scholarly journals Impaired interferon-γ production as a consequence of STAT4 deficiency after autologous hematopoietic stem cell transplantation for lymphoma

Blood ◽  
2005 ◽  
Vol 106 (3) ◽  
pp. 963-970 ◽  
Author(s):  
Michael J. Robertson ◽  
Hua-Chen Chang ◽  
David Pelloso ◽  
Mark H. Kaplan
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Tyrosine Phosphorylation ◽  
Cell Transplantation ◽  
Cd4 T Cells ◽  
Interferon Γ ◽  
Hematopoietic Stem ◽  
Patient Pbmcs ◽  
Ifn Γ

AbstractProduction of interferon γ (IFN-γ) is critical for optimal antitumor immunotherapy in several preclinical animal models. Interleukin-12 (IL-12)–induced IFN-γ production is markedly defective after autologous stem cell transplantation. Quantitative deficiency in CD4 T cells, relative increase in CD25+CD4+ T cells, and bias toward T helper 2 (Th2) differentiation are not the primary mechanisms of defective IFN-γ production. IL-12 receptor β1 (IL-12Rβ1) and IL-12Rβ2 are expressed at equivalent or higher levels on posttransplantation patient peripheral blood mononuclear cells (PBMCs) as compared with control PBMCs. IL-12–induced tyrosine phosphorylation of signal transducer and activator of transcription 4 (STAT4) was undetectable or barely detectable in posttransplantation patient PBMCs, whereas IL-4–induced tyrosine phosphorylation of STAT6 did not differ in posttransplantation patient and control PBMCs. Levels of STAT4 protein were decreased by 97% in posttransplantation patient PBMCs. Levels of STAT4 mRNA were also significantly decreased in posttransplantation patient PBMCs. Incubation with IL-12 and IL-18 in combination partially reversed the defective IFN-γ production by posttransplantation patient PBMCs. IFN-γ production in response to IL-12 plus IL-18 did not require increased expression of STAT4 but was dependent on the activity of p38 mitogen-activated protein kinase (MAPK). These results indicate that defective IFN-γ production is due to an intrinsic deficiency in STAT4 expression by posttransplantation patient lymphocytes and suggest strategies for circumventing this deficiency in cancer immunotherapy.

Increased Functional T Cell Defects in Patients with low CD4 Counts after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4588-4588
Author(s):  
Udo Holtick ◽  
Lukas P. Frenzel ◽  
Shimabukuro-Vornhagen Alexander ◽  
Sebastian Theurich ◽  
Julia Claasen ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Hematopoietic Stem ◽  
Cd4 Counts ◽  
Graft Vs Host Disease

Background The recovery of the host immune system after allogeneic hematopoietic stem cell transplantation is pivotal to prevent infections, relapse and secondary malignancies. In particular, numerical CD4 T-cell reconstitution is delayed and CD4-helper cell function considered impaired as consequence of the transplant procedure and concommitant immunosuppressive medication. From HIV/AIDS patients it is known that numerical and functional CD4 defects increase the risk of opportunistic infections. Therefore, even in the absence of immunosuppressants and graft-vs-host disease, anti-infective prophylaxis is usually given for at least six months. We hypothesized that the numerical CD4 defect in patients may be reflected by immunosuppressive RNA fingerprints previously established for certain immuno-inhibitory molecules and tested whether the functional CD4 capacity was different according to the CD4 cell number. Methods RNA was separated from CD4 T-cells of 10 patients with CD4 counts >500/µl, 10 patients with CD4 counts <200/µl and four healthy controls. All patients had to be off immunosuppression and without any clinical signs of graft-vs-host disease. Transcriptional activity was assessed with regard to previously defined fingerprints motives for CTLA-4, IL-10, PD-1, TGF-β and PGE-2. CD4 T-cells from all groups were further tested for their proliferative capacity and cytokine production. Results Hierarchical clustering segregated the three groups. Applying the immunosuppressive fingerprints, patients with CD4 T-cells >500/µl were demonstrated to be under the influence of PGE2, whereas patients with CD4 T-cells <200/µl were demonstrated to be under the influence of PGE2 and CTLA-4. In normal controls, no association was found. The proliferative capacity of patient CD4 T-cells upon CD3-CD28-bead stimulation was not significantly different from healthy controls. The production of IL-2 by stimulated CD4 T-cells was significantly downregulated in patients with CD4 T-cells <200/µl, while there was no difference in IFN-ƴ and TNF-α secretion. Conclusion The severity of the CD4 numerical defect reflects the state of immunosuppression as demonstrated by RNA immuno-inhibitory fingerprint motives. This partially translates into functional differences as measured by decreased IL-2 secretion. In addition to time after transplant, CD4 T-cell numbers should be considered for the decision to stop or maintain anti-microbial prophylaxis in patients after allogeneic stem cell transplantation. (UH, LPF and CW, JMC contributed equally to this work.) Disclosures: No relevant conflicts of interest to declare.

scholarly journals Differential rates of replacement of human dermal dendritic cells and macrophages during hematopoietic stem cell transplantation

2009 ◽  
Vol 206 (2) ◽  
pp. 371-385 ◽  
Author(s):  
Muzlifah Haniffa ◽  
Florent Ginhoux ◽  
Xiao-Nong Wang ◽  
Venetia Bigley ◽  
Michal Abel ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Cd4 T Cells ◽  
Critical Role ◽  
Hematopoietic Stem ◽  
Memory Cd4 T Cells

Animal models of hematopoietic stem cell transplantation have been used to analyze the turnover of bone marrow–derived cells and to demonstrate the critical role of recipient antigen-presenting cells (APC) in graft versus host disease (GVHD). In humans, the phenotype and lineage relationships of myeloid-derived tissue APC remain incompletely understood. It has also been proposed that the risk of acute GVHD, which extends over many months, is related to the protracted survival of certain recipient APC. Human dermis contains three principal subsets of CD45+HLA-DR+ cells: CD1a+CD14− DC, CD1a−CD14+ DC, and CD1a−CD14+FXIIIa+ macrophages. In vitro, each subset has characteristic properties. After transplantation, both CD1a+ and CD14+ DC are rapidly depleted and replaced by donor cells, but recipient macrophages can be found in GVHD lesions and may persist for many months. Macrophages isolated from normal dermis secrete proinflammatory cytokines. Although they stimulate little proliferation of naive or memory CD4+ T cells, macrophages induce cytokine expression in memory CD4+ T cells and activation and proliferation of CD8+ T cells. These observations suggest that dermal macrophages and DC are from distinct lineages and that persistent recipient macrophages, although unlikely to initiate alloreactivity, may contribute to GVHD by sustaining the responses of previously activated T cells.

scholarly journals Phosphorylated ERK1/2 in CD4 T cells is associated with acute GVHD in allogeneic hematopoietic stem cell transplantation

2020 ◽  
Vol 4 (4) ◽  
pp. 667-671
Author(s):  
Hidekazu Itamura ◽  
Takero Shindo ◽  
Satoshi Yoshioka ◽  
Takayuki Ishikawa ◽  
Shinya Kimura
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Acute Gvhd ◽  
Hematopoietic Stem

Abstract To diagnose graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is sometimes difficult. We showed previously that MEK inhibitors selectively suppress murine GVHD while retaining antiviral and antitumor immunity. Here, we asked whether the RAS/MEK/ERK pathway is activated in human allo-HSCT recipients with GVHD, and whether the phosphorylated ERK1/2 can be a biomarker of GVHD. Peripheral blood was sequentially collected from 20 allo-HSCT recipients: 1 bone marrow transplant, 7 peripheral blood stem cell transplants (PBSCT), and 12 cord blood transplants. Ten of the 20 allo-HSCT recipients developed GVHD, and phosphorylation of ERK1/2 in T and B cells was analyzed by flow cytometry. Occurrence of acute GVHD was associated with phosphorylation of ERK1/2 in CD4+ T cells at day 30 (P &lt; .001), which was suppressed by ex vivo exposure to a MEK inhibitor trametinib at clinically achievable concentrations. In particular, ERK1/2 was phosphorylated preferentially in naive/central memory CD4+ T cells. Notably, phosphorylation of ERK1/2 fell as GVHD improved. These results suggest that phosphorylation status of ERK1/2 in peripheral blood CD4+ T cells may be a future biomarker for diagnosing human GVHD, and the potential efficacy of MEK inhibitors against human GVHD.

scholarly journals Levels of CMV Specific CD4 T Cells Are Dynamic and Correlate with CMV Viremia after Allogeneic Stem Cell Transplantation

PLoS ONE ◽  
2008 ◽  
Vol 3 (11) ◽  
pp. e3634 ◽  
Author(s):  
Thomas Widmann ◽  
Urban Sester ◽  
Barbara C. Gärtner ◽  
Jörg Schubert ◽  
Michael Pfreundschuh ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Cd4 T Cells

scholarly journals Mouse Models of Antigen Presentation in Hematopoietic Stem Cell Transplantation

2021 ◽  
Vol 12 ◽  
Author(s):  
Motoko Koyama ◽  
Geoffrey R. Hill
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Mouse Models ◽  
Major Complication ◽  
Hematopoietic Stem ◽  
Curative Therapy ◽  
Donor T Cells ◽  
Immune Pathology

Allogeneic stem cell transplantation (alloSCT) is a curative therapy for hematopoietic malignancies. The therapeutic effect relies on donor T cells and NK cells to recognize and eliminate malignant cells, known as the graft-versus-leukemia (GVL) effect. However, off target immune pathology, known as graft-versus-host disease (GVHD) remains a major complication of alloSCT that limits the broad application of this therapy. The presentation of recipient-origin alloantigen to donor T cells is the primary process initiating GVHD and GVL. Therefore, the understanding of spatial and temporal characteristics of alloantigen presentation is pivotal to attempts to separate beneficial GVL effects from detrimental GVHD. In this review, we discuss mouse models and the tools therein, that permit the quantification of alloantigen presentation after alloSCT.

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