Alterations of CCR5 and CCR7 expression on donor peripheral blood T cell subsets after mobilization with rhG-CSF correlate with acute graft-versus-host disease

Abstract Abstract 2251 Poster Board II-228 Introduction: Dendritic cells (DC) are central to the development of acute graft-versus-host disease (GvHD) following allogeneic hematopoietic cell transplantation (alloHCT). We previously showed that the activation status, as assessed by CMRF-44 antigen expression, of blood CD11c+ myeloid DC is highly associated with the severity of acute GvHD, and that activated DC may be detected in the circulation prior to clinical presentation of GvHD (Transplantation 2007;83: 839–846). Because DC migration is tightly regulated by the interaction between chemokine receptors on DC and their ligands, we investigated the relationship between the severity of acute GvHD and the expression of the chemokine receptors CCR5 and CCR7 on CD11c+myeloid and CD11c- plasmacytoid from the peripheral blood of 32 patients post alloHCT. Methods: Peripheral blood was collected twice weekly up to day 100 post transplant from 22 patients who received transplants from matched siblings, 10 from unrelated donors. Nineteen transplants were performed with myeloablative conditioning, 13 with reduced intensity conditioning. The expression of each chemokine receptor on CD11c+ and CD11c- DC was calculated using multiparameter flow cytometry. The percentage of CD11c+ DC expressing a given receptor was added to the percentage of CD11c- DC expressing the same receptor to give a maximum score that could vary from 0 to 200%. Results: Eleven of 32 patients developed moderate to severe acute GvHD (grade II-IV), the remaining 21 patients developed either no GvHD or only grade I GvHD. The percentage of DC expressing either CCR5 or CCR7 was correlated with the development of acute GvHD. CCR7 expression was detected in 13 of 32 patients post-HCT with a median of 2.3% of DC positive (range 0 to 39%). CCR7 expression on DC showed no association with the severity of acute GvHD (p=1.0). In contrast, higher CCR5 expression was detected on DC in patients developing grade II-IV GvHD (median 98.0%, SEM 9.1%) than in those with grade 0-I GvHD (median 5.2%, SEM 5.1%) p<0.0001. All eleven patients with grade II-IV GvHD expressed CCR5 at a level of >35% of myeloid and plasmacytoid DC. Only two of 21 patients with grade I GvHD expressed CCR5 at the same level (66% and 94%). Most importantly, the expression of CCR5 preceded the development of moderate to severe GvHD in all patients by a median of 19 days (range 2 to 47 days, SEM 4.3 days). Using a receiver operator curve analysis, CCR5 expression above 35% demonstrated a sensitivity of 100% and a specificity of 90.5% for predicting grade II-IV GvHD. Conclusion: Expression of CCR5 on circulating DC post allo-HCT predicts for the development of moderate to severe GvHD, and detection could allow earlier therapeutic intervention prior to the development of clinical GVHD, if these findings are confirmed in a larger study Disclosures: No relevant conflicts of interest to declare.

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

International Journal of Hematology-Oncology and Stem Cell Research ◽

10.18502/ijhoscr.v13i4.1892 ◽

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.

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

Blood ◽

10.1182/blood.v118.21.4709.4709 ◽

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.

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Bone Marrow NK1.1− and NK1.1+ T Cells Reciprocally Regulate Acute Graft versus Host Disease

Journal of Experimental Medicine ◽

10.1084/jem.189.7.1073 ◽

1999 ◽

Vol 189 (7) ◽

pp. 1073-1081 ◽

Cited By ~ 239

Author(s):

Defu Zeng ◽

David Lewis ◽

Sussan Dejbakhsh-Jones ◽

Fengshuo Lan ◽

Marcos García-Ojeda ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Cd8 T Cells ◽

Peripheral Blood ◽

T Cell Subsets ◽

Host Disease ◽

Graft Versus Host ◽

Ifn Γ

Sorted CD4+ and CD8+ T cells from the peripheral blood or bone marrow of donor C57BL/6 (H-2b) mice were tested for their capacity to induce graft-versus-host disease (GVHD) by injecting the cells, along with stringently T cell–depleted donor marrow cells, into lethally irradiated BALB/c (H-2d) host mice. The peripheral blood T cells were at least 30 times more potent than the marrow T cells in inducing lethal GVHD. As NK1.1+ T cells represented <1% of all T cells in the blood and ∼30% of T cells in the marrow, the capacity of sorted marrow NK1.1− CD4+ and CD8+ T cells to induce GVHD was tested. The latter cells had markedly increased potency, and adding back marrow NK1.1+ T cells suppressed GVHD. The marrow NK1.1+ T cells secreted high levels of both interferon γ (IFN-γ) and interleukin 4 (IL-4), and the NK1.1− T cells secreted high levels of IFN-γ with little IL-4. Marrow NK1.1+ T cells obtained from IL-4−/− rather than wild-type C57BL/6 donors not only failed to prevent GVHD but actually increased its severity. Together, these results demonstrate that GVHD is reciprocally regulated by the NK1.1− and NK1.1+ T cell subsets via their differential production of cytokines.

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

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2003.12.302 ◽

2004 ◽

Vol 10 (5) ◽

pp. 298-309 ◽

Cited By ~ 8

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

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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 ◽

10.1182/blood-2018-99-116099 ◽

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.

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17910 Using clonality of T-cell repertoire to distinguish between drug hypersensitivity reaction and acute graft-versus-host disease

Journal of the American Academy of Dermatology ◽

10.1016/j.jaad.2020.06.435 ◽

2020 ◽

Vol 83 (6) ◽

pp. AB87

Author(s):

Li-Wei Chang ◽

Linda T. Doan ◽

Paul Fields ◽

Marissa Vignali ◽

Oleg Akilov

Keyword(s):

T Cell ◽

Hypersensitivity Reaction ◽

Graft Versus Host Disease ◽

Drug Hypersensitivity ◽

T Cell Repertoire ◽

Cell Repertoire ◽

Host Disease ◽

Graft Versus Host ◽

Drug Hypersensitivity Reaction ◽

Acute Graft

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In vivo T-cell clonal amplification at time of acute graft-versus-host disease

Blood ◽

10.1182/blood.v84.8.2815.bloodjournal8482815 ◽

1994 ◽

Vol 84 (8) ◽

pp. 2815-2820 ◽

Cited By ~ 7

Author(s):

PY Dietrich ◽

A Caignard ◽

A Lim ◽

V Chung ◽

JL Pico ◽

...

Keyword(s):

T Cell ◽

Graft Versus Host Disease ◽

Donor Blood ◽

Host Disease ◽

Graft Versus Host ◽

Junctional Region ◽

Run Off ◽

Pcr Products ◽

Acute Graft

In a series of patients transplanted with HLA-matched allogeneic bone marrow grafts (alloBMT), we previously showed that a few T-cell receptor (TCR) V alpha and V beta gene segment transcripts were overexpressed in skin compared with blood at the time of acute graft- versus-host disease (aGVHD). Here, in one selected patient with overexpressed V beta 16 and V alpha 11 transcripts in skin, we analyzed the junctional variability of these transcripts in donor blood, patient blood, and skin collected at aGVHD onset. A unique junctional region sequence accounted for 81% of in frame V beta 16 transcripts (13 of 16) in skin and 59% (13 of 22) in patient blood. Similarly, two recurrent junctional region sequences were found in skin V alpha 11 transcripts, one accounting for 66% (21 of 32) and the other for 16% (5 of 32). These recurrences were also found in patient blood (36% and 15% of V alpha 11 transcripts, respectively). To extend our analysis, a polymerase chain reaction (PCR)-based method was used to precisely determine TCR beta transcript length in run-off reactions using uncloned bulk cDNA samples. All V beta-C beta PCR products analyzed in donor blood, as well as the majority of those analyzed in patient blood, included transcripts with highly diverse junctional region sizes. As expected from the sequence data, most V beta 16-C beta PCR products in skin and patient blood were of the same size (ie, same junctional region). In addition, V beta 3, V beta 5, and V beta 17 transcripts in skin were shown to display highly restricted size variability. The clonality of the V beta 16-C beta and V beta 17-C beta transcripts was further supported by the results of run-off reactions using 13 J beta specific primers. We have identified several recurrent TCR transcripts in skin, some of them also present in patient blood. These data support the view that several T-cell subpopulations are clonally expanded in vivo at the time of aGVHD onset in this case of related HLA-matched alloBMT.

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Biology-driven developments in the therapy of acute graft-versus-host disease

Hematology ◽

10.1182/asheducation-2018.1.236 ◽

2018 ◽

Vol 2018 (1) ◽

pp. 236-241 ◽

Cited By ~ 6

Author(s):

Robert Zeiser

Keyword(s):

Graft Versus Host Disease ◽

Chemokine Receptors ◽

Kinase Inhibitors ◽

Hematopoietic Cell Transplantation ◽

T Cell Subsets ◽

Major Life ◽

Host Disease ◽

Graft Versus Host ◽

Conventional Immunosuppression ◽

Acute Graft

Abstract Allogeneic hematopoietic cell transplantation is a potentially curative treatment of different hematological malignancies. A major life-threatening complication is acute graft-versus-host disease (GVHD), in particular when the disease becomes steroid refractory. Based on the detection of pathogenic cytokines, chemokines, and T-cell subsets in individuals developing GVHD or experimental GVHD models, different therapeutic strategies have been developed. A potential cause why targeting individual receptors can lack efficacy could be that multiple cytokines, danger signals, and chemokine that have redundant functions are released during GVHD. To overcome this redundancy, novel strategies that do not target individual surface molecules like chemokine receptors, integrins, and cytokine receptors, but instead inhibit signaling pathways downstream of these molecules, have been tested in preclinical GVHD models and are currently being tested in clinical GVHD trials. Another important development is tissue regenerative approaches that promote healing of GVHD-related tissue damage as well as strategies that rely on microbiota modifications. These approaches are promising because they act very differently from conventional immunosuppression, instead aiming at reinstalling tissue homeostasis and microbiome diversity. This review discusses major novel developments in GVHD therapy that are based on a better understanding of GVHD biology, the repurposing of novel kinase inhibitors, microbiome modification strategies, and tissue-regenerative approaches.

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