Tryptophan metabolite analog, N-(3,4-dimethoxycinnamonyl) anthranilic acid, ameliorates acute graft-versus-host disease through regulating T cell proliferation and polarization

2013 ◽  
Vol 17 (3) ◽  
pp. 601-607 ◽  
Author(s):  
Jinhuan Xu ◽  
Jia Wei ◽  
Min Huang ◽  
Xianmin Zhu ◽  
Jun Guan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Anthranilic Acid ◽  
T Cell Proliferation ◽  
Host Disease ◽  
Graft Versus Host ◽  
Tryptophan Metabolite ◽  
Metabolite Analog ◽  
Acute Graft

Th17/Th22 Cells Mediate Breakthrough Graft-Versus-Host-Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1878-1878
Author(s):  
Scott N. Furlan ◽  
Victor Tkachev ◽  
Ben Watkins ◽  
Kayla Betz ◽  
Angela Panoskaltsis-Mortari ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
T Cell Proliferation ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Flow Cytometric ◽  
Th1 Cytokine

Abstract Acute graft-versus-host disease (aGVHD) develops in more than half of patients after allogeneic hematopoietic cell transplantation (allo-HCT) despite poly-pharmacy immunoprophylaxis. Importantly, the dysregulated pathways responsible for this breakthrough disease remain largely unidentified. Thus, the discovery of these pathways represents one of the critical challenges for the field of allo-HCT. To address these needs, we have developed a model of aGVHD in rhesus macaques, which allows us to study the mechanisms of aGVHD both in its untreated state and in a variety of immunoprophylactic settings. Using a systems-based approach, we have created both a multiparameter flow cytometric and transcriptomic map of the immune landscape of aGVHD in allo-HCT recipients, in comparison to two critical control groups: (1) healthy untransplanted controls, and (2) those receiving autologous transplantation. We find that recipients of allo-HCT receiving 1) no immunoprophylaxis 2) monotherapy with CTLA4Ig or 3) monotherapy with sirolimus develop early fulminant aGVHD with multi-organ disease (Figure 1a-grouped as 'Primary GVHD'). The immunophenotype of T cells from the Primary GVHD cohort exhibits an effector/memory phenotype with robust proliferation and acquisition of cytotoxic function. Transcriptomic analysis reveals enrichment of Th1-associated transcripts (IL12RB2, CCR5, CXCR3) as well as programs of proliferation early in the post transplant period (Figure 1b). Flow cytometric data confirms an increase in the number of CD4 and CD8 T cells producing the Th1 cytokine, IFN-g at this time-point (Figure 1c). In contrast, standard-of-care Tacrolimus/Methotrexate (Tac/Mtx) as well as novel CTLA4Ig/sirolimus combination immunoprophylaxis (CoBS) both significantly improved survival of animals after allo-HCT. However, similar to human patients undergoing allo-HCT, these recipients often developed clinical signs of breakthrough aGVHD (starting around day 30 post-transplant) characterized by both gastrointestinal and skin pathology. This cohort was thus termed the "Breakthrough GVHD" cohort (Figure 1a). Unexpectedly, despite the presence of breakthrough clinical aGVHD, the Tac/Mtx and CoBS cohorts were still able to control programs of T cell proliferation, effector phenotype acquisition and Th1 cytokine skewing. However, both transcriptional and flow cytometric profiles demonstrated enrichment for molecules that reflect Th17/Th22 skewing (RORC, IL17A, AHR, and IL22) (Figure 2a) and production of IL17a (Figure 2b). These results suggest that while current methods of immunoprophylaxis are able to limit both T cell proliferation and Th1 polarization, breakthrough Th17/Th22 pathway activation occurs despite these therapies. These data suggest that emphasis should be placed on exploration of pharmacologic inhibitors of IL17/IL22 for the prevention/treatment of breakthrough aGVHD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Indoleamine 2,3-dioxygenase is a critical regulator of acute graft-versus-host disease lethality

Blood ◽  
2008 ◽  
Vol 111 (6) ◽  
pp. 3257-3265 ◽  
Author(s):  
Lisa K. Jasperson ◽  
Christoph Bucher ◽  
Angela Panoskaltsis-Mortari ◽  
Patricia A. Taylor ◽  
Andrew L. Mellor ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Tissue Injury ◽  
T Cell Proliferation ◽  
Colonic Inflammation ◽  
Host Disease ◽  
Graft Versus Host ◽  
Indoleamine 2,3 Dioxygenase

AbstractGraft-versus-host disease (GVHD) is initiated after activation of donor T cells by host antigen-presenting cells (APCs). The immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) is expressed by APCs and parenchymal cells and is further inducible by inflammation. We investigated whether lethal conditioning and GVHD induce IDO and if IDO prevents tissue injury by suppressing immune responses at the induction site. We determined that IDO is a critical regulator of GVHD, most strikingly in the colon, where epithelial cells dramatically up-regulated IDO expression during GVHD. IDO−/− mice died more quickly from GVHD, displaying increased colonic inflammation and T-cell infiltration. GVHD protection was not mediated by control of T-cell proliferation, apoptosis, or effector mechanisms in lymphoid organs, nor did it require donor T regulatory cells. Instead, T cells in IDO−/− colons underwent increased proliferation and decreased apoptosis compared with their wild-type counterparts. This evidence suggests that IDO can act at the site of expression to decrease T-cell proliferation and survival, diminishing colonic inflammation and reducing disease severity. These studies are the first to identify a function for IDO in GVHD lethality and indicate that modulation of the IDO pathway may be an effective strategy for treatment of this disease.

scholarly journals Blockade of CD28 by a synthetical peptoid inhibits T-cell proliferation and attenuates graft-versus-host disease

2010 ◽  
Vol 7 (2) ◽  
pp. 133-142 ◽  
Author(s):  
Na Li ◽  
Faliang Zhu ◽  
Fei Gao ◽  
Qun Wang ◽  
Xiaoyan Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
T Cell Proliferation ◽  
Host Disease ◽  
Graft Versus Host

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

Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2815-2820 ◽  
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.

scholarly journals Systematic comparison of hUC-MSCs at various passages reveals the variations of signatures and therapeutic effect on acute graft-versus-host disease

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Qinjun Zhao ◽  
Leisheng Zhang ◽  
Yimeng Wei ◽  
Hao Yu ◽  
Linglin Zou ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Therapeutic Effect ◽  
Graft Versus Host Disease ◽  
Cytokine Secretion ◽  
Differentiation Potential ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Abstract Background Mesenchymal stem cells are heterogenous populations with hematopoietic supporting and immunomodulating capacities. Enormous studies have focused on their preclinical or clinical therapeutic effects, yet the systematic study of continuous in vitro passages on signatures and functions of UC-MSCs at both the cellular and molecular levels is still lacking. Methods In this study, to systematically evaluate the biological properties of MSCs at various passages, we analyzed biomarker expression, cell proliferation and apoptosis, chromosome karyotype, and tri-lineage differentiation potential. Subsequently, we took advantage of whole-exome sequencing to compare the somatic hypermutation of hUC-MSCs at P3, P6, and P15 including SNV and INDEL mutations. In addition, to explore the safety of the abovementioned hUC-MSCs, we performed metabolic pathway enrichment analysis and in vivo transplantation analysis. Furthermore, we cocultured the abovementioned hUC-MSCs with UCB-CD34+ HSCs to evaluate their hematopoietic supporting capacity in vitro. Finally, we transplanted the cells into acute graft-versus-host disease (aGVHD) mice to further evaluate their therapeutic effect in vivo. Results The hUC-MSCs at P3, P6, and P15 showed similar morphology, biomarker expression, and cytokine secretion. hUC-MSCs at P15 had advantages on adipogenic differentiation and some cytokine secretion such as IL-6 and VEGF, with disadvantages on cell proliferation, apoptosis, and osteogenic and chondrogenic differentiation potential. Based on the SNP data of 334,378 exons and bioinformatic analyses, we found the somatic point mutations could be divided into 96 subsets and formed 30 kinds of signatures but did not show correlation with risk of tumorigenesis, which was confirmed by the in vivo transplantation experiments. However, hUC-MSCs at P15 showed impaired hematologic supporting effect in vitro and declined therapeutic effect on aGVHD in vivo. Conclusions In this study, we systematically evaluated the biological and genetic properties of hUC-MSCs at various passages. Our findings have provided new references for safety and effectiveness assessments, which will provide overwhelming evidence for the safety of hUC-MSCs after continuous in vitro passages both at the cellular and molecular levels for the first time. Taken together, our studies could help understand the controversial effects of disease treatment and benefit the clinical research of UC-MSCs.

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

Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2815-2820 ◽  
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

Abstract 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.

scholarly journals Skin-Selective CD8 T-Cell Depletion by Photoimmunotherapy Inhibits Human Cutaneous Acute Graft-Versus-Host Disease

2020 ◽  
Vol 140 (7) ◽  
pp. 1455-1459.e6
Author(s):  
Lukas Freund ◽  
Stephanie Oehrl ◽  
Galina Gräbe ◽  
Patrick Gholam ◽  
Thomas Plum ◽  
...  
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
Cd8 T Cell ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Interleukin-1 blockade does not prevent acute graft-versus-host disease: results of a randomized, double-blind, placebo-controlled trial of interleukin-1 receptor antagonist in allogeneic bone marrow transplantation

Blood ◽  
2002 ◽  
Vol 100 (10) ◽  
pp. 3479-3482 ◽  
Author(s):  
Joseph H. Antin ◽  
Daniel Weisdorf ◽  
Donna Neuberg ◽  
Roberta Nicklow ◽  
Shawn Clouthier ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Receptor Antagonist ◽  
Graft Versus Host Disease ◽  
Interleukin 1 ◽  
Double Blind ◽  
Host Disease ◽  
Double Blind Placebo ◽  
Graft Versus Host ◽  
Acute Graft

Acute graft-versus-host disease (GVHD) is thought to derive from direct T-cell injury of target tissues through perforin/granzyme, Fas/FasL interactions, and the effects of inflammatory cytokines. Animal models and some clinical trials support the notion that inhibition of inflammatory mediators such as interleukin-1 (IL-1), tumor necrosis factor α, and interferon γ may ameliorate or prevent GVHD. We hypothesized that blockade of IL-1 during the period of initial T-cell activation would reduce the risk of severe GVHD. We tested this hypothesis in a double-blind, placebo-controlled randomized trial of recombinant human IL-1 receptor antagonist (IL-1Ra) in 186 patients undergoing allogeneic stem cell transplantation. Randomization was stratified by degree of histocompatibility and stem cell source. All patients were conditioned with cyclophosphamide and total body irradiation. GVHD prevention consisted of cyclosporine and methotrexate in all patients. Recombinant human IL-1Ra or saline placebo was given from day −4 to day +10. Randomization was stratified according to GVHD risk. The 2 groups were well-matched for pretreatment characteristics. Moderate to severe GVHD (grades B-D) developed in 57 (61%) of 94 patients receiving IL-1Ra and in 51 (59%) of 86 patients on placebo (P = .88). There was no difference in hematologic recovery, transplantation-related toxicity, event-free survival, or overall survival. We conclude that blockade of IL-1 using IL-1Ra during conditioning and 10 days immediately after transplantation is not sufficient to reduce GVHD or toxicity or to improve survival.

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