scholarly journals Selective depletion of alloreactive donor lymphocytes: a novel method to reduce the severity of graft-versus-host disease in older patients undergoing matched sibling donor stem cell transplantation

Blood ◽  
2005 ◽  
Vol 106 (3) ◽  
pp. 1123-1129 ◽  
Author(s):  
Scott R. Solomon ◽  
Stephan Mielke ◽  
Bipin N. Savani ◽  
Aldemar Montero ◽  
Laura Wisch ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Older Patients ◽  
Acute Gvhd ◽  
Ex Vivo ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cd34 Cells ◽  
Donor T Cells

AbstractWe have selectively depleted host-reactive donor T cells from peripheral blood stem cell (PBSC) transplant allografts ex vivo using an anti-CD25 immunotoxin. We report a clinical trial to decrease graft-versus-host disease (GVHD) in elderly patients receiving selectively depleted PBSC transplants from HLA-identical sibling donors. Sixteen patients (median age, 65 years [range, 51-73 years]), with advanced hematologic malignancies underwent transplantation following reduced-intensity conditioning with fludarabine and either cyclophosphamide (n = 5), melphalan (n = 5), or busulfan (n = 6). Cyclosporine was used as sole GVHD prophylaxis. The allograft contained a median of 4.5 × 106 CD34 cells/kg (range, 3.4-7.3 × 106 CD34 cells/kg) and 1.0 × 108/kg (range, 0.2-1.5 × 108/kg) selectively depleted T cells. Fifteen patients achieved sustained engraftment. The helper T-lymphocyte precursor (HTLp) frequency assay demonstrated successful (mean, 5-fold) depletion of host-reactive donor T cells, with conservation of third-party response in 9 of 11 cases tested. Actuarial rates of acute GVHD were 46% ± 13% for grades II to IV and 12% ± 8% for grades III to IV. These results suggest that allodepletion of donor cells ex vivo is clinically feasible in older patients and may reduce the rate of severe acute GVHD. Further studies with selectively depleted transplants to evaluate graft-versus-leukemia (GVL) and survival are warranted.

Selective Depletion of Alloreacting CD25+ Cells from Stem Cell Allografts Can Reduce Acute Graft-Versus-Host Disease Following Matched Related Donor Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 426-426
Author(s):  
Scott R. Solomon ◽  
Thao Tran ◽  
Charles S. Carter ◽  
Nancy Hensel ◽  
Laura Wisch ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Cell Transplant ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Donor T Cells ◽  
Related Donor

Abstract Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic stem cell transplant (SCT), especially in older patients. We previously showed that host-reactive donor T cells are selectively depleted (SD) from an allograft ex vivo, following a short co-culture of donor cells with irradiated T cell stimulators from the recipient and subsequent treatment with an anti-CD25 immunotoxin. We report a pilot study to test the hypothesis that GVHD could be decreased in a cohort of elderly patients receiving SD allografts from HLA-identical sibling donors. Sixteen patients, median age 65 years (range 51–73), with advanced hematologic malignancies were transplanted following reduced-intensity conditioning with fludarabine and either cyclophosphamide (n=5), melphalan (n=5), or busulfan (n=6). Cyclosporine was used as the only additional GVHD prophylaxis. SD allografts contained a median CD34 dose of 4.5x106/kg (range 3.5–7.3) and an SD CD3 dose of 1.0x108/kg (range 0.2–1.5). Fifteen patients achieved sustained engraftment. The helper T lymphocyte precursor (HTLp) frequency assay demonstrated depletion of host-reactive donor T cells in 9/11 cases tested from a mean of 1/182,089 to 1/822,354 (mean 5.5-fold depletion), while third party responses were conserved. Kaplan-Meier estimates of probability of grade II-IV and grade III-IV acute GVHD were lower than those seen in a historical control group of patients receiving cyclosporine alone for GVHD prophylaxis (35±13% vs. 57±10%, p=0.34) and (7±6% vs. 38±6%, p=0.05), respectively. Of note, the two patients who developed visceral (gut ± liver) GVHD showed ineffective allodepletion by HTLp (figure). Chronic GVHD occurred in five of 14 evaluable patients. At a median follow-up of 212 days (range 60 – 690), seven of sixteen patients remain alive and in remission. Relapse deaths occurred in four patients (refractory AML [2], therapy-related MDS [1], and CMML [1]). Non-relapse mortality in this high-risk cohort of patients included graft failure [1], GVHD [2], infection [1], and myocardial infarction [1]. In summary, CD25-directed allodepletion of stem cell allografts can reduce clinically relevant acute GVHD following matched related donor transplantation. Figure Figure

The Role of Selective Depletion of Alloreactive Donor T Cells in Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5167-5167
Author(s):  
Yihuan Chai ◽  
Huiying Qiu ◽  
Hui Lv
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Allogeneic Bone Marrow ◽  
Third Party ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells

Abstract One of the main goals in allogeneic bone marrow(BM) transplantation is the abrogation of graft-versus-host disease (GVHD) with the preservation of antileukemia and antiviral activity. The Study present a selective T cell depletion strategy based on the physical separation of the alloreactive T cells, which were identified by expression of two activation-induced antigens (CD25 and CD69). T cells from C57BL/6(H-2b) mice were first activated with BALB/c (H-2d) recipient spleen cells in a 2-day mixed-lymphocyte-culture (MLC). Following this activation, this compound is selectively depleted based on expression of two activation-induced antigens CD25 and CD69 using magnetic cell sorting. The depleted cells or the untreated cells were then rechallenged respectively in a secondary MLC, with the same stimulator cells or a third-party (DBAH-2k) or tumor- specific (SP2/0, BALB/c-origin myeloma) cells. Cells proliferation were assayed at the indicated time points(1, 2, 3, 4, 5 days). These treated cells or control-cultured cells (2.0×106) mixed with 5.0×106 BM cells from C57BL/6 were transfused respectively by the trail vain into the lethally irradiated BALB/c to observe the survival time, GVHD incidence and pathological analysis. MLC assays demonstrated that this technique led to a significant decrease in alloreactivity of donor cells(29.02~64.17%), which at the same time preserved reactivity against third party cells(49.61~75.69%)and anti-tumor cells(61.14~68.62%). The mice in the group of control-coclutured were died of acute GVHD within 24days. The 7 recipient mice in the treated group were free of acute GVHD, and 3 mice were died of acute GVHD (aGVHD) within 23 days. MACS-based ex-vivo depletion of alloreactive donor T cells based on expression of two activation-induced antigens (CD25 and CD69) could inhibit anti-host responses, by contrast, anti-SP2/O and anti-third-party responses were preserved. Cotransplantation of these selected depleted cells and BM cells could reduce aGVHD.

MiR-146a Regulates the TRAF6/TNF-Axis in Donor T Cells during Graft-Versus-Host Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 843-843
Author(s):  
Natalie Stickel ◽  
Gabriele Prinz ◽  
Dietmar Pfeifer ◽  
Annette Schmitt-Graeff ◽  
Marie Follo ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Negative Regulator ◽  
Snp Analysis ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells

Abstract Introduction: Acute graft-versus-host disease (GvHD) arises from the attack of recipient tissues by donor allogeneic T cells and represents one of the major limitations of allogeneic hematopoietic cell transplantation (allo-HCT). In spite of many clinical trials, the standard immunosuppressive regimens for prevention of acute GvHD have improved little in the last two decades. Hence, a better understanding of the biology of acute GvHD may improve therapeutic options. MicroRNA-146a (miR-146a) was found to be increased in the sera of patients with GvHD. Therefore, we aimed to decipher the role of miR-146a in allogeneic donor T cells during GvHD by functional studies and in patients undergoing allo-HCT by single nucleotide polymorphism (SNP) analysis. Methods: We used two different murine major MHC mismatch models for acute GvHD. Recipient mice were conditioned with irradiation before transplantation of bone marrow and either wildtype or miR-146a deficient T cells from allogeneic donor mice. Furthermore, genomic DNA from 289 patients that underwent allo-HCT and their respective hematopoietic stem cell donors was isolated in order to determine their miR-146a rs2910164genotype. Results: We observed miR-146a upregulation in T cells of mice developing acute GvHD compared to untreated mice in a major MHC and a minor histocompatibility antigen mismatch model. Transfer of miR-146a deficient T cells caused increased GvHD severity, elevated TNF serum levels and reduced survival. Conversely, the phytochemical induction of miR-146a or its overexpression in donor T cells using a specific miR-146a mimic reduced GvHD severity. TNF receptor-associated factor 6 (TRAF6), a verified target of miR-146a, was upregulated in miR-146a-/- T cells following alloantigen stimulation. Higher TRAF6 levels translated into increased NF-κB activity and TNF production in miR-146a-/- T cells, while other pro-inflammatory cytokine levels were unaffected. The detrimental effect of miR-146a deficiency in T cells could be antagonized by TNF blockade in vivo. Moreover, in contrast to WT T cells, over expression of miR-146a in Tnf deficient T cells had no effect on their alloreactivity. In the human system, the minor genotype of the SNP rs2910164, which causes reduced miR-146a expression, was more frequent in patients developing acute GvHD grade III/IV compared to all other allo-HCT recipients (n=289). Conclusions: Taken together we show that miR-146a functions as a negative regulator of the TRAF6/TNF-axis in allogeneic donor T cells during GvHD, leading to reduced TNF transcription. Given our observation on the predictive role of the SNP leading to decreased miR-146a expression in acute GvHD in patients and the possibility to exogenously enhance miR-146a expression, we provide a novel and targeted molecular approach to mitigate GvHD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Interleukin-18 Regulates Acute Graft-Versus-Host Disease by Enhancing Fas-mediated Donor T Cell Apoptosis

2001 ◽  
Vol 194 (10) ◽  
pp. 1433-1440 ◽  
Author(s):  
Pavan Reddy ◽  
Takanori Teshima ◽  
Mark Kukuruga ◽  
Rainer Ordemann ◽  
Chen Liu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Host Disease ◽  
Murine Bone Marrow ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Ifn Γ ◽  
Acute Graft

Interleukin (IL)-18 is a recently discovered cytokine that modulates both T helper type 1 (Th1) and Th2 responses. IL-18 is elevated during acute graft-versus-host disease (GVHD). We investigated the role of IL-18 in this disorder using a well characterized murine bone marrow transplantation (BMT) model (B6 → B6D2F1). Surprisingly, blockade of IL-18 accelerated acute GVHD-related mortality. In contrast, administration of IL-18 reduced serum tumor necrosis factor (TNF)-α and lipopolysaccharide (LPS) levels, decreased intestinal histopathology, and resulted in significantly improved survival (75 vs. 15%, P < 0.001). Administration of IL-18 attenuated early donor T cell expansion and was associated with increased Fas expression and greater apoptosis of donor T cells. The administration of IL-18 no longer protected BMT recipients from GVHD when Fas deficient (lpr) mice were used as donors. IL-18 also lost its ability to protect against acute GVHD when interferon (IFN)-γ knockout mice were used as donors. Together, these results demonstrate that IL-18 regulates acute GVHD by inducing enhanced Fas-mediated apoptosis of donor T cells early after BMT, and donor IFN-γ is critical for this protective effect.

scholarly journals Interleukin-12 Inhibits Graft-Versus-Host Disease Through an Fas-Mediated Mechanism Associated With Alterations in Donor T-Cell Activation and Expansion

Blood ◽  
1998 ◽  
Vol 91 (9) ◽  
pp. 3315-3322 ◽  
Author(s):  
Bimalangshu R. Dey ◽  
Yong-Guang Yang ◽  
Gregory L. Szot ◽  
Denise A. Pearson ◽  
Megan Sykes
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Interleukin 12 ◽  
Cd4 Cells ◽  
Activation Markers ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells

We have recently made the paradoxical observation that a single injection of recombinant murine interleukin-12 (IL-12) on the day of bone marrow transplantation (BMT) inhibits graft-versus-host disease (GVHD) in lethally irradiated mice receiving fully major histocompatability complex (MHC)-mismatched bone marrow and spleen cells. We have now examined the mechanism of this effect of IL-12 on acute GVHD. By day 4 post-BMT, IL-12–treated mice showed marked reductions in splenic donor CD4+ and CD8+ T cells compared with GVHD controls. Expression of the early activation markers IL-2R alpha chain (CD25) and CD69 on splenic donor CD4+ cells was considerably higher at early time points (36 and 72 hours post-BMT) in IL-12–treated mice compared with GVHD controls. However, the later, GVHD-associated increase in CD25 and very late antigen-4 (VLA-4) expression on donor T cells was greatly depressed in IL-12–protected mice compared with GVHD controls. The marked GVHD-associated expansion of host-reactive T helper cells by day 4 was also completely inhibited in the IL-12–treated group. Expression of Fas was increased on donor CD4 cells of IL-12–treated mice compared with those of controls on days 3 through 7 post-BMT. Furthermore, the ability of IL-12 to protect against GVHD was at least partially dependent on the ability of donor cells to express functional Fas molecules. We conclude that IL-12 treatment at the time of BMT markedly perturbs the activation of alloreactive donor CD4+ T cells that play a critical role in the pathogenesis of acute GVHD. We hypothesize that these perturbations culminate in Fas-dependent apoptosis of donor T cells, thus impeding their expansion and their GVHD-promoting 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.

Fatty Acid Metabolism Provides a Potential Therapeutic Target To Treat Graft-Versus-Host Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2002-2002
Author(s):  
Craig A. Byersdorfer ◽  
Victor Tkachev ◽  
Stefanie Goodell ◽  
Jacob Swanson ◽  
James L.M. Ferrara
Keyword(s):  
T Cells ◽  
Fatty Acid ◽  
Graft Versus Host Disease ◽  
Ex Vivo ◽  
Cell Metabolism ◽  
Cell Types ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells

Abstract The metabolism of lymphocytes activated in vivo remains poorly understood. Previous work has demonstrated that T cells activated during graft-versus-host disease (GVHD) adopt metabolic profiles distinct from other cell types. We hypothesized that a deeper understanding of allogeneic T cell metabolism, followed by exploitation of metabolic differences, might allow selective elimination of pathogenic T cells while preserving normal immune responses following bone marrow transplantation (BMT). We tested this hypothesis by evaluating fatty acid (FA) metabolism in proliferating donor T cells during a parent into F1 model of GVHD (C57Bl/6 into B6D2F1). Compared to naive donor T cells, T cells from allogeneic recipients increased FA transport (44.3 ±6.9% vs. 0.7 ±0.1%, p=0.003) and up-regulated a regulator of oxidative metabolism, PGC-1α (0.9 ±0.2 vs. 0.03 ±0.01, p=0.005). These changes were present in T cells recovered from both the liver and the spleen. Allogeneic T cells also up-regulated mRNA and protein levels for FA oxidation enzymes (e.g. CPT1a) and oxidized more fatty acids ex vivo. We confirmed these changes in a second, minor histocompatibility model of GVHD, where we observed significantly increased levels of FA transport, PGC-1α, and FA oxidation enzymes. To identify potential therapeutic targets selective for alloreactive T cells, we compared the metabolic profile of allogeneic T cells to the profile observed in T cells following acute activation in vivo. We injected OT-I T cells into naïve C57Bl/6 mice, challenged mice one day later with ovalbumin-bearing dendritic cells, and harvested T cells 7 days after immunization. OT-I T cells proliferated robustly to cellular immunization, but did not increase FA transport or levels of PGC-1α (Figure 1A,B). We then tested the ability of inhibitors of FA oxidation (targeting CPT1a) to selectively eliminate allogeneic T cells during GVHD. A single dose of etomoxir decreased the total number of donor T cells in allogeneic recipients by 35% and eight doses over 14 days significantly improved clinical GVHD scores (Figure 1C). Treatment with a second CPT1a inhibitor improved post-transplant survival (78% vs. 50%, inhibitor vs. PBS respectively). Importantly, CPT1a inhibition did not diminish the number of regulatory T cells or the number of T cells reconstituting via homeostatic proliferation following syngeneic BMT. In total, these data demonstrate that allogeneic T cells increase FA metabolism during GVHD and that this phenotype differentiates allogeneic cells from T cells responding to acute activation or proliferating during homeostatic reconstitution. This study challenges the paradigm of effector lymphocyte metabolism in vivo and we conclude that inhibition of FA oxidation may be a selective way to eliminate pathogenic T cells causing immune-mediated disease. Disclosures: Ferrara: University of Michigan: Patent for GVHD Biomarkers, Patent for GVHD Biomarkers Patents & Royalties.

scholarly journals SOCS3 regulates graft-versus-host disease

Blood ◽  
2010 ◽  
Vol 116 (2) ◽  
pp. 287-296 ◽  
Author(s):  
Geoffrey R. Hill ◽  
Rachel D. Kuns ◽  
Neil C. Raffelt ◽  
Alistair L. J. Don ◽  
Stuart D. Olver ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Transforming Growth Factor ◽  
Chronic Gvhd ◽  
Cytokine Signaling ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells

Abstract Suppressor of cytokine signaling-3 (SOCS3) is the main intracellular regulator of signaling by granulocyte colony-stimulating factor, an immune-modulatory cytokine used to mobilize stem cells for transplantation. We have therefore studied the contribution of SOCS3 to the spectrum of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Grafts from SOCS3−/Δvav donor mice in which SOCS3 deficiency is restricted to the hematopoietic compartment had an augmented capacity to induce acute GVHD. With the use of SOCS3−/ΔLysM and SOCS3−/Δlck donors in which SOCS3 deficiency was restricted to the myeloid or T-cell lineage, respectively, we confirmed SOCS3 deficiency promoted acute GVHD mortality and histopathology within the gastrointestinal tract by effects solely within the donor T cell. SOCS3−/Δlck donor T cells underwent enhanced alloantigen-dependent proliferation and generation of interleukin-10 (IL-10), IL-17, and interferon-γ (IFNγ) after SCT. The enhanced capacity of the SOCS3−/Δlck donor T cell to induce acute GVHD was dependent on IFNγ but independent of IL-10 or IL-17. Surprisingly, SOCS3−/Δlck donor T cells also induced severe, transforming growth factor β– and IFNγ-dependent, sclerodermatous GVHD. Thus, the delivery of small molecule SOCS3 mimetics may prove to be useful for the inhibition of both acute and chronic GVHD.

Protection from lethal murine graft-versus-host disease without compromise of alloengraftment using transgenic donor T cells expressing a thymidine kinase suicide gene

Blood ◽  
2001 ◽  
Vol 97 (8) ◽  
pp. 2506-2513 ◽  
Author(s):  
William R. Drobyski ◽  
Herbert C. Morse ◽  
William H. Burns ◽  
James T. Casper ◽  
Gordon Sandford
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Thymidine Kinase ◽  
Graft Versus Host Disease ◽  
Ex Vivo ◽  
Suicide Gene ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells

Abstract Donor T cells play a pivotal role in facilitating alloengraftment but also cause graft-versus-host disease (GVHD). Ex vivo T-cell depletion (TCD) of donor marrow is the most effective strategy for reducing GVHD but can compromise engraftment. This study examined an approach whereby donor T cells are selectively eliminated in vivo after transplantation using transgenic mice in which a thymidine kinase(TK) suicide gene is targeted to the T cell using a CD3 promoter/enhancer construct. Lethally irradiated B10.BR mice transplanted with major histocompatibility complex (MHC)–incompatible TCD C57BL/6 (B6) bone marrow (BM) plus TK+ T cells were protected from GVHD after treatment with ganciclovir (GCV) in a schedule-dependent fashion. To examine the effect of GCV treatment on alloengraftment, sublethally irradiated AKR mice underwent transplantation with TCD B6 BM plus limiting numbers (5 × 105) of B6 TK+ T cells. Animals treated with GCV had comparable donor engraftment but significantly reduced GVHD when compared with untreated mice. These mice also had a significantly increased number of donor splenic T cells when assessed 4 weeks after bone marrow transplantation. Thus, the administration of GCV did not render recipients T-cell deficient, but rather enhanced lymphocyte recovery. Adoptive transfer of spleen cells from GCV-treated chimeric mice into secondary AKR recipients failed to cause GVHD indicating that donor T cells were tolerant of recipient alloantigens. These studies demonstrate that administration of TKgene–modified donor T cells can be used as an approach to mitigate GVHD without compromising alloengraftment.

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