scholarly journals Correlation of T Cell Subsets and Hypercholesterolemia of the Donor and Its Association with Acute Graft-versus-Host Disease

2019 ◽  
Author(s):  
MM Rivera-Franco ◽  
Eucario León-Rodríguez ◽  
Diana Gómez-Martín
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
Inflammatory Responses ◽  
T Cell Subsets ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor Bone Marrow ◽  
A Prospective Study ◽  
Acute Graft

Background: Acute graft-versus-host disease (aGVHD) is an important cause of death following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The association between cholesterol and aGVHD was previously described potentially resulting from pro-inflammatory responses associated with hypercholesterolemia. The aim of this study was to correlate T-cell subsets in donor bone marrow (BM) samples with their levels of cholesterol and associate these results with recipients who developed aGVHD and those who did not. Materials and Methods: A prospective study was performed in 39 donor samples. T-cell subsets were analyzed by flow cytometry. Results: Eleven (28%) donors had hypercholesterolemia. Donor samples with hypercholesterolemia had less Tregs compared to donors with normal levels of cholesterol (22.69 (IQR=30.6) cells/µL vs 52.62 (IQR=44.68) cells/µL, p=0.04). Among all individuals in the cohort, aGVHD was observed in 21%: 36% from donors with hypercholesterolemia versus 14% from donors with normal levels of cholesterol. Conclusion: As we described the association between hypercholesterolemia and diminished Tregs, our results might suggest that normalizing the levels of total cholesterol in the donor, prior performing allo-HSCT, might be an effective approach to diminish the risk of the receptor to develop aGVHD.

scholarly journals Dynamic regulation of effector IFN-γ-producing and IL-17-producing T cell subsets in the development of acute graft-versus-host disease

2015 ◽  
Vol 13 (2) ◽  
pp. 1395-1403 ◽  
Author(s):  
KAI ZHAO ◽  
SUHONG RUAN ◽  
LINGLING YIN ◽  
DONGMEI ZHAO ◽  
CHONG CHEN ◽  
...  
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
T Cell Subsets ◽  
Dynamic Regulation ◽  
Host Disease ◽  
Graft Versus Host ◽  
Ifn Γ ◽  
Acute Graft

scholarly journals Antibody to the dendritic cell surface activation antigen CD83 prevents acute graft-versus-host disease

2009 ◽  
Vol 206 (2) ◽  
pp. 387-398 ◽  
Author(s):  
John Wilson ◽  
Hannah Cullup ◽  
Rohan Lourie ◽  
Yonghua Sheng ◽  
Anna Palkova ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Target Cells ◽  
Malignant Cells ◽  
Antibody Treatment ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Allogeneic (allo) hematopoietic stem cell transplantation is an effective therapy for hematological malignancies but it is limited by acute graft-versus-host disease (GVHD). Dendritic cells (DC) play a major role in the allo T cell stimulation causing GVHD. Current immunosuppressive measures to control GVHD target T cells but compromise posttransplant immunity in the patient, particularly to cytomegalovirus (CMV) and residual malignant cells. We showed that treatment of allo mixed lymphocyte cultures with activated human DC-depleting CD83 antibody suppressed alloproliferation but preserved T cell numbers, including those specific for CMV. We also tested CD83 antibody in the human T cell–dependent peripheral blood mononuclear cell transplanted SCID (hu-SCID) mouse model of GVHD. We showed that this model requires human DC and that CD83 antibody treatment prevented GVHD but, unlike conventional immunosuppressants, did not prevent engraftment of human T cells, including cytotoxic T lymphocytes (CTL) responsive to viruses and malignant cells. Immunization of CD83 antibody-treated hu-SCID mice with irradiated human leukemic cell lines induced allo antileukemic CTL effectors in vivo that lysed 51Cr-labeled leukemic target cells in vitro without further stimulation. Antibodies that target activated DC are a promising new therapeutic approach to the control of GVHD.

Bortezomib Inhibit Acute Graft-Versus-Host Disease Via Shifting the Combination of T Cells Subpopulations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4709-4709
Author(s):  
Jianyu Weng ◽  
Shaoze Lin ◽  
Peilong Lai ◽  
Meikun Lv ◽  
Xin Du ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cytokine Level ◽  
T Cell Subsets ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Regulator T Cells ◽  
Acute Graft

Abstract Abstract 4709 Objective: Acute graft-versus-host disease (aGVHD) confines the wider application of allogeneic bone marrow transplantation (allo-BMT), but recently studies indicate that it is possible to reduce the incidence and severity of aGVHD while preserving the GVT by using bortezomib. In current study, we explored the changes of T cell subsets after allo-BMT administrated with bortezomib immediately, in order to establish the mechanism about bortezomib attenuation aGVHD. Materials and Methods: BALB/c mouse were injected of 0.5 mL PBS containing C57BL/6 2×107 nucleated BM cells plus 1×107 splenocytes followed a single dose of lethal total body irradiation (TBI, 0.7 Gy/min, 8.0 Gy) with or without bortezomib at 1.0 mg/kg. The level of CD4+ CD25+ Foxp3+ regulator T cells is quantified by flow cytometry, and the cytokine level of IL-2 and IL-4 is quantified by ELISA. Results: Bortezomib remarkably reduce aGVHD severity and prolonged the surviving time. Along with bortezomib injection, the level of CD4+ CD25+ Foxp3+ regulator T cell is significantly increased, the cytokine level of IL-2 is decreased but IL-4 is increased. Conclusion: Bortezomib inhibit aGVHD through shifting the combination of T cell subpopulations with up regulation CD4+CD25+ Foxp3+ regulator T cells lead to reset Th1/Th2 cytokine balance. Disclosures: No relevant conflicts of interest to declare.

scholarly journals CD25 expression distinguishes functionally distinct alloreactive CD4+ CD134+ (OX40+) T-cell subsets in acute graft-versus-host disease

2004 ◽  
Vol 10 (5) ◽  
pp. 298-309 ◽  
Author(s):  
Philip R Streeter ◽  
Xingqi Zhang ◽  
Thomas V Tittle ◽  
Catherine N Schön ◽  
Andrew D Weinberg ◽  
...  
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
T Cell Subsets ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cd25 Expression ◽  
Acute Graft

Low Absolute CD4 Central Memory Count On Day 30 Is Associated with An Increased Incidence of Chronic Graft-Versus-Host Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 516-516
Author(s):  
Zachariah A. McIver ◽  
Andrew Grim ◽  
Nicolas Naguib ◽  
A. John Barrett
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
Central Memory ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade Ii

Abstract Abstract 516 Early lymphocyte recovery is an important determinant of hematopoietic stem cell transplant (SCT) outcome. We found that robust day 30 lymphocyte counts are associated with a decreased incidence of relapse, decreased rates of both acute and chronic graft-versus-host disease (a-GvHD, c-GvHD), and increased survival. Natural killer (NK) cells contribute to lymphocyte recovery and may be associated with a strong graft-versus-leukemia and anti-GvHD effect. However, the contribution of the recovery of specific T cell subsets to transplant outcome has not been fully explored. We studied 43 patients undergoing a myeloablative matched-sibling T-cell depleted or selectively depleted SCT for a variety of hematological malignancies including AML, ALL, CML, and MDS. Median age was 43 years (range, 13–68), and median CD34 cell dose was 6.1×106/kg (range, 3.1-10.1). Thirty-one patients developed a-GvHD (12 grade I, 18 grade II, 1 grade II). Twelve patients had c-GvHD (7 limited, 5 extensive). On day 30 after SCT a peripheral blood sample was collected on all patients and cryopreserved. In preparation for analysis, mononuclear cells from these samples were thawed and rested overnight. Flow cytometry was then performed on a BD FACS CantoII flow cytometer with multicolor fluorochrome antibodies to CD3, CD4, CD8, CD27, and CD45RO. Subsets were defined as follows: Naive (N) CD27+CD45RO-, Central Memory (CM) CD27+CD45RO+, Effector Memory (EM) CD27-CD45RO+, and Effectors (E) CD27-CD45RO-. Data was analyzed by BD FACSDiva software, and Kaplan-Meier survival statistical analysis was performed on the readouts. Median subset frequencies were CD3+: 254 /μL (range, 75-2085), CD4+ : 132 /μL (range, 3-501), CD8+ :101 /μL (range, 9-1361), CD4+ EM 49/μL (range, 2-252), CD4+CM 60/μL (range, 1-253), CD8+ EM: 50 cells/μL (range 2-977), CD8+ CM 28 /μL (range, 2-401), Naïve and Effector cells were minimally or non-detected in both CD4+ and CD8+ compartments. When T cell subset recovery was correlated with transplant outcomes (a-GVHD, c-GVHD, relapse and survival) one significant association was identified: low CD4+ CM counts correlated with a higher incidence of c-GvHD. Patients that had less than the median value of 60 CD4+ CM cells/μL had a significantly higher likelihood of developing c-GvHD (HR 4.28, p=0.039, see figure). Additionally, when considering degree of disease, low CD4+ CM counts were associated with the severest manifestations of c-GvHD (p=0.021). As a result, we conclude that low absolute concentrations of CD4+ CM cells on day 30 after SCT reflects a deficiency in regulatory mechanisms important in the control of alloreactivity, and may be used as a surrogate marker for individuals at risk of developing c-GvHD. 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 T-Cell Costimulatory Molecules in Acute-Graft-Versus Host Disease: Therapeutic Implications

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Javier Briones ◽  
Silvana Novelli ◽  
Jorge Sierra
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Critical Role ◽  
Costimulatory Molecules ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Acute Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. Although this process is thought to consist of several phases, T-cell activation plays a critical role in the pathogenesis of acute GVHD. To become efficient effectors, T-cells require additional costimulation after T-cell receptor signaling. A number of molecules are involved in costimulation of T-cells such as CD28, CD40L, CD30, OX40, 4-1BB, ICOS, and LIGHT. The system is regulated by inhibitory molecules, CTLA-4, and PD-1. There is experimental evidence that those molecules are implicated in the pathogenesis of GHVD. We describe how these molecules are involved in acute GVHD and how the blockade of costimulatory molecules may have potential implications for the treatment of patients with acute GVHD.

scholarly journals Impact of High Donor-Derived CD4+ CCR7+ T Cell Count on Incidence of Grade II-IV Acute Graft-Versus-Host Disease Following Haploidentical Hematopoietic Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5721-5721
Author(s):  
Pauline Varlet ◽  
Tamim Alsuliman ◽  
Jacques Trauet ◽  
Julie Demaret ◽  
Myriam Labalette ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Memory T Cells ◽  
T Cell Subsets ◽  
Host Disease ◽  
Graft Versus Host ◽  
Central Memory T Cells ◽  
Grade Ii ◽  
Acute Graft

Abstract Introduction Historically the administration of post-transplant high-dose Cyclophosphamide (PTCy) has led to haplo-HCT re-innovation. Although PTCy has a positive impact towards reducing severe acute graft-versus-host disease (aGVHD), this drug has serious adverse side effects and makes haploidentical-HCT more difficult in some patients-particularly in older patients and/or those presenting other comorbidities. Considering our previous published experience in the effect of graft lymphocyte composition, this work aims to explore the impact of infused T cell subsets on Overall Survival (OS), Event Free Survival (EFS) and acute GVHD in a retrospective cohort receiving allogeneic haplo-HCT. Methods This study retrospectively analyzed 29 adult patients who underwent first allogeneic haplo-HCT for hematologic malignancies at Lille University Hospital (CHRU Lille, France). Graft samples were analyzed by flow cytometry, and CD4 and CD8 T cell subsets were defined as follows: TN=naïve T cells; , TCM=central memory T cells; TEM=effector memory T cells; TTD =terminally differentiated T cells. Results The median follow-up of patients was 11 months (0.4-44.3). The cohort median recipient age was 59 years old. Cumulative incidences of grade 2 to 4 aGVHD were 31%. The rate of grade 3 to 4 severe GVHD was 17%. Eleven patients died with 14% of deaths due to non-relapse mortality. We found a correlation between high percentage of donor-derived CD4+ CCR7+ T cells (>69.2% for CD4+ T cells-the median value in our study) and aGVHD (p=0.028) without any impact on OS and EFS (Table 1). In multivariate analysis, only high proportions of donor CD4+ CCR7+ T cells correlated significantly with aGVHD (HR=0.203, 95% CI [0,042-0,980], p=0,047) without any impact on OS and EFS (Figure 1). Conclusion Naïve and central memory T cells expressing CCR7 exhibit higher alloreactivity potential than CCR7- T cells. In this study, even with PTCy administration, we observed that a high percentage of donor-derived CD4+ CCR7+ T cells can be considered as a predictive indicator of grade II-IV aGVHD post Haplo-HCT. Thus, selective depletion of CD4+ CCR7+ T cells might be enough to prevent aGVHD in haplo-HCT, enabling the use of low doses of PTCy in order to reduce post haplo-HCT complications. Disclosures No relevant conflicts of interest to declare.

scholarly journals Effect of Early Post-Transplantation Tacrolimus Concentration on the Risk of Acute Graft-Versus-Host Disease in Allogenic Stem Cell Transplantation

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 613
Author(s):  
Nidhi Sharma ◽  
Qiuhong Zhao ◽  
Bin Ni ◽  
Patrick Elder ◽  
Marcin Puto ◽  
...  
Keyword(s):  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Tacrolimus Concentration ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
The Impact ◽  
Risk Of Relapse ◽  
Acute Graft

Acute graft versus host disease (aGVHD) remains a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT). Tacrolimus (TAC), a calcineurin inhibitor that prevents T-cell activation, is commonly used as a GVHD prophylaxis. However, there is variability in the serum concentrations of TAC, and little is known on the impact of early TAC levels on aGVHD. We retrospectively analyzed 673 consecutive patients undergoing allo-HSCT at the Ohio State University between 2002 and 2016. Week 1 TAC was associated with a lower risk of aGVHD II–IV at TAC level ≥10.15 ng/mL (p = 0.03) compared to the lowest quartile. The cumulative incidence of relapse at 1, 3 and 5 years was 33%, 38% and 41%, respectively. TAC levels at week 2, ≥11.55 ng/mL, were associated with an increased risk of relapse (p = 0.01) compared to the lowest quartile. Subset analysis with acute myeloid leukemia and myelodysplastic syndrome patients showed significantly reduced aGVHD with TAC level ≥10.15 ng/mL at week 1 and a higher risk of relapse associated with week 2 TAC level ≥11.55 ng/mL (p = 0.02). Hence, achieving ≥10 ng/mL during the first week of HCT may mitigate the risk of aGVHD. However, levels (>11 ng/mL) beyond the first week may be associated with suppressed graft versus tumor effect and higher relapse.

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