Graft rejection as a Th1-type process amenable to regulation by donor Th2-type cells through an interleukin-4/STAT6 pathway

Mariotti, Jacopo; Foley, Jason; Ryan, Kaitlyn; Buxhoeveden, Nicole; Kapoor, Veena; Amarnath, Shoba; Fowler, Daniel H.

doi:10.1182/blood-2008-05-154278

Cited by 33 publications

(28 citation statements)

References 43 publications

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“…Another fundamental role of JAK-STAT signaling is to dictate immune cells activation and differentiation (13). We have previously shown that STAT signaling is not dispensable for development of T-cell alloreactivity (14) in graft rejection experiments and that STAT3 activation is of fundamental importance for the onset of acute GVHD (15). In addition, other reports have extensively studied the role of different proteins of the STATs family for the onset of GVHD (16,17).…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute GVHD While Preserving GVT Effects

Carniti

Gimondi

Vendramin

et al. 2015

Clinical Cancer Research

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107

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Purpose: Immune-mediated graft-versus-tumor (GVT) effects can occur after allogeneic hematopoietic stem cell transplantation (HSCT), but GVT is tightly linked to its main complication, graft-versus-host disease (GVHD). Strategies aimed at modulating GVHD, while maintaining the GVT effect, are needed to improve the cure rate of transplant. Given the emerging role of Janus-activated kinase (JAK) signaling in lymphoproliferative and myeloproliferative diseases and its established function at dictating T-cell differentiation, we postulated that JAKs might be potential therapeutic targets through a pharmacologic approach.Experimental Design: We examined the effect of JAK1/JAK2 modulation by ruxolitinib in a mouse model of fully MHC mismatched bone marrow transplant comprising in vivo tumor inoculation.Results: JAK1/JAK2 inhibition by ruxolitinib improved both overall survival (P ¼ 0.03) and acute GVHD pathologic score at target organs (P 0.001) of treated mice. In addition, treatment with ruxolitinib was associated with a preserved GVT effect, as evidenced by reduction of tumor burden (P ¼ 0.001) and increase of survival time (P ¼ 0.01). JAK1/JAK2 inhibition did not impair the in vivo acquisition of donor T-cell alloreactivity; this observation may account, at least in part, to the preserved GVT effect. Rather, JAK1/JAK2 inhibition of GVHDwas associated withthe modulation of chemokine receptor expression, which may have been one factor in the reduced infiltration of donor T cells in GVHD target organs.Conclusions: These data provide further evidence that JAK inhibition represents a new and potentially clinically relevant approach to GVHD prevention.

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Section: Introductionmentioning

confidence: 99%

Pharmacologic Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute GVHD While Preserving GVT Effects

Carniti

Gimondi

Vendramin

et al. 2015

Clinical Cancer Research

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107

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“…17 Furthermore, delayed administration of rapamycin-resistant Th2 cells after an initial donor Th1-type response optimized the balance of GVT effects and GVHD, 16 thereby indicating that a mixed pattern of Th2 and Th1 immune reconstitution was desirable in the setting of cancer therapy. And finally, rapamycinresistant Th2 cells prevented graft rejection through host T-cell conversion to a Th2-type profile, 19 thus illustrating that this novel donor T-cell population may have particular application in transplant settings associated with increased graft rejection, such as the use of low-intensity host conditioning.…”

mentioning

confidence: 97%

“…In our studies, we found that ex vivo rapamycin increased the capacity of interleukin (IL) 4 polarized donor Th2 cells to promote a balanced pattern of Th2/Th1 immune reconstitution for promotion of GVT effects and alloengraftment with reduced GVHD. [16][17][18][19] Ex vivo rapamycin creates a state of T-cell starvation that induces autophagy, 20 thereby resulting in an antiapoptotic T-cell phenotype that dictates persistent T-cell engraftment in mouse-into-mouse 18 or human-into-mouse 21 transplantation models. Rapamycin-resistant Th2 cells inhibited GVHD by multiple mechanisms, including IL-4 and IL-10 secretion, consumption of IL-2 required for propagation of pathogenic effector T cells, and modulation of host antigen-presenting cell.…”

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confidence: 99%

Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation

Fowler

Mossoba

Steinberg

et al. 2013

Blood

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• Donor T-Rapa cells were composed of Th1 and Th2 effectors with a reproducible gene expression profile.• Preemptive T-Rapa donor lymphocyte infusion was safe and associated with donor engraftment without excessive GVHD.In experimental models, ex vivo induced T-cell rapamycin resistance occurred independent of T helper 1 (Th1)/T helper 2 (Th2) differentiation and yielded allogeneic CD4 1T cells of increased in vivo efficacy that facilitated engraftment and permitted graftversus-tumor effects while minimizing graft-versus-host disease (GVHD). To translate these findings, we performed a phase 2 multicenter clinical trial of rapamycin-resistant donor CD4 1 Th2/Th1 (T-Rapa) cells after allogeneic-matched sibling donor hematopoietic cell transplantation (HCT) for therapy of refractory hematologic malignancy. T-Rapa cell products, which expressed a balanced Th2/Th1 phenotype, were administered as a preemptive donor lymphocyte infusion at day 14 post-HCT. After T-Rapa cell infusion, mixed donor/host chimerism rapidly converted, and there was preferential immune reconstitution with donor CD4 1 Th2 and Th1 cells relative to regulatory T cells and CD8 1 T cells. The cumulative incidence probability of acute GVHD was 20% and 40% at days 100 and 180 post-HCT, respectively. There was no transplant-related mortality. Eighteen of 40 patients (45%) remain in sustained complete remission (range of follow-up: 42-84 months). These results demonstrate the safety of this low-intensity transplant approach and the feasibility of subsequent randomized studies to compare T-Rapa cell-based therapy with standard transplantation regimens. This trial was registered at www.cancer.gov/clinicaltrials as #NCT 00077480. (Blood. 2013;121(15):2864-2874

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“…The increasingly expressed genes include FYVE domain NF-κB activation (39). Stat1 (10:1, p = 0.003) deficient T cells cannot differentiate into Th1-type cells in vivo containing 1 (Ankfy1), basic helix-loop-helix domain containing, class B, 2 (Bhlhb2), Glrx2, interferon regulaand fail to mediate rejection (41). Constitutive overexpression of Stat1 leads to the suppression of the cytotory factor 2 (Irf2), mediator of RNA polymerase II transcription, subunit 8 homolog (yeast) (Med8), mediator toxic response and renders the cells resistant to ionizing radiation (IR) and other inducers of cell death (30).…”

Section: Cd25mentioning

confidence: 99%

Alternatively Expressed Genes Identified in the CD4⁺ T Cells of Allograft Rejection Mice

Wang

Zhang

et al. 2011

Cell Transplant

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Allograft rejection is a leading cause for the failure of allotransplantation. CD4+ T cells play critical roles in this process. The identification of genes that alternatively expressed in CD4 + T cells during allograft rejection will provide critical information for studying the mechanism of allograft rejection, finding specific gene markers for monitoring, predicting allograft rejection, and opening new ways to regulate and prevent allograft rejection. Here, we established allograft and isograft transplantation models by adoptively transferring wild-type BALB/c mouse CD4+ T cells into severe combined immunodeficient (SCID) mice with a C57BL/ 6 or BALB/c mouse skin graft. Using the whole transcriptome sequencing-based serial analysis of gene expression (SAGE) technology, we identified 97 increasingly and 88 decreasingly expressed genes that may play important roles in allograft rejection and tolerance. Functional classification of these genes shows that apoptosis, transcription regulation, cell growth and maintenance, and signal transduction are among the frequently changed functional groups. This study provides a genome-wide view for the candidate genes of CD4 + T cells related to allotransplantation, and this report is a good resource for further microarray studies and for identifying the specific markers that are associated with clinical organ transplantations.

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Graft rejection as a Th1-type process amenable to regulation by donor Th2-type cells through an interleukin-4/STAT6 pathway

Abstract: Graft rejection has been defined as the mirror image of graft-versus-host disease, which is biologically characterized primarily as a Th1-type process.

Cited by 33 publications

References 43 publications

Pharmacologic Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute GVHD While Preserving GVT Effects

Pharmacologic Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute GVHD While Preserving GVT Effects

Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation

Alternatively Expressed Genes Identified in the CD4⁺ T Cells of Allograft Rejection Mice

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Graft rejection as a Th1-type process amenable to regulation by donor Th2-type cells through an interleukin-4/STAT6 pathway

Abstract: Graft rejection has been defined as the mirror image of graft-versus-host disease, which is biologically characterized primarily as a Th1-type process.

Cited by 33 publications

References 43 publications

Pharmacologic Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute GVHD While Preserving GVT Effects

Pharmacologic Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute GVHD While Preserving GVT Effects

Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation

Alternatively Expressed Genes Identified in the CD4+ T Cells of Allograft Rejection Mice

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Alternatively Expressed Genes Identified in the CD4⁺ T Cells of Allograft Rejection Mice