection prophylaxis, OB remains the single most frequent cause of late graft dysfunction and death after lung transplantation. 2 Current limitations in prevention and treatment of OB likely reflect incomplete understanding of the responsible immunopathogenic mechanisms. Accordingly, having a model to generate novel insights regarding the disease paradigm, and a ready means to test these hypotheses, could be a boon for the development of more effective modalities to prevent or counter this frequent complication of lung transplantation.Animal models have been immeasurably important in advancing our understanding of many disease processes, including allograft rejection mechanisms. 3 With particular respect to pulmonary transplantation, heterotopic tracheal allografts in mice undergo histological abnormalities that reproduce the progression of OB in humans, including an initial lymphocytic infiltration, followed by successive stages of epithelial metaplasia and denudation and, ultimately, intraluminal fibroproliferation. [3][4][5][6][7] Although this mo...

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Human Lymphoid and Myeloid Cell Development in NOD/LtSz-scid IL2Rγnull Mice Engrafted with Mobilized Human Hemopoietic Stem Cells

Cited by 1,515 publications

References 73 publications

Half of the T‐cell repertoire combinatorial diversity is genetically determined in humans and humanized mice

Half of the T‐cell repertoire combinatorial diversity is genetically determined in humans and humanized mice

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

A Human-Mouse Chimeric Model of Obliterative Bronchiolitis after Lung Transplantation

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