A new Hu-PBL model for the study of human islet alloreactivity based on NOD-scid mice bearing a targeted mutation in the IL-2 receptor gamma chain gene

King, Marie; Pearson, Todd; Shultz, Leonard D.; Leif, Jean; Bottino, Rita; Trucco, Massimo; Atkinson, Mark A.; Wasserfall, Clive; Herold, Kevan C.; Woodland, Robert T.; Schmidt, Madelyn R.; Woda, Bruce A.; Thompson, Michael; Rossini, Aldo A.; Greiner, Dale L.

doi:10.1016/j.clim.2007.11.001

Cited by 151 publications

(215 citation statements)

References 42 publications

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“…Streptozotocin-induced type 1 diabetes in NOD-scid Il2rγ null mice In a previous study, we documented that streptozotocin is effective at inducing hyperglycaemia in NOD-scid Il2rγ null mice, but did not determine if sex-specific differences exist in their susceptibility to streptozotocin, nor was an optimal dose determined [24]. Therefore, we delivered several different doses of a single administration of streptozotocin to cohorts of male and female NOD-scid Il2rγ null mice.…”

Section: Resultsmentioning

confidence: 98%

“…Human islets designated for research were obtained from the Juvenile Diabetes Research Foundation (JDRF) Islet Isolation Center at the University of Pittsburgh (Pittsburgh, PA, USA) or the Islet Cell Resource Consortium. Islet equivalents (IEQ) were enumerated and transplanted into recipient mice as described [23,24]. Human IEQs at doses between 1,000 and 4,000, suspended in RPMI were transplanted into the renal subcapsular space of spontaneously diabetic NOD-Rag1 null Prf1 null Ins2 Akita mice or NOD-scid Il2rγ null mice that had been rendered chemically diabetic (blood glucose >25 mmol/l) by a single i.p.…”

Section: Human Islet Transplantationmentioning

confidence: 99%

“…Immunohistochemistry Samples were prepared for immunohistochemical analysis as described [24]. Briefly, tissues were recovered from mice at necropsy, fixed in 10% (vol./vol.)…”

Section: Human Islet Transplantationmentioning

confidence: 99%

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A new immunodeficient hyperglycaemic mouse model based on the Ins2 Akita mutation for analyses of human islet and beta stem and progenitor cell function

et al. 2008

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Aims/hypothesis To develop and validate a new immunodeficient mouse strain that spontaneously develops a nonautoimmune hyperglycaemia to serve as a diabetic host for human islets and human beta stem and progenitor cells without the need for induction of hyperglycaemia by toxic chemicals with their associated side effects. Methods We generated and characterised a new strain of immunodeficient spontaneously hyperglycaemic mice, the NOD-Rag1 null Prf1 null Ins2 Akita strain and compared this strain with the NOD-scid Il2rγ null (also known as Il2rg) immunodeficient strain rendered hyperglycaemic by administration of a single dose of streptozotocin. Hyperglycaemic mice were transplanted with human islets ranging from 1,000 to 4,000 islet equivalents (IEQ) and were monitored for normalisation of blood glucose levels. Results NOD-Rag1 null Prf1 null Ins2 Akita mice developed spontaneous hyperglycaemia, similar to Ins2 Akita -harbouring strains of immunocompetent mice. Histological examination of islets in the host pancreas validated the spontaneous loss of beta cell mass in the absence of mononuclear cell infiltration. Human islets transplanted into spontaneously diabetic NOD-Rag1 null Prf1 null Ins2 Akita and chemically diabetic NOD-scid Il2rγ null mice resulted in a return to euglycaemia that occurred with transplantation of similar beta cell masses. Conclusions/interpretation The NOD-Rag1 null Prf1 null Ins2 Akita mouse is the first immunodeficient, spontaneously hyperglycaemic mouse strain described that is based on the Ins2 Akita mutation. This strain is suitable as hosts for human islet and human beta stem and progenitor cell transplantation in the absence of the need for pharmacological induction of diabetes. This strain of mice also has low levels of innate immunity and can be engrafted with a human immune system for the study of human islet allograft rejection.

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Section: Resultsmentioning

confidence: 98%

Section: Human Islet Transplantationmentioning

confidence: 99%

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A new immunodeficient hyperglycaemic mouse model based on the Ins2 Akita mutation for analyses of human islet and beta stem and progenitor cell function

et al. 2008

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“…Thus, the model of humanized mice should be considered for experimental studies in which the extent of T-cell repertoire diversity is of major importance. These would include vaccination [18], infectious [19,20], transplantation [21] or cancer studies [22]. Given the recent progress in the development of new strains of immunodeficient mice in which human T-cell reconstitution and functionality are improved [23], it is expected that high conservation of the repertoire, as reported herein in 'first generation' humanized mice, will also apply to subsequent models.…”

Section: Discussionmentioning

confidence: 96%

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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“…This recently developed strain is reportedly deficient in inherent NK-cell activity, as well as being devoid of T and B lymphocytes. 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).…”

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

confidence: 99%

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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A new Hu-PBL model for the study of human islet alloreactivity based on NOD-scid mice bearing a targeted mutation in the IL-2 receptor gamma chain gene

Cited by 151 publications

References 42 publications

A new immunodeficient hyperglycaemic mouse model based on the Ins2 Akita mutation for analyses of human islet and beta stem and progenitor cell function

A new immunodeficient hyperglycaemic mouse model based on the Ins2 Akita mutation for analyses of human islet and beta stem and progenitor cell function

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

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

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