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.

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 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.

Attempting to Classify Prolonged Graft-Versus-Host-Disease According to Monocyte Activation Status in Addition to T-Cell

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3045-3045
Author(s):  
Rie Kuroda ◽  
Hideaki Maeba ◽  
Shintaro Mase ◽  
Raita Araki ◽  
Toshihiro Fujiki ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Monocyte Activation ◽  
Activation Markers ◽  
Host Disease ◽  
Graft Versus Host ◽  
Major Player

Abstract Abstract 3045 We have reported that measuring the activation markers and homing molecules on T-cells obtained from human peripheral blood (PB) samples provides useful information for predicting acute graft-versus-host disease (GVHD) severity in affected organs. Although T-cells are major player for developing GVHD, rodent GVHD studies have demonstrated that other immune cells such as monocytes/macrophages, B-cells, and mast cells involved in the pathogenesis of acute and chronic GVHD. We, therefore, evaluated activation markers and homing molecules regularly not only on T-cells but also on monocytes in PB obtained from 31 childhood patients (more than 600 samples at various time points) receiving hematopoietic stem cell transplantation (HSCT) by multicolor flow cytometry. The following markers were used: CD69, CD25, and HLA-DR for T cell activation, CCR4, CCR5, CXCR3, CCR9, and CLA for homing markers. Inflammatory monocytes were defined as CD14dimCD16+ cells or CD14+CD163+ cells. In addition we combined the data of cytokine profiles secreted mainly by T cells such as soluble interleukin 2 receptor, or monocytes such as neopterin, or both such as tumor necrosis factor-α (TNF-α), soluble TNF-αRI, and soluble TNF-αRII. In all cases showing acute GVHD, both T-cell and monocyte activation markers were elevated. Only either T-cell or monocyte activation was not observed in acute GVHD cases. However, we have some interesting results classified according to the status of T-cells and monocytes after day 100: 1) In the cases both T-cells and monocytes were highly activated as shown in Figure 1A, tapering of immunosuppressants led to exacerbation of GVHD, and prolonged administration of the drugs including steroids were needed. However steroid response itself was relatively good. 2) In the cases only T-cells, much less monocytes, were activated as shown in Figure 1B, calcineurin inhibitors were quite effective in improving GVHD. 3) In the cases of sustained chronic GVHD, neither T-cells nor mononytes were activated as shown in Figure 1C. Response to immunosuppressants was quite low. 4) When CD4 T-cell repertoire, not CD8, became normal, tapering of drugs was successful. In all cases successfully tapered immunosuppressive drugs, elevated activation markers of T-cells and monocytes completely returned to same levels of normal volunteers. In conclusion, evaluating the activation markers and homing molecules not only on T-cells but also on monocytes, combined with cytokine profiling, might provide useful information for management of patients with prolonged GVHD. Disclosures: No relevant conflicts of interest to declare.

Emergence of Donor T Cells That Recognize Nonpolymorphic Antigens During Graft Versus Host Disease,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4013-4013
Author(s):  
Hemalatha Rangarajan ◽  
Maryam Yassai ◽  
Xiao Chen ◽  
Richard Komorowski ◽  
Jack Gorski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
High Frequency ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
T Cell Response ◽  
Spleen Cells ◽  
Graft Versus Host ◽  
Donor T Cells

Abstract Abstract 4013 Chronic graft versus host disease (GVHD) is a major cause of morbidity and mortality in allogeneic stem cell transplant recipients and typically develops from antecedent acute GVHD. In contrast to acute GVHD which is characterized by a restricted set of organ involvement, chronic GVHD has more protean manifestations with much broader tissue involvement that can affect nearly all organ sites. Moreover, clinical manifestations in chronic GVHD often bear striking similarity to what is observed in autoimmune diseases. How GVHD evolves from an acute inflammatory syndrome in which donor T cells recognize polymorphic antigens expressed by host APCs to one that is characterized by autoimmune manifestations is not well understood. More specifically, it is not clear whether T cells that mediate autoimmune manifestations during chronic GVHD continue to respond to polymorphic antigens or whether T cells that recognize nonpolymorphic antigens emerge in these recipients. To address this issue, we performed a comprehensive analysis of the clonotypic T cell response in mice that developed autoimmune-mediated GVHD. To conduct these studies, lethally irradiated Balb/c [H-2d] mice were transplanted with C57BL/6 [H-2b] bone marrow and spleen cells to induce acute GVHD. At 19–21 days post transplantation, spleen cells or purified T cells from completely donor-engrafted mice were transferred into non irradiated syngeneic B6 Rag animals. In this model, animals develop pathological damage in the colon 60–70 days post transfer characterized by lamina propria inflammation, goblet cell depletion, and crypt cell destruction. This is attributed to the presence of autoreactive donor T cells in the original spleen cell inoculum that expand in syngeneic recipients due to loss of effective T cell regulation. To examine the clonotypic T cell response, we performed T cell receptor beta spectratyping on pathologically involved colonic tissue to identify over represented, skewed bands that were shared by replicate mice within the 21 Vβ families. These bands within a given Vβ family were sequenced to define the specific T cell clonotypes within colitic tissue. In the vast majority of families across multiple experiments, there were high frequency clonotypes that were present in all replicate mice and comprised 50–90% of all sequences. Notably, these shared clonotypes between replicate animals had the same CDR3 nucleotide sequence, indicating that they were the same T cell clones. The presence of high frequency clonotypes was also evidence that autoimmunity was characterized by antigen-driven expansion of a limited number of clones. During the progression from acute to chronic GVHD in humans, host APCs are eliminated and presentation of host peptides is by donor APCs through the indirect alloreactive pathway. To simulate this condition in our experimental model, we created chimeric animals by transplanting B6 Rag BM cells into lethally irradiated Balb/c Rag mice. Spleen cells from primary B6→Balb/c GVHD mice were then transferred into these fully donor-engrafted chimeric animals. Clonotypic analysis of T cells obtained from replicate mice with colitis revealed that dominant clonotypes were observed and comprised 65–80% of all sequences, similar to what was observed during conditions of autoimmunity. Given these similar results in models of autoimmunity and indirect alloimmunity, we then determined whether T cells that were capable of responding to B6 and Balb/c antigens when presented by B6 APCs could be identified. To address this question, the same pooled spleen cell suspension from primary (B6→Balb/c) GVHD mice was transferred into B6 Rag and chimeric (B6 Rag→Balb/c Rag) animals. We observed that T cell clonotypes with the same nucleotide sequences could be identified in pathologically involved colon tissue from both cohorts of mice indicating the emergence of T cells that were capable of recognizing both B6 and Balb/c antigens presented by B6 APCs. These results demonstrate that the loss of self tolerance which occurs during acute GVHD leads to the emergence of broadly reactive donor T cells that are capable of recognizing nonpolymorphic antigens that are shared between donor and host. These data also provide a mechanistic explanation for how autoimmunity develops as a consequence of GVHD and help explain the progression of tissue involvement that characterizes the transition from acute to chronic GVHD. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The role of antigen-presenting cells in triggering graft-versus-host disease and graft-versus-leukemia

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 9-17 ◽  
Author(s):  
Ronjon Chakraverty ◽  
Megan Sykes
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Tissue Injury ◽  
Chronic Gvhd ◽  
Host Disease ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Donor T Cells ◽  
Antigen Presenting

After allogeneic blood or bone marrow transplantation, donor T cells interact with a distorted antigen-presenting cell (APC) environment in which some, but not all, host APCs are replaced by APCs from the donor. Significantly, host APCs are required for the priming of acute graft-versus-host disease (GVHD). Donor APCs play a lesser role in the induction of acute GVHD despite their predicted capacity to cross-present host antigens. In contrast, donor APCs may play a role in perpetuating the tissue injury observed in chronic GVHD. Host APCs are also required for maximal graft-versus-leukemia responses. Recent studies have suggested potential strategies by which the continued presence of host APCs can be exploited to prime strong donor immunity to tumors without the induction of GVHD.

scholarly journals Signaling Through the Type 2 Cannabinoid Receptor Regulates the Severity of Acute and Chronic Graft versus Host Disease

Blood ◽  
2020 ◽  
Author(s):  
Cheng Yin Yuan ◽  
Vivian Zhou ◽  
Garrett Sauber ◽  
Todd M Stollenwerk ◽  
Richard Komorowski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Acute Gvhd ◽  
Cannabinoid Receptor ◽  
Therapeutic Targeting ◽  
Host Disease ◽  
Graft Versus Host

Graft versus host disease (GVHD) pathophysiology is a complex interplay between cells that comprise the adaptive and innate arms of the immune system. Effective prophylactic strategies are therefore contingent upon approaches that address contributions from both immune cell compartments. In the current study, we examined the role of the type 2 cannabinoid receptor (CB2R) which is expressed on nearly all immune cells and demonstrated that absence of the CB2R on donor CD4+ or CD8+ T cells, or administration of a selective CB2R pharmacological antagonist, exacerbated acute GVHD lethality. This was accompanied primarily by the expansion of proinflammatory CD8+ T cells indicating that constitutive CB2R expression on T cells preferentially regulated CD8+ T cell alloreactivity. Using a novel CB2R-EGFP reporter mouse, we observed significant loss of CB2R expression on T cells, but not macrophages, during acute GVHD, indicative of differential alterations in receptor expression under inflammatory conditions. Therapeutic targeting of the CB2R with the agonists, tetrahydrocannabinol (THC) and JWH-133, revealed that only THC mitigated lethal T cell-mediated acute GVHD. Conversely, only JWH-133 was effective in a sclerodermatous chronic GVHD model where macrophages contribute to disease biology. In vitro, both THC and JWH-133 induced arrestin recruitment and ERK phosphorylation via CB2R, but THC had no effect on CB2R-mediated inhibition of adenylyl cyclase. These studies demonstrate that the CB2R plays a critical role in the regulation of GVHD and suggest that effective therapeutic targeting is dependent upon agonist signaling characteristics and receptor selectivity in conjunction with the composition of pathogenic immune effector cells.

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.

Single Nucleotide Polymorphism (SNP) Approach of Multiple Candidate Pathways Predicting the Risk of Acute / Chronic Graft-Versus-Host Disease or Transplant Outcomes Following Allogeneic Hematopoietic Stem Cell Transplantation: Potential Involvement of Nuclear Factor Kappa-B (NFKB), Platelet-Derived Growth Factor (PDGF) and Transforming Growth Factor-Beta (TGF-β) Pathway with Chronic Graft-Versus-Host Disease Graft-Versus-Host Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2221-2221
Author(s):  
Dong Hwan (Dennis) Kim ◽  
Jina Yun ◽  
Jee Hyun Kong ◽  
Chul Won Jung ◽  
Ahmed Galal ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Growth Factor ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Transforming Growth Factor ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cytokine Activation

Abstract Abstract 2221 Poster Board II-198 Background: Acute graft-versus-host disease (GVHD) was known to be involved in the Th1 cytokine activation and alloreactive T-cell cytotoxicity, while the pathogenesis of chronic GVHD is yet revealed fully although in which Th2 cytokine activation or transforming growth factor (TGF) mediated pathway was suggested to be involved. The current study is a hypothesis generating study in order to identify potential predictive surrogate associated with the risk of acute or chronic GVHD in addition with transplant outcomes after allogeneic hematopoietic stem cell transplantation (HSCT). Methods: The current study was performed to identify genetic surrogates predicting the risk of acute / chronic GVHD, relapse free survival, non-relapse mortality and overall survival in 394 pairs transplanted at the Princess Margaret Hospital, Toronto, ON, Canada. In addition, the predictive markers for organ specific incidence of acute / chronic GVHD were also evaluated (i.e. for skin/liver/gut acute GVHD or skin, eye, oral, lung or liver chronic GVHD). Total of 261 single nucleotide polymorphisms (SNPs) in 56 genes were determined for donor/recipients' genotypes using MALDI-TOF based platform, involving in the pathways of 1) cytokines (i.e. IL1A, IL1B and its receptor, IL1R1, IL2 & IL2RA, IL4 & IL4R, IL6 & IL6R, IL8, IL10 & IL10RA, RB, IL12A/BandIL12RB1, IFNG & IFNGR1/2, TNFTI/II/II), 2) NFKB (NFKB1/2/A, NFKBIA/B, IKB, IKK1, IKBKB, RelB), 3) apoptosis (FAS, TRAIL & TRAILR1), 4) endothelium nitric oxide regulation (EDN1, NOS1/2A/3), 5) PDGF (PDGFB/C/D & PDGFRA/B), 6) TGF-β (TGFB1/2 & TGFBR1/2/3, TGFRB1), 7) Toll-like receptor (TLR4/5), 8) NOD2/CARD15 and 9) prostaglandin-endoperoxide synthase (PTGS1/2). The candidate genotypes have been selected by choosing the SNPs in non-synonymous SNPs in exon region with minor allele frequency of > 0.05 to 0.1. Results: Followings are the lists of recipients' and donors' genotypes with p-value<0.05 thus associating with clinical outcomes following allogeneic HSCT: In summary, the risk of chronic GVHD was significantly associated with SNP of the genes involved in the pathway of NFKB, PDGF, TGF-β, and some of cytokines (esp. type II, IL6 & IL4), while that of acute GVHD associates with the genotypes in the pathway of TNF and apoptosis. In addition, survival after allogeneic transplantation was associated with the genotypes in NOS (nitric oxide synthase, endothelial nitric oxide synthesis pathway), IL-2 and TGF pathway. Conclusion: Because of complex nature of GVHD pathogenesis, multiple candidate pathway SNPs has been explored targeting SNPs in the pathway of cytokines, NFKB, apoptosis, endothelium nitric oxide regulation, NOD2/CARD15, PDGF, PTGS1/2, TGF-β and TLR. Different involvements were noted of TGF-β, PDGF or NFKB with chronic GVHD versus TNF and apoptosis-associated SNPs with acute GVHD. Further study will help us to reach more clear conclusion which genotype is the predictor of the risk of GVHD. Disclosures: No relevant conflicts of interest to declare.

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