scholarly journals Adoptive transfer of allogeneic gamma delta T cells promotes HIV replication in a humanized mouse model

2021 ◽  
Author(s):  
Shivkumar Biradar ◽  
Yash Agarwal ◽  
Michael T. Lotze ◽  
Charles R. Rinaldo ◽  
Moses T. Bility ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Hiv Infection ◽  
Adoptive Transfer ◽  
T Cell Subsets ◽  
Gamma Delta ◽  
Humanized Mouse ◽  
Hiv Replication ◽  
Humanized Mouse Model

AbstractGamma-delta (γδ) T cells recognize antigens in an MHC-independent manner, with demonstrable cytotoxicity against cancer and virally infected cells. Human immunodeficiency virus (HIV) infection severely depletes the Vγ9Vδ2 (Vδ2) subset of these T cells in most infected individuals, with the exception of elite controllers. The capacity of Vδ2 cells to kill HIV-infected targets has been demonstrated in vitro, but this has not been verified in vivo. Here, we examined the immunotherapeutic potential of Vδ2 cells in controlling HIV replication in vivo and provide the first characterization of reconstituted γδ T cell subsets in the peripheral blood and lymphoid tissue in a humanized mouse model. We demonstrate the depletion of Vδ2 cells and increase in Vδ1 cells in the blood following HIV infection, similar to that observed in HIV-infected humans. The functionality of human Vδ2 cells isolated from humanized mice was confirmed via ex vivo expansion in response to zoledronate and IL-2 treatment. The adoptive transfer of activated Vδ2 cells failed to control HIV infection in vivo but instead exacerbated viremia by serving as early targets for HIV infection. Our findings suggest that Vδ2 cells play a critical and unappreciated role as early HIV targets of infection to promote viral dissemination.

scholarly journals A novel humanized mouse model to study the function of human cutaneous memory T cells in vivo in human skin

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Maria M. Klicznik ◽  
Ariane Benedetti ◽  
Laura M. Gail ◽  
Suraj R. Varkhande ◽  
Raimund Holly ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Human Skin ◽  
Memory T Cells ◽  
Humanized Mouse ◽  
Humanized Mouse Model

scholarly journals Successful Regulatory T Cell-Based Therapy Relies on Inhibition of T Cell Effector Function and Enrichment of FOXP3+ Cells in a Humanized Mouse Model of Skin Inflammation

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
S. Landman ◽  
V. L. de Oliveira ◽  
M. Peppelman ◽  
E. Fasse ◽  
E. van Rijssen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mouse Model ◽  
Human Skin ◽  
Skin Inflammation ◽  
Effector T Cells ◽  
Effector Function ◽  
Humanized Mouse ◽  
Humanized Mouse Model

Background. Recent clinical trials using regulatory T cells (Treg) support the therapeutic potential of Treg-based therapy in transplantation and autoinflammatory diseases. Despite these clinical successes, the effect of Treg on inflamed tissues, as well as their impact on immune effector function in vivo, is poorly understood. Therefore, we here evaluated the effect of human Treg injection on cutaneous inflammatory processes in vivo using a humanized mouse model of human skin inflammation (huPBL-SCID-huSkin). Methods. SCID beige mice were transplanted with human skin followed by intraperitoneal (IP) injection of 20‐40×106 allogeneic human PBMCs. This typically results in human skin inflammation as indicated by epidermal thickening (hyperkeratosis) and changes in dermal inflammatory markers such as the antimicrobial peptide hBD2 and epidermal barrier cytokeratins K10 and K16, as well as T cell infiltration in the dermis. Ex vivo-expanded human Treg were infused intraperitoneally. Human cutaneous inflammation and systemic immune responses were analysed by immunohistochemistry and flow cytometry. Results. We confirmed that human Treg injection inhibits skin inflammation and the influx of effector T cells. As a novel finding, we demonstrate that human Treg injection led to a reduction of IL-17-secreting cells while promoting a relative increase in immunosuppressive FOXP3+ Treg in the human skin, indicating active immune regulation in controlling the local proinflammatory response. Consistent with the local control (skin), systemically (splenocytes), we observed that Treg injection led to lower frequencies of IFNγ and IL-17A-expressing human T cells, while a trend towards enrichment of FOXP3+ Treg was observed. Conclusion. Taken together, we demonstrate that inhibition of skin inflammation by Treg infusion, next to a reduction of infiltrating effector T cells, is mediated by restoring both the local and systemic balance between cytokine-producing effector T cells and immunoregulatory T cells. This work furthers our understanding of Treg-based immunotherapy.

scholarly journals 4308 DEEP-PRIMED IL-15 SUPERAGONIST IMPROVES ANTIVIRAL EFFICACY OF HIV-SPECIFIC CD8+ T-CELLS IN HUMANIZED MOUSE MODEL

2020 ◽  
Vol 4 (s1) ◽  
pp. 4-5
Author(s):  
Chase Daniel McCann ◽  
Elizabeth Zale ◽  
Adam Ward ◽  
Thomas Dilling ◽  
Ali Danesh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mouse Model ◽  
Critical Role ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Viral Loads ◽  
Specific Ctls ◽  
The Impact

OBJECTIVES/GOALS: HIV-specific CD8+ T-cells play a critical role in partially controlling viral replication in infected-individuals, but ultimately fail to eliminate infection. Enhancing these T-cell responses through lymphocyte engineering approaches has the potential as a novel therapy capable of achieving durable control or eradication of infection. METHODS/STUDY POPULATION: IL-15 Superagonist (IL-15SA) potently supports the in vivo persistence and antiviral activity of adoptively transferred CD8+ T-cells. The Deep-PrimingTM technology platform, developed by Torque, allows for loading of immunomodulators onto the surface of T-cells via electrostatic ‘nanogels’, which slowly release to deliver sustained autocrine immune stimulation without the harmful effects of systemic exposure. Here, we investigate the impact of IL-15SA Deep-Priming on HIV-specific CD8+ T-cells in a humanized mouse model of HIV infection. Humanized mice were generated by engrafting NOD-scid-IL2Rgnull mice with memory CD4+ T-cells isolated from an ARV-suppressed HIV+ donor. An autologous HIV-specific Cytotoxic T-Lymphocyte (CTL) clone was isolated, and killing potential confirmed. Four weeks post humanization, mice were infected with HIV and received an infusion of unmodified HIV-Specific CTLs, or IL-15SA Deep-Primed HIV-specific CTLs (CTL-DP). T-cell numbers and plasma viral loads were quantified weekly by flow cytometry and qRT-PCR. RESULTS/ANTICIPATED RESULTS: Mice receiving unmodified CTLs trended toward reduced viral loads compared to the No Treatment condition, while mice receiving CTL-DP saw significant, 2-Log10 reductions in VL (p < 0.01). At 41 days post-infection 100% (5/5) of the No Treatment, 66.7% (4/6) of the CTL treatment, and 16.7% (1/6) of CTL-DP treatment mice had detectable viremia. IL-15SA Deep-Priming increased CTL expansion and persistence in peripheral blood which correlated with improved CD4+T-cell preservation. DISCUSSION/SIGNIFICANCE OF IMPACT: Here we demonstrate the first in vivo analysis of IL-15SA Deep-Priming of HIV-Specific CTLs. These data suggest that Deep-Priming of patient T-cells can enhance in vivo function and persistence, leading to improved viral suppression; a significant advancement in the field of HIV cure research. CONFLICT OF INTEREST DESCRIPTION: Austin Boesch, Thomas Andresen, and Douglas Jones are employees of Torque. Darrell Irvine is a co-founder of Torque and Chairman of Torque’s Scientific Advisory Board.

scholarly journals Humanized mouse model supports development, function, and tissue residency of human natural killer cells

2017 ◽  
Vol 114 (45) ◽  
pp. E9626-E9634 ◽  
Author(s):  
Dietmar Herndler-Brandstetter ◽  
Liang Shan ◽  
Yi Yao ◽  
Carmen Stecher ◽  
Valerie Plajer ◽  
...  
Keyword(s):  
Mouse Model ◽  
Nk Cells ◽  
Natural Killer ◽  
Cancer Biology ◽  
Nk Cell ◽  
T Cell Subsets ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Hematopoietic Stem

Immunodeficient mice reconstituted with a human immune system represent a promising tool for translational research as they may allow modeling and therapy of human diseases in vivo. However, insufficient development and function of human natural killer (NK) cells and T cell subsets limit the applicability of humanized mice for studying cancer biology and therapy. Here, we describe a human interleukin 15 (IL15) and human signal regulatory protein alpha (SIRPA) knock-in mouse on a Rag2−/− Il2rg−/− background (SRG-15). Transplantation of human hematopoietic stem and progenitor cells into SRG-15 mice dramatically improved the development and functional maturation of circulating and tissue-resident human NK and CD8+ T cells and promoted the development of tissue-resident innate lymphoid cell (ILC) subsets. Profiling of human NK cell subsets by mass cytometry revealed a highly similar expression pattern of killer inhibitory receptors and other candidate molecules in NK cell subpopulations between SRG-15 mice and humans. In contrast to nonobese diabetic severe combined immunodeficient Il2rg−/− (NSG) mice, human NK cells in SRG-15 mice did not require preactivation but infiltrated a Burkitt’s lymphoma xenograft and efficiently inhibited tumor growth following treatment with the therapeutic antibody rituximab. Our humanized mouse model may thus be useful for preclinical testing of novel human NK cell-targeted and combinatory cancer immunotherapies and for studying how they elicit human antitumor immune responses in vivo.

Soluble GARP has potent antiinflammatory and immunomodulatory impact on human CD4+ T cells

Blood ◽  
2013 ◽  
Vol 122 (7) ◽  
pp. 1182-1191 ◽  
Author(s):  
Susanne A. Hahn ◽  
Heiko F. Stahl ◽  
Christian Becker ◽  
Anita Correll ◽  
Franz-Joseph Schneider ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Mouse Model ◽  
Cd4 T Cells ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Key Points ◽  
Destructive Inflammation

Key Points GARP efficiently represses proliferation of naïve and resting CD4+ T cells and is involved in the induction of adaptive regulatory T cells. In vivo, GARP prevents T cell–mediated destructive inflammation in a preclinical humanized mouse model of GVHD.

scholarly journals 15 A novel CD28 humanized mouse model for efficacy assessment of CD28-targeting therapies

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A15-A15
Author(s):  
Fabiane Sônego ◽  
Gaelle Martin ◽  
Chloé Beuraud ◽  
Audrey Beringer ◽  
Yacine Cherifi ◽  
...  
Keyword(s):  
T Cells ◽  
Amino Acid ◽  
Mouse Model ◽  
Cytokine Production ◽  
List Type ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Efficacy Assessment ◽  
Human And Mouse ◽  
Stimulation Of

BackgroundImmuno-intervention through targeting of activating and inhibitory immune checkpoints (ICP), has shown promising results in the clinic over the last years. To facilitate these researches, mouse models expressing humanized ICP instead of their mouse counterparts were developed. Herein, we describe a novel CD28 humanized mouse model (hCD28 model), designed to test compounds targeting human CD28 (hCD28).MethodsHuman and mouse CD28 (mCD28) have different signalling responses, with hCD28 being known for inducing higher levels of pro-inflammatory cytokines upon stimulation with ligands/superagonists. This can be explained by the expression of CD28i, a hCD28 amplifier isoform which is not found in mouse. Additionally, evidences suggested that the different signalling between human and mCD28 relies on one amino acid change in the intracellular domain (ICD).1 Because the hCD28 model was developed to assess hCD28-targeting therapeutics, we decided to keep the expression of both canonical and CD28i isoforms to avoid undermining the biological effects of the testing antibodies. Although keeping the human ICD could favour the evaluation of cytokine production and therefore the safety of the test therapeutics, we decided to keep the mouse ICD to enable a proper interaction of CD28 with its signalling partners, allowing a physiological stimulation of CD28 in efficacy studies.Results hCD28 mice express hCD28 on T cells and the frequency of CD3 T cells is comparable in both WT and hCD28 mice. Stimulation of hCD28 mice-isolated T cells with hCD28 ligands and agonist antibodies resulted in T cell proliferation and cytokine production, suggesting that hCD28 is functional in mouse cells. MC38 uptake rate and kinetic of growth were comparable in WT and hCD28 mice, suggesting no major defect in the immune response in the hCD28 mice. Importantly, splenocytes and tumor draining lymph nodes cells isolated from tumor-bearing hCD28 mice showed higher production of IL-2 and IFN-gamma upon in vitro re-challenged with MC38 when compared to WT cells. Since the frequency of CD3 cells (Treg, CD4+ and CD8+) is comparable to WT mice, this could be explained by the expression of the amplifier CD28i isoform, which is absent in WT mice.ConclusionsThe hCD28 model described here supports the efficacy assessment of hCD28-targeting biologics, enabling PK/PD studies as hCD28 expression levels and pattern are physiological. However, after careful consideration of the CD28 biology, we decided to keep the mouse ICD, although it triggers lower pro-inflammatory cytokine production than CD28 human ICD. As such, this model is not suitable for toxicology/safety studies.ReferencePorciello N, Grazioli P, Campese AF, et al. A non-conserved amino acid variant regulates differential signalling between human and mouse CD28. Nat Commun 2018; 9:1–16.

scholarly journals P06.07 In vivo studies of immunomodulatory a-CTLA-4 antibody in a humanized mouse model

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A22.1-A22
Author(s):  
C Reitinger ◽  
F Nimmerjahn
Keyword(s):  
Immune System ◽  
Mouse Model ◽  
Cancer Immunotherapy ◽  
Model Systems ◽  
Checkpoint Control ◽  
Human Immune System ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Human Immune

BackgroundRecent findings in cancer immunotherapy have reinforced the hypothesis that the immune system is able to control most cancers. Immunomodulatory antibodies can enhance immune responses, having the potential to generate anti-cancer immunity.1–4Materials and MethodsMost current studies addressing this question are performed in murine mouse model systems or use in vitro culture systems, which do not reflect the human in vivo situation, potentially leading to results that cannot be fully translated into human cancer therapy. Therefore, it is necessary to establish a new mouse model, which allows the study of cancer immunotherapy in the context of a human immune system. We focused on the establishment of a humanized mouse model, in which different immunomodulatory antibodies can be tested in the presence of a human immune system.ResultsFirst experiments concerning the suitability to test immunomodulatory antibodies in the humanized mouse model, revealed that effects of checkpoint-control antibody a-CTLA-4 were similar to the effects seen in patients of clinical studies. To analyse the anti-tumor activities of immunomodulatory antibodies in vivo we are establishing a human melanoma-like tumor model in humanized mice.ConclusionsThis enables us to test the efficacy of immunomodulatory agonistic antibodies (such as CP-870,893) and checkpoint control antibodies (such as anti-CTLA-4) in eliminating a melanoma-like tumor. Furthermore, parameters like tumor infiltrating human cells und cytokine/chemokine production can be analysed.ReferencesSchuster M, Nechansky A, Loibner H. Cancer immunotherapy. Biotechnol J 2006;1:138–147.Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature rev 2011;480:480–489.Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Annals of Oncology 2012;23:vii6–vii9.Langer LF, Clay TM, Morse MA. Update on anti-CTLA-4 in clinical trials. Expert Opin Biol Ther 2007;8:1245–1256.Disclosure InformationC. Reitinger: None. F. Nimmerjahn: None.

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