Human T cells depend on functional calcineurin, tumour necrosis factor-α and CD80/CD86 for expansion and activation in mice

Søndergaard, Henrik; Kvist, Peter Helding; Haase, Claus

doi:10.1111/cei.12051

Cited by 23 publications

(48 citation statements)

References 47 publications

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“…On the other hand, transplantation of Th17-polarized cells alone (not combined with PBMCs) revealed that Th17 cells did not generate lethal xGVHD by themselves, nor did Th0 and Th1 cells. This finding is in accordance with previous reports in NSG mice showing that purified CD4 + T cells only mediated delayed and mild xGVHD [23,30,33,35,51]. Thus, although Th17 cells were not sufficient to individually induce lethal xGVHD, our experiments using Th17 cotransfer with PBMCs demonstrated that these cells nevertheless could exacerbate the disease.…”

Section: Discussionsupporting

confidence: 93%

“…Over the past several decades, humanized murine models of xenogeneic GVHD (xGVHD) have been developed via the injection of human peripheral blood mononuclear cells (PBMCs) into severely immunodeficient NOD/Shi-scid IL2rg-null (NOG) or NOD/LtSz-scid IL2rg-null (NSG) mice [23][24][25][26][27][28][29][30][31][32]. These models are T cell dependent, and main triggers of T cell activation and expansion are xenogeneic MHC (H-2) class I and class II molecules [23,30,33,34] and xenogeneic costimulatory signals [27,35]. Previous studies have demonstrated a crucial interplay between CD4 + and CD8 + T cells during xGVHD [23,35]; however, the concrete role of individual T cell subsets has not yet been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

“…These models are T cell dependent, and main triggers of T cell activation and expansion are xenogeneic MHC (H-2) class I and class II molecules [23,30,33,34] and xenogeneic costimulatory signals [27,35]. Previous studies have demonstrated a crucial interplay between CD4 + and CD8 + T cells during xGVHD [23,35]; however, the concrete role of individual T cell subsets has not yet been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

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In Vitro Th17-Polarized Human CD4+ T Cells Exacerbate Xenogeneic Graft-versus-Host Disease

Delens

Ehx

Somja

et al. 2019

Biology of Blood and Marrow Transplantation

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A B S T R A C T Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. The role of Th17 cells in its pathophysiology remains a matter of debate. In this study, we assessed whether enrichment of human peripheral blood mononuclear cells (PBMCs) with in vitro Th17-polarized CD4 + T cells would exacerbate xenogeneic GVHD (xGVHD) into NOD-scid IL-2Rg null (NSG) mice. Naive human CD4 + T cells were stimulated under Th17-skewing conditions for 8 to 10 days and then coinjected in NSG mice with fresh PBMCs from the same donor. We observed that Th17-polarized cells engrafted and migrated toward xGVHD target organs. They also acquired a double-expressing IL-17A + IFNg + profile in vivo. Importantly, cotransfer of Th17polarized cells (1 £ 10 6 ) with PBMCs (1 £ 10 6 ) exacerbated xGVHD compared with transplantation of PBMCs alone (2 £ 10 6 ). Furthermore, PBMC cotransfer with Th17-polarized cells was more potent for xGVHD induction than cotransfer with naive CD4 + T cells stimulated in nonpolarizing conditions (Th0 cells, 1 £ 10 6 + 1 £ 10 6 PBMCs) or with Th1-polarized cells (1 £ 10 6 + 1 £ 10 6 PBMCs). In summary, our results suggest that human Th17-polarized cells can cooperate with PBMCs and be pathogenic in the NSG xGVHD model.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

In Vitro Th17-Polarized Human CD4+ T Cells Exacerbate Xenogeneic Graft-versus-Host Disease

Delens

Ehx

Somja

et al. 2019

Biology of Blood and Marrow Transplantation

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“…A prior report shows that CD4 + T cells in humanized mice can exhibit regulatory capacity 51 and raises the possibility that stimulation of Treg by MSC therapy could alter bone marrow destruction after injury. We www.nature.com/scientificreports/ therefore examined T lymphocyte frequencies in various organs.…”

Section: Resultsmentioning

confidence: 99%

Injury intensifies T cell mediated graft-versus-host disease in a humanized model of traumatic brain injury

Díaz

Horton

Kumar

et al. 2020

Sci Rep

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The immune system plays critical roles in promoting tissue repair during recovery from neurotrauma but is also responsible for unchecked inflammation that causes neuronal cell death, systemic stress, and lethal immunodepression. Understanding the immune response to neurotrauma is an urgent priority, yet current models of traumatic brain injury (TBI) inadequately recapitulate the human immune response. Here, we report the first description of a humanized model of TBI and show that TBI places significant stress on the bone marrow. Hematopoietic cells of the marrow are regionally decimated, with evidence pointing to exacerbation of underlying graft-versus-host disease (GVHD) linked to presence of human T cells in the marrow. Despite complexities of the humanized mouse, marrow aplasia caused by TBI could be alleviated by cell therapy with human bone marrow mesenchymal stromal cells (MSCs). We conclude that MSCs could be used to ameliorate syndromes triggered by hypercytokinemia in settings of secondary inflammatory stimulus that upset marrow homeostasis such as TBI. More broadly, this study highlights the importance of understanding how underlying immune disorders including immunodepression, autoimmunity, and GVHD might be intensified by injury. Traumatic brain injury (TBI) is a major contributor to long-term disability and mortality in children and adults, and, despite intensive efforts, there are no effective treatments for TBI 1,2. Sequelae of TBI and soft tissue injuries resulting from polytrauma include changes in cerebral metabolism, excitotoxicity, induction of emergency hematopoiesis, infiltration of fluid and inflammatory cells into the brain, systemic cytokine storm and localized cytokine release, and activation of microglia, the resident macrophage of the central nervous system 3-8. The immune system plays critical roles in promoting tissue repair and clearance of dying neurons during recovery from neurotrauma but is also responsible for the deleterious inflammation that kills healthy neurons. Systemic immunodepression and vulnerability to infection often follow the acute phase of TBI wherein hypercytokinemia and inflammation resolve, placing patients at increased risk of pneumonia and sepsis 9. Thus, understanding the contribution of the immune system to recovery is critical to development of efficacious therapies for neurotrauma 10,11 .

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“…The NSG, NRG, and NOG lines all natively express murine major histocompatibility complex (MHC), and in the presence of human T-cells restricted by human leukocyte antigen (HLA), such as in the PBMC and BLT models, a xeno-MHC mismatch occurs that drives GvHD development (50). CD8 + T-cells mediate GvHD in PBMC humanized mice, while CD4 + T-cells alone are not sufficient to cause this disease (51). The HSC model relies on human T-cell selection and development in the murine thymus, resulting in T-cells likely restricted by murine MHC (50,52,53).…”

Section: Development Of Humanized Mouse Models That Mitigate Gvhdmentioning

confidence: 99%

The Development of Next-generation PBMC Humanized Mice for Preclinical Investigation of Cancer Immunotherapeutic Agents

et al. 2020

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Investigation of the efficacy and mechanisms of human immuno-oncology agents has been hampered due to species-specific differences when utilizing preclinical mouse models. Peripheral blood mononuclear cell (PBMC) humanized mice provide a platform for investigating the modulation of the human immune-mediated antitumor response while circumventing the limitations of syngeneic model systems. Use of humanized mice has been stymied by model-specific limitations, some of which include the development of graft versus host disease, technical difficulty and cost associated with each humanized animal, and insufficient engraftment of some human immune subsets. Recent advances have addressed many of these limitations from which have emerged humanized models that are more clinically relevant. This review characterizes the expanded usage, advantages and limitations of humanized mice and provides insights into the development of the next generation of murine humanized models to further inform clinical applications of cancer immunotherapeutic agents.

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Human T cells depend on functional calcineurin, tumour necrosis factor-α and CD80/CD86 for expansion and activation in mice

Cited by 23 publications

References 47 publications

In Vitro Th17-Polarized Human CD4+ T Cells Exacerbate Xenogeneic Graft-versus-Host Disease

In Vitro Th17-Polarized Human CD4+ T Cells Exacerbate Xenogeneic Graft-versus-Host Disease

Injury intensifies T cell mediated graft-versus-host disease in a humanized model of traumatic brain injury

The Development of Next-generation PBMC Humanized Mice for Preclinical Investigation of Cancer Immunotherapeutic Agents

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