Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease

Key Points Ecto+ ILC neutralize extracellular ATP and suppress autologous T cells via the production of adenosine. Human acute GVHD is associated with a depletion of tissue ecto+ ILC3 and a reduction in serum adenosine levels.

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Blockade of TIM-1 on the donor graft ameliorates graft-versus-host disease following hematopoietic cell transplantation

Blood Advances ◽

10.1182/bloodadvances.2019000286 ◽

2019 ◽

Vol 3 (21) ◽

pp. 3419-3431

Author(s):

Bettina P. Iliopoulou ◽

Katie Hsu ◽

Magdiel Pérez-Cruz ◽

Sai-Wen Tang ◽

Wendy W. Pang ◽

...

Keyword(s):

T Cells ◽

Cell Transplantation ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Host Disease ◽

Graft Versus Host ◽

Key Points ◽

Donor Graft

Key Points Administration of anti–TIM-1 blocking mAb ameliorates acute GVHD while preserving graft-versus-tumor effects. Treatment with anti–TIM-1 blocking mAb does not affect proliferation of donor allogeneic T cells.

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Donor-derived CMV-specific T cells reduce the requirement for CMV-directed pharmacotherapy after allogeneic stem cell transplantation

Blood ◽

10.1182/blood-2012-08-448977 ◽

2013 ◽

Vol 121 (18) ◽

pp. 3745-3758 ◽

Cited By ~ 136

Author(s):

Emily Blyth ◽

Leighton Clancy ◽

Renee Simms ◽

Chun K. K. Ma ◽

Jane Burgess ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Graft Versus Host Disease ◽

Allogeneic Stem Cell Transplantation ◽

Organ Damage ◽

Host Disease ◽

Graft Versus Host ◽

Key Points

Key Points Infusion of CMV-specific T cells early posttransplant does not increase acute or chronic graft-versus-host disease. CMV-specific T cells early posttransplant reduce the need for pharmacotherapy without increased rates of CMV-related organ damage.

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Hsp90 inhibition destabilizes Ezh2 protein in alloreactive T cells and reduces graft-versus-host disease in mice

Blood ◽

10.1182/blood-2016-08-735886 ◽

2017 ◽

Vol 129 (20) ◽

pp. 2737-2748 ◽

Cited By ~ 17

Author(s):

Qingrong Huang ◽

Shan He ◽

Yuanyuan Tian ◽

Yuting Gu ◽

Pan Chen ◽

...

Keyword(s):

T Cells ◽

Protein Stability ◽

Graft Versus Host Disease ◽

Hsp90 Inhibition ◽

Host Disease ◽

Graft Versus Host ◽

Alloreactive T Cells ◽

Graft Versus Leukemia ◽

Key Points ◽

And Function

Key Points Ezh2 requires Hsp90 to maintain Ezh2 protein stability and function in alloreactive T cells. Pharmacological inhibition of Hsp90 destabilizes Ezh2 protein in alloreactive T cells and reduces GVHD but preserves graft-versus-leukemia effects.

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IL-6 dysregulation originates in dendritic cells and mediates graft-versus-host disease via classical signaling

Blood ◽

10.1182/blood.2019000396 ◽

2019 ◽

Vol 134 (23) ◽

pp. 2092-2106 ◽

Cited By ~ 4

Author(s):

Andrew N. Wilkinson ◽

Karshing Chang ◽

Rachel D. Kuns ◽

Andrea S. Henden ◽

Simone A. Minnie ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Graft Versus Host Disease ◽

Host Disease ◽

Graft Versus Host ◽

Key Points ◽

Donor T Cells ◽

Principal Source

Key Points DCs are the principal source of IL-6 dysregulation after alloSCT. IL-6–dependent GVHD is driven by classical signaling of IL-6R on donor T cells but is regulated by trans signaling.

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

Blood ◽

10.1182/blood.2020004871 ◽

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.

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

Blood ◽

10.1182/blood.v104.11.426.426 ◽

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

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

Blood ◽

10.1182/blood.v108.11.5167.5167 ◽

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.

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Recipient CD4+ T cells that survive irradiation regulate chronic graft-versus-host disease

Blood ◽

10.1182/blood-2004-01-0328 ◽

2004 ◽

Vol 104 (5) ◽

pp. 1565-1573 ◽

Cited By ~ 148

Author(s):

Britt E. Anderson ◽

Jennifer M. McNiff ◽

Catherine Matte ◽

Ionna Athanasiadis ◽

Warren D. Shlomchik ◽

...

Keyword(s):

T Cells ◽

Graft Versus Host Disease ◽

Cd4 T Cells ◽

Acute Gvhd ◽

Cell Receptor ◽

Host Disease ◽

Graft Versus Host ◽

Pathologic Features ◽

Radiation Resistant ◽

Tcr Diversity

Abstract Chronic graft-versus-host disease (cGVHD) is an increasingly common cause of morbidity and mortality in allogeneic stem cell transplantation (alloSCT). Relative to acute GVHD (aGVHD), much less is understood about cGVHD. Using the B10.D2 → BALB/c murine cGVHD model, which shares critical pathologic features with human cGVHD, we find that radiation-resistant host T cells regulate cGVHD. We initially observed that recipients lacking all lymphocytes developed accelerated and more severe cGVHD. Using genetically deficient recipients, we determined that αβ+CD4+ T cells were required to regulate cGVHD. Increased cGVHD severity was not due to the absence of T cells per se. Rather, the potency of regulation was proportional to host T-cell receptor (TCR) diversity. Only CD4+CD25+, and not CD4+CD25-, host T cells ameliorated cGVHD when added back, indicating that host T cells acted not via host-versus-graft activity or by reducing homeostatic proliferation but by an undefined regulatory mechanism. Thus, preparative regimens that spare host CD4+CD25+ T cells may reduce cGVHD. Donor CD4+CD25+ T cells also reduced cGVHD. Depletion of CD4+CD25+ cells from the inoculum exacerbated disease, whereas transplantation of additional CD4+CD25+ cells protected against severe cGVHD. Additional CD4+CD25+ cells also promoted healing of established lesions, suggesting that their effects persist during the evolution of cGVHD.

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Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease

Blood ◽

10.1182/blood-2007-05-091074 ◽

2007 ◽

Vol 110 (10) ◽

pp. 3804-3813 ◽

Cited By ~ 160

Author(s):

Xiao Chen ◽

Sanja Vodanovic-Jankovic ◽

Bryon Johnson ◽

Melissa Keller ◽

Richard Komorowski ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Graft Versus Host Disease ◽

Th17 Cells ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Allogeneic Bone Marrow Transplantation ◽

Allogeneic Bone ◽

Host Disease ◽

Graft Versus Host

Abstract Graft-versus-host disease (GVHD) remains the major complication after allogeneic bone marrow transplantation (BMT). The process whereby acute GVHD mediated by alloreactive donor T cells transitions into chronic GVHD, which is characterized by prominent features of auto-immunity, has long been unresolved. In this study, we demonstrate that GVHD-associated autoimmunity and, by extension, chronic GVHD is attributable to the progressive loss of CD4+CD25+Foxp3+ regulatory T cells during the course of acute GVHD. This leads to the expansion of donor-derived CD4+ T cells with TH1 and TH17 cytokine phenotypes that release proinflammatory cytokines and cause autoimmune-mediated pathological damage. These T cells are present early after transplantation, indicating that the pathophysiological events that lead to chronic GVHD are set in motion during the acute phase of GVHD. We conclude that the absence of CD4+CD25+ regulatory T cells coupled with unregulated TH1 and TH17 cells leads to the development of autoimmunity and that donor-derived TH1 and TH17 cells serve as the nexus between acute and chronic GVHD.

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