apyrase and Graft-vs-Host-Disease

Allogeneic hematopoietic cell transplantation (allo-HCT) represents the only curative treatment approach for many patients with benign or malignant diseases of the hematopoietic system. However, post-transplant morbidity and mortality are significantly increased by the development of acute graft-versus-host disease (GvHD). While alloreactive T cells act as the main cellular mediator of the GvH reaction, recent evidence suggests a critical role of the innate immune system in the early stages of GvHD initiation. Danger-associated molecular patterns released from the intracellular space as well as from the extracellular matrix activate antigen-presenting cells and set pro-inflammatory pathways in motion. This review gives an overview about danger signals representing therapeutic targets with a clinical perspective with a particular focus on extracellular nucleotides and ectonucleotidases.

Topics: Acute Disease; Animals; Antigens, CD; Apyrase; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunity, Innate; Pyrophosphatases; Receptors, Pattern Recognition; T-Lymphocytes; Transplantation, Homologous

Chikungunya is an important mosquito-borne disease caused by the arthritogenic chikungunya virus, characterized by sporadic outbreaks all around the world. Although CD4+ T cells seem to have an important role in the pathogenesis of chikungunya, the mechanisms involved in this process are not yet fully elucidated. The ectoenzymes CD39 and CD73, also expressed by CD4 T lymphocytes, are involved in the hydrolysis of pro-inflammatory extracellular ATP and generation of immunosuppressive adenosine and seem to be modulated in some arthritogenic pathologies. However, their involvement in Chikungunya disease is unclear. Thus, using flow cytometry, we investigated peripheral CD4+ T cells from patients with acute and chronic chikungunya to assess the expression of ectonucleotidases CD39 and CD73 and coinhibitory receptors and production of cytokine and cytolytic granules. Patients in the acute phase displayed increased levels of PD-1, CTLA-4, IL-10, and IFN-γ compared to healthy individuals and patients in the chronic phase. Moreover, during chronic Chikungunya, analyses of Mean Fluorescent Intensity (MFI) demonstrated a reduced density of LAP, Perforin and Granzyme B compared to the healthy control. Finally, reduced levels of the ectoenzymes CD39 and CD73 expression was found during the chronic phase suggesting a possible modulation of extracellular ATP and adenosine by CD4+ T cells that may be involved in the persistence of arthritogenic symptoms.

Topics: Adenosine; Adenosine Triphosphate; Animals; Apyrase; CD4-Positive T-Lymphocytes; Chikungunya Fever; Down-Regulation; Graft vs Host Disease; Humans

Regulatory T cells (Tregs) protect against graft-versus-host disease (GVHD), a life-threatening complication of allogeneic hematopoietic stem cell transplantation. The ectoenzyme CD39 is important for increasing the immunosuppressive function of Tregs. The rs10748643 (A → G) single-nucleotide polymorphism (SNP) in intron 1 of the human ENTPD1 gene is associated with increased proportions of CD39

Topics: Animals; Apyrase; Australia; Graft vs Host Disease; Humans; Leukocytes, Mononuclear; Mice; Mice, Inbred NOD; Mice, SCID; Polymorphism, Single Nucleotide; T-Lymphocytes, Regulatory

Many patients with systemic lupus erythematosus (SLE) have lupus nephritis, one of the severe complications of SLE. We previously reported that CD8+CD103+ T regulatory cells induced ex vivo with transforming growth factor β (TGF-β) (iTregs) inhibited immune cells responses to ameliorate excessive autoimmune inflammation. However, the molecular mechanism(s) underlying the role of these CD8+ iTregs is still unclear. Here we identified that CD39, which is highly expressed on CD8+ iTregs, crucially contributes to the immunosuppressive role of the CD8+CD103+ iTregs. We showed that adoptive transfer of CD8+CD103+ iTregs significantly relieves the chronic graft-versus-host disease with lupus nephritis and CD39 inhibitor mostly abolished the functional activities of these CD8+ iTregs in vitro and in vivo. CD39+ cells sorted from CD8+CD103+ iTregs were more effective in treating lupus nephritis than CD39- partner cells in vivo. Furthermore, human CD8+ iTregs displayed increased CD103 and CD39 expressions, and CD39 was involved in the suppressive function of human CD8+ iTregs. Thus, our data implicated a crucial role of CD39 in CD8+CD103+ iTregs in treating lupus nephritis, and CD39 could be a new phenotypic biomarker for the identification of highly qualified CD8+ Tregs. This subpopulation may have therapeutic potential in patients with SLE nephritis and other autoimmune diseases.

Topics: Antigens, CD; Apyrase; CD8-Positive T-Lymphocytes; Cell Differentiation; Cell Proliferation; Chronic Disease; Graft vs Host Disease; Humans; Immune Tolerance; Immunomodulation; Integrin alpha Chains; Lupus Nephritis; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Human gingival tissue-derived mesenchymal stem cells (GMSCs) present an accessible source of mesenchymal stem cells (MSCs) for treating autoimmune diseases. Here we show that human GMSCs can prevent and treat acute graft-versus-host disease (GVHD) in two different mouse models. Our results indicate that besides exhibiting suppressive function in vitro and in vivo, GMSCs may also regulate the conversion of Tregs to Th1 and/or Th17-like cells, as well as stabilize Foxp3 expression. Furthermore, GMSC-mediated prevention of acute GVHD was dependent on CD39 signaling that play an important role in the function and stability of Tregs. Finally, we also observed stronger protective ability of GMSCs with greater expansion ability compared with BMSCs or ASCs. These results indicate that human GMSCs have the potential to be used to treat GVHD.

Topics: Adoptive Transfer; Animals; Antigens, CD; Apyrase; Cells, Cultured; Cytokines; Disease Models, Animal; Forkhead Transcription Factors; Gene Knock-In Techniques; Gingiva; Graft vs Host Disease; Humans; Mesenchymal Stem Cell Transplantation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Severity of Illness Index; T-Lymphocytes, Regulatory; Th1 Cells; Th17 Cells

Autoimmune diseases are characterized by an imbalance between regulatory T cells and effector T-cell subsets, such as Th1 and Th17 cells. Studies have confirmed that natural CD4

Topics: Animals; Antigens, CD; Apyrase; Autoimmunity; Cells, Cultured; DNA Methylation; Forkhead Transcription Factors; Graft vs Host Disease; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Mice; Mice, SCID; STAT1 Transcription Factor; STAT3 Transcription Factor; Stem Cell Transplantation; T-Lymphocytes, Regulatory; Th1 Cells; Th17 Cells; Transplantation, Heterologous

Topics: Animals; Antigens, CD; Apyrase; Graft vs Host Disease; Humans; Immune Tolerance; Mice; Receptor, Notch1; T-Lymphocytes; T-Lymphocytes, Regulatory

CD4(+)CD25(+)FoxP3(+) regulatory T (Treg) cells which consist of naturally occurring Treg (nTreg) and induced Treg (iTreg) cells are associated with the maintenance of immune homeostasis. Previous studies were focused on their potential to ameliorate graft-versus-host disease (GVHD) in human and mice. CD39 is a surface marker both expressed on CD4(+)CD25(-) T cells and Treg cells. CD39(+) Treg cells demonstrate stronger suppressive ability compared to conventional Treg cells. However, whether the potential of CD39(+) naïve T cells induced Treg cells is different from conventional naïve T cells induced Treg cells in vivo and vitro remains to be inconclusive. Here we demonstrate that CD39(+) iTreg cells show enhanced proliferation and suppressive ability as well as lower inflammatory cytokines compared to CD39(-) iTreg cells. To conclude, our findings demonstrate that CD39(+) iTreg cells acquire high suppressive capacity in vitro and vivo, and this may provide a new insight into Treg cell therapy in GVHD clinical trials.

Topics: Animals; Antigens, CD; Apoptosis; Apyrase; Cell Proliferation; Cytokines; Graft vs Host Disease; Humans; Mice; T-Lymphocytes, Regulatory

Activation and migration of regulatory T cells (Treg) into tissue is critical in control of inflammation, but has not been examined extensively in chronic graft versus host disease (cGVHD). In parallel studies of tissues and blood, we determined that FoxP3(+) T cells increased in proportion to T effectors (Teff) in tissue infiltrates in oral and cutaneous lichenoid cGVHD. These FoxP3(+) cells expressed distinguishing phenotypic and functional markers of Treg (CD3(+), CD4(+), CD27(+), ICOS(+) and CD39(+)), not found on FoxP3(-) Teff. Both Teff and FoxP3(+) Treg expressed T-bet and the chemokine receptor CXCR3, however, consistent with a common mechanism of chemokine-mediated migration into tissue. Furthermore, functional markers (ICOS and CD39) and chemokine receptors (CXCR3) were both present in a higher proportion of FoxP3(+) cells in tissues than in peripheral blood, consistent with recruitment and activation of Treg in cGVHD target tissues. Finally, the 'activated' CD45RA(-)FoxP3(hi) subset of Treg cells, which highly express functional markers, were found in comparable frequencies in cGVHD patients and normal controls, despite a significant deficit in naive 'resting' Treg. These findings are consistent with Treg capacity to upregulate functional markers and traffick into tissue in cGVHD.

Topics: Adolescent; Adult; Aged; Antigens, CD; Apyrase; CD3 Complex; CD4 Antigens; Female; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Inducible T-Cell Co-Stimulator Protein; Male; Middle Aged; Phenotype; Receptors, CXCR3; T-Lymphocytes, Regulatory; Tumor Necrosis Factor Receptor Superfamily, Member 7; Young Adult

During extracorporeal photophoresis (ECP), peripheral blood mononuclear cells are treated with DNA-intercalating agents and irradiated with ultraviolet light. This procedure exerts immunosuppressive effects, most likely mediated by regulatory T cells (Treg). However, the underlying mechanisms are not clear yet. In our study, we investigated the effect of ECP on frequency and function of Treg in the peripheral blood of patients suffering from graft-versus-host disease.. Whole blood samples from graft-versus-host disease patients were taken before and after the ECP treatment on 2 consecutive days. Phenotypical analysis of changes in distinct leukocyte subsets within the peripheral blood of patients and healthy controls was performed by means of flow cytometry. Functional analysis of the Treg population after magnetic bead isolation was performed using conventional suppression assays, and adenosine was detected by means of high pressure liquid chromatography and Lanzetta assays.. We show that the frequency of CD4/CD25/FoxP3 Treg in the peripheral blood increases after each cycle of ECP and also in the course of treatment. The suppressive capacity of Treg after ECP was increased compared with that of Treg before ECP, although not reaching the suppression levels obtained with Treg from healthy controls. Furthermore, we show that ECP stimulates the CD39-mediated production of adenosine by Treg, which substantially reduces the T-cell proliferation in in vitro suppression assays.. Our data indicate that ECP stimulates the conversion of ATP to adenosine by the ectonucleotiodase CD39, which acts as a novel soluble immunosuppressive reagent mediating immunosuppression of Treg.

Topics: Adenosine; Antigens, CD; Apyrase; Case-Control Studies; CD8-Positive T-Lymphocytes; Cell Proliferation; Cells, Cultured; Female; Forkhead Transcription Factors; Graft vs Host Disease; Humans; Immunophenotyping; Immunosuppression Therapy; Interleukin-2 Receptor alpha Subunit; Lipopolysaccharide Receptors; Lymphocyte Activation; Male; Photopheresis; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Time Factors