scholarly journals Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2476-2484 ◽  
Author(s):  
Hong Zheng ◽  
Catherine Matte-Martone ◽  
Hongmei Li ◽  
Britt E. Anderson ◽  
Srividhya Venketesan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Myelogenous Leukemia ◽  
Effector Memory ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Donor T Cells

Much of the efficacy of allogeneic hematopoietic stem cell transplantation (alloSCT) in curing hematologic malignancies is due to a graft-versus-leukemia (GVL) effect mediated by donor T cells that recognize recipient alloantigens on leukemic cells. Donor T cells are also important for reconstituting immunity in the recipient. Unfortunately, donor T cells can attack nonmalignant host tissues and cause graft-versus-host disease (GVHD). We previously reported that donor CD4+ effector memory T cells (TEMs) do not cause GVHD but transfer functional T-cell memory. In the present work, we demonstrate in an MHC-mismatched model that CD4+ TEMs (unprimed to recipient antigens) mediate GVL against clinically relevant mouse models of chronic phase and blast crisis chronic myelogenous leukemia, without causing GVHD. By creating gene-deficient leukemias and using perforin-deficient T cells, we demonstrate that direct cytolytic function is essential for TEM-mediated GVL, but that GVL is retained when killing via FasL, TNF-α, TRAIL, and perforin is individually impaired. However, TEM-mediated GVL was diminished when both FasL and perforin pathways were blocked. Taken together, our studies identify TEMs as a clinically applicable cell therapy for promoting GVL and immune reconstitution, particularly in MHC-mismatched haploidentical alloSCTs in which T cell–depleted allografts are commonly used to minimize GVHD.

Nanoparticle-Encapsulated Allogeneic T Cells Mitigate Graft-Versus-Host Disease but Retain Graft-Versus-Leukemia Activity

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3820-3820
Author(s):  
Lingling Zhang ◽  
Shuting Zhao ◽  
Steven M. Devine ◽  
Xiaoming He ◽  
Jianhua Yu
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Conflicts Of Interest ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Electrostatic Deposition ◽  
Graft Versus Leukemia ◽  
Donor T Cells

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) has curative potential for hematological malignancies, but is often associated with life-threatening complications including graft-versus-host disease (GVHD). The graft-versus-leukemia (GVL) activity which accompanies HSCT is responsible for eradication of tumor cells and prevention of relapse. GVHD and GVL are usually associated with each other and the separation of the two activities occurs in limited circumstances. In this study, we aimed to mitigate GVHD but retain GVL through transplantation of allogeneic T cells encapsulated with bio-degradable nanoparticle materials. For the above purpose, donor T cells were encapsulated with chitosan and alginate through layer-by-layer coating using electrostatic deposition. Encapsulated donor T cells were characterized in vitro, and their ability to inhibit GVHD and retain GVL was determined in vivo after being transplanted together with non-encapsulated donor bone marrow (BM) cells in a C57BL/6 → BALB/c HSCT mouse model. We found 85.7% of donor T cells were successfully encapsulated by the above method (Fig 1A). In vitro studies showed that the encapsulation did not change the phenotype of T cells as defined through the following parameters: size, viability, proliferation, antibody binding, cytokine secretion, and cytotoxicity of T cells (Fig. 1B and data not shown). Mice transplanted with encapsulated allogeneic T cells exhibited less severe acute GVHD and prolonged survival (Fig. 1 C-E). The mice showed a lower GVHD score, less liver damage, a smaller CD8/CD4 T cell ratio, and a higher number of donor BM-derived cells following transplantation with encapsulated donor T cells (Fig. 1 C-E and data not shown). When this GVHD model was combined with implantation of A20 lymphoma cells, GVL of encapsulated T cells was not compromised, while GVHD was still suppressed and the mouse survival also prolonged (Figure 2). In summary, nanoencapsulation of T cells with bio-degradable materials attenuated the severity of GVHD but retained GVL, presenting a novel and potentially safer and effective approach of allogeneic HSCT for future clinical application. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Graft Versus Leukemia With Little Graft Versus Host Disease? Long Term Follow-Up Of a Study Using Transduced Donor T-Cells For Donor Leukocyte Transfusion

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4207-4207
Author(s):  
Eva M Weissinger ◽  
Sylvia Borchers ◽  
Justyna Ogonek ◽  
Kriti Verma ◽  
Steve Ehrlich ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Conflicts Of Interest ◽  
Myelogenous Leukemia ◽  
Period Range ◽  
Host Disease ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Donor T Cells

Abstract Fourteen patients with myeloid leukemia (12 with acute and 2 with chronic myelogenous leukemia) were transplanted from their HLA-identical (n = 9) or haploidentical (n = 5) family donors with CD34-enriched stem cells (HSCT) without further immunosuppression. In order to induce a graft versus leukemia (GvL) effect and to investigate the possibility of controlling graft-versus-host disease (GvHD), the standard transplantation protocol was adapted to include transfusion of gene-modified donor T-cells after HSCT in 11 patients, 3 did not receive any T-cells. Donor-T-cells were transduced with the replication-deficient retrovirus SFCMM-3 which expresses the herpes simplex thymidine kinase (HSV-Tk) as a suicide gene and the truncated low affinity nerve growth factor receptor (ΔLNGFR) for selection purposes. After transfusion, SFCMM-3 transduced T-cells were detectable in all 11 patients by PCR and FACS analyses immediately after transfusion and during the follow up period (range: 1.1-11 years). Two of 9 patients developed acute GvHD: one of the skin, grade 1, 56 days after transfusion of the transduced cells, the other grade II which was successfully treated with ganciclovir. Loss of bcr-abl gene expression was achieved in one patient after expansion of transduced cells. Donor chimerism was stabilized after transfusion of transduced cells in all patients treated. In one patient a cytomegalovirus-reactivation was treated by the transfusion of gene-modified donor T-cells also indicating effectiveness of treatment. To date, 5 patients have relapsed, and died, one after a second HSCT. Two of the patients without transduced T-cells died due to relapse and 7 patients are alive and well and in complete clinical remission. Thus we have shown that transfusion of transduced T-cells is effective and safe in a long follow-up of 11 years post transfusion. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Blockade of osteopontin reduces alloreactive CD8+ T cell–mediated graft-versus-host disease

Blood ◽  
2011 ◽  
Vol 117 (5) ◽  
pp. 1723-1733 ◽  
Author(s):  
Fang Zhao ◽  
Yi Zhang ◽  
Hao Wang ◽  
Min Jin ◽  
Shan He ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells

Abstract Graft-versus-host disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem cell transplantation, is caused by alloreactive donor T cells that trigger host tissue damage. The inflammatory environment inside recipients is critical for GVHD pathogenesis, but the underpinning mechanisms remain elusive. Using mouse model of human GVHD, we demonstrate osteopontin (OPN), a potent proinflammatory cytokine, plays an important role in regulating activation, migration, and survival of alloreactive T cells during GVHD. OPN was significantly elevated after irradiation and persisted throughout the course of GVHD. Blockade of OPN attenuated GVHD with reduced accumulation of donor T cells in recipient organs. Amelioration was the result of migration and survival suppression caused by anti-OPN treatment on donor-derived T cells for 2 reasons. First, OPN promoted the migration and infiltration of naive and alloreactive CD8+ T cells into host organs. Second, it also facilitated activation and viability of donor-derived CD8+ T cells via synergizing with T-cell receptor/CD3 signaling. Finally, anti-OPN treatment retained graft-versus-leukemia effect of alloreactive CD8+ T cells. This study demonstrates, to our knowledge for the first time, the critical effect of OPN in the initiation and persistence of CD8+ T cell-mediated GVHD and validates OPN as a potential target in GVHD prevention.

scholarly journals Absence of β7 integrin results in less graft-versus-host disease because of decreased homing of alloreactive T cells to intestine

Blood ◽  
2006 ◽  
Vol 107 (4) ◽  
pp. 1703-1711 ◽  
Author(s):  
Elisha Waldman ◽  
Sydney X. Lu ◽  
Vanessa M. Hubbard ◽  
Adam A. Kochman ◽  
Jeffrey M. Eng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Morbidity And Mortality ◽  
Cell Infiltration ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
T Cell Infiltration ◽  
Donor T Cells

The α4β7 integrin plays a central role in the homing of T cells to the gut. We hypothesized that absence of the β7 subunit would result in a reduction of intestinal graft-versus-host disease (GVHD) and an improvement in overall GVHD morbidity and mortality in recipients of hematopoietic stem cell transplantation (HSCT). Analysis of alloreactive β7-/- T cells showed intact activation, proliferation, cytokine production, and cytotoxicity. However, recipients of β7-/- donor T cells in murine HSCT models experienced less GVHD morbidity and mortality than recipients of wild-type (WT) T cells, associated with a decrease in donor T-cell infiltration of the liver and intestine and with an overall significant decrease in hepatic and intestinal GVHD. In graft-versus-tumor (GVT) experiments, we demonstrated intact or even enhanced GVT activity of β7-/- donor T cells. In conclusion, β7-/- donor T cells caused less GVHD morbidity and mortality than WT donor T cells because of selectively decreased T-cell infiltration of the liver and intestines. Our data suggest that strategies to target the β7 integrin have the clinical potential to alleviate or prevent GVHD while sparing or potentiating GVT activity.

scholarly journals Tolerogenic anti-IL-2 mAb prevents graft-versus-host disease while preserving strong graft-versus-leukemia activity

Blood ◽  
2021 ◽  
Author(s):  
Qingxiao Song ◽  
Xiaoning Wang ◽  
Xiwei Wu ◽  
Hanjun Qin ◽  
Yingfei Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Lymphoid Tissues ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gm Csf ◽  
Graft Versus Leukemia ◽  
Donor T Cells

Donor T cells mediate both graft-versus-leukemia (GVL) activity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (Allo-HCT). Development of methods that preserve GVL activity while preventing GVHD remains a long-sought goal. Tolerogenic anti-IL-2 monoclonal antibody (mAb) (JES6-1) forms anti-IL-2/IL-2 complexes that block IL-2 binding to IL-2Rb and IL-2Rg on Tcon cells that have low expression of IL-2Rα. Here we show that administration of JES6 early after Allo-HCT in mice markedly attenuates acute GVHD while preserving GVL activity that is dramatically stronger than observed with tacrolimus (TAC) treatment. The anti-IL-2 treatment down-regulated activation of IL-2-Stat5 pathway and reduced production of GM-CSF. In GVHD target tissues, enhanced T cell PD-1 interaction with tissue-PD-L1 led to reduced activation of AKT-mTOR pathway and increased expression of Eomes and Blimp-1, increased T cell anergy/exhaustion, expansion of Foxp3-IL-10-producing Tr1 cells, and depletion of GM-CSF-producing Th1/Tc1 cells. In recipient lymphoid tissues, lack of donor T cell PD-1 interaction with tissue-PD-L1 preserved donor PD-1+TCF-1+Ly108+CD8+ T memory progenitors (Tmp) and functional effectors that have strong GVL activity. Anti-IL-2 and TAC treatments have qualitatively distinct effects on donor T cells in the lymphoid tissues, and CD8+ Tmp cells are enriched with the anti-IL-2 treatment compared to TAC treatment. We conclude that administration of tolerogenic anti-IL-2 mAb early after Allo-HCT represents a novel approach for preventing acute GVHD while preserving GVL activity.

Separation of Graft-Versus-Host Disease and Graft-Versus-Leukemia Effects by Targeting T-Bet and RORγt Transcription Factors

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 728-728 ◽  
Author(s):  
Yu Yu ◽  
Dapeng Wang ◽  
Kenrick Semple ◽  
Claudio Anasetti ◽  
Xue-Zhong Yu
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Hematological Malignancies ◽  
Acute Gvhd ◽  
Host Disease ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Donor T Cells

Abstract Abstract 728 Background: Allogeneic hemopoietic stem cell transplantation (HCT) is an effective therapy with potential cure of hematological malignancies through T cell-mediated graft-versus-leukemia (GVL) effects. However, beneficial GVL effects are frequently offset by the development of destructive graft-versus-host disease (GVHD) also induced by donor T cells. Recent studies including ours have demonstrated that donor T cells differentiated into type 1 or type 17-subset contribute to GVHD. Thus, we hypothesize that blocking both Th1 and Th17 lineage via disrupting Th1-specific (T-bet) and Th17-specific (RORγt) transcription factors can significantly reduce GVHD after allo-HCT. Method: Two murine models of bone marrow transplantation (BMT) that represent clinical GVHD and GVL were used: C57BL/6 (B6)→BALB/c and B6→(B6 × DBA2)F1. To mimic clinical residual hematological malignant disease, B cell lymphoma (A20) and mastocytoma (p815) were infused into BALB/c and (B6 × DBA2)F1 mice, respectively. Results: We first compared the ability of WT, T-bet−/−, RORγt−/−, and T-bet−/−/RORγt−/− T cells in the induction of GVHD, and found that RORγt−/− T cells had a comparable ability to cause GVHD as WT T cells, whereas T-bet−/− T cells were less pathogenic. The T-bet−/−/RORγt−/− T cells failed to induce acute GVHD but caused minor to modest chronic GVHD in some of recipients at the doses tested. To investigate whether recipients of T-bet−/−/RORγt−/− T cells had less severe target organ GVHD damage, we analyzed GVHD associated organ damage in liver, lung and bowel. Fourteen days after adoptive transfer of WT, T-bet−/−, RORγt−/−, and T-bet−/−/RORγt−/− T cells, recipients which received T-bet−/−/RORγt−/− donor T cells showed markedly reduced T cell infiltration and tissue damage in liver, lung, and bowel. Mechanistic studies revealed that T-bet−/−/RORγt−/− T cells produced significantly less IFNγ (Th1 cytokine) and IL-17 (Th17-cytokine) but significantly more IL-4 and IL-5 (Th2-cytokines) as compared to WT T cells. In addition, T-bet−/−/RORγt −/− donor T-cells express significantly less CXCR3 and CCR6, chemokine receptors required for infiltration of alloreactive T cells into GVHD targeted organ, which could be the reason that significantly fewer T-bet−/−/RORγt−/− T cells were accumulated in recipient liver and lung than WT T cells. Furthermore, we tested the ability of WT and T-bet−/−/RORγt−/− T cells in mediating GVL effect. Although T-bet−/−/RORγt−/− T cells failed to induce acute GVHD, their ability to reject A20 or p815 cells was comparable to that of the WT T cells at the dose tested. Conclusions: These results indicate that blocking T-bet and RORγt prevents acute GVHD by suppressing donor T cell differentiation towards Th1 and Th17 and promoting differentiation towards Th2, and inhibiting donor T cell expansion and infiltration into GVHD target organs. Furthermore, blocking T-bet and RORγt could preserve GVL effect. Thus, the current study validates new targets for the separation of donor T cell–mediated GVHD and GVL activity, which could eventually be beneficial to patients with hematological malignancies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Cytokines and costimulation in acute graft-versus-host disease

Blood ◽  
2020 ◽  
Vol 136 (4) ◽  
pp. 418-428 ◽  
Author(s):  
Geoffrey R. Hill ◽  
Motoko Koyama
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Interleukin 12 ◽  
Target Tissue ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Acute Graft

Abstract Allogeneic hematopoietic stem cell transplantation (alloSCT) is an important curative therapy for high-risk hematological malignancies, but the development of severe and/or steroid-refractory acute graft-versus-host disease (aGVHD) remains a significant limitation to optimal outcomes. New approaches to prevent and treat aGVHD remain an unmet need that can be best addressed by understanding the complex disease pathophysiology. It is now clear that chemoradiotherapy used prior to alloSCT induces the release of endogenous alarmins (eg, HMGB-1, ATP, IL-1α, IL-33) from recipient tissue. Exogenous pathogen-derived molecules (eg, lipopolysaccharide, nucleic acids) also translocate from the gastrointestinal tract lumen. Together, these danger signals activate antigen-presenting cells (APCs) to efficiently present alloantigen to donor T cells while releasing cytokines (eg, interleukin-12 [IL-12], IL-23, IL-6, IL-27, IL-10, transforming growth factor-β) that expand and differentiate both pathogenic and regulatory donor T cells. Concurrent costimulatory signals at the APC–T-cell interface (eg, CD80/CD86-CD28, CD40-CD40L, OX40L-OX40, CD155/CD112-DNAM-1) and subsequent coinhibitory signals (eg, CD80/CD86-CTLA4, PDL1/2-PD1, CD155/CD112-TIGIT) are critical to the acquisition of effector T-cell function and ensuing secretion of pathogenic cytokines (eg, IL-17, interferon-γ, tissue necrosis factor, granulocyte-macrophage colony-stimulating factor) and cytolytic degranulation pathway effectors (eg, perforin/granzyme). This review focuses on the combination of cytokine and costimulatory networks at the T-cell surface that culminates in effector function and subsequent aGVHD in target tissue. Together, these pathways now represent robust and clinically tractable targets for preventing the initiation of deleterious immunity after alloSCT.

scholarly journals β2 integrins separate graft-versus-host disease and graft-versus-leukemia effects

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 954-962 ◽  
Author(s):  
Yaming Liang ◽  
Chen Liu ◽  
Julie Y. Djeu ◽  
Bin Zhong ◽  
Thorsten Peters ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Morbidity And Mortality ◽  
Host Disease ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Donor T Cells ◽  
Β2 Integrins

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation. Migration of donor-derived T cells into GVHD target organs plays an essential role in the development of GVHD. β2 integrins are critically important for leukocyte extravasation through vascular endothelia and for T-cell activation. We asked whether CD18-deficient T cells would induce less GVHD while sparing the graft-versus-leukemia (GVL) effect. In murine allogeneic bone marrow transplantation models, we found that recipients of CD18−/− donor T cells had significantly less GVHD morbidity and mortality compared with recipients of wild-type (WT) donor T cells. Analysis of alloreactivity showed that CD18−/− and WT T cells had comparable activation, expansion, and cytokine production in vivo. Reduced GVHD was associated with a significant decrease in donor T-cell infiltration of recipient intestine and with an overall decrease in pathologic scores in intestine and liver. Finally, we found that the in vivo GVL effect of CD18−/− donor T cells was largely preserved, because mortality of the recipients who received transplants of CD18−/− T cells plus tumor cells was greatly delayed or prevented. Our data suggest that strategies to target β2 integrin have clinical potential to alleviate or prevent GVHD while sparing GVL activity.

scholarly journals Interleukin-2 inhibits graft-versus-host disease-promoting activity of CD4+ cells while preserving CD4- and CD8-mediated graft-versus-leukemia effects

Blood ◽  
1994 ◽  
Vol 83 (9) ◽  
pp. 2560-2569 ◽  
Author(s):  
M Sykes ◽  
MW Harty ◽  
GL Szot ◽  
DA Pearson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Interleukin 2 ◽  
Cell Subset ◽  
Spleen Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
T Cell Subset ◽  
Graft Versus Leukemia

Abstract We have recently shown that a short course of high-dose interleukin-2 (IL-2) can markedly inhibit the graft-versus-host disease (GVHD)- promoting activity of donor CD4+ T cells. The difficulty in dissociating GVHD-promoting from graft-versus-leukemia (GVL) effects of alloreactive donor T cells currently prevents clinical bone marrow transplantation (BMT) from fulfilling its full potential. To test the capacity of IL-2 treatment to promote such a dissociation, we have developed a new murine transplantable acute myelogenous leukemia model using a class II major histocompatibility complex-positive BALB/c Moloney murine leukemia virus-induced promonocytic leukemia, 2B-4–2. BALB/c mice receiving 2.5 x 10(5) 2B-4–2 cells intravenously 1 week before irradiation and syngeneic BMT died from leukemia within 2 to 4 weeks after BMT. Administration of syngeneic spleen cells and/or a 2.5- day course of IL-2 treatment alone did not inhibit leukemic mortality. In contrast, administration of non-T-cell-depleted fully allogeneic B10 (H-2b) spleen cells and T-cell-depleted B10 marrow led to a significant delay in leukemic mortality in IL-2-treated mice. In these animals GVHD was inhibited by IL-2 treatment. GVL effects were mediated entirely by donor CD4+ and CD8+ T cells. Remarkably, IL-2 administration did not diminish the magnitude of the GVL effect of either T-cell subset. This was surprising, because CD4-mediated GVHD was inhibited in the same animals in which CD4-mediated GVL effects were not reduced by IL-2 treatment. These results suggest a novel mechanism by which GVHD and GVL effects of a single unprimed alloreactive T-cell subset can be dissociated; different CD4 activities promote GVHD and GVL effects, and the former, but not the latter activities are inhibited by treatment with IL-2.

scholarly journals Clinical-Grade–Expanded Regulatory T Cells Prevent Graft-versus-Host Disease While Allowing a Powerful T Cell–Dependent Graft-versus-Leukemia Effect in Murine Models

2017 ◽  
Vol 23 (11) ◽  
pp. 1847-1851 ◽  
Author(s):  
Beatrice Del Papa ◽  
Loredana Ruggeri ◽  
Elena Urbani ◽  
Stefano Baldoni ◽  
Debora Cecchini ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Graft Versus Host Disease ◽  
Clinical Grade ◽  
Murine Models ◽  
Host Disease ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Graft Versus Leukemia Effect
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