bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myeloid-derived suppressor cells mobilized by G-CSF in allografts correlate with low risk of acute graft-versus host disease in patients undergoing unmanipulated allogeneic blood and marrow transplantation (126.18)
Authors: Lv Meng , Zhao Xiang-yu , Wang Ya-zhe , Liu Yan-rong , Xu Lan-ping , Liu Dai-hong , Liu Kai-yan , Huang Xiao-jun 
Published: January 2023

Abstract
Introduction:The aim of this study was to investigate the association of donor myeloid-derived suppressor cells (MDSCs) in allografts with acute graft-versus host disease(aGVHD) in patients who had undergone granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood progenitor cell (G-PBPC) and G-CSF-primed bone marrow (G-BM) transplantation. Methods: Unmanipulated allografts from 71 patients were prospectively analyzed for MDSCs with respect to aGVHD, in which 23 patients got HLA-matched donors and 48 patients had haploidentical donors. Results: Median numbers (range) of monocytic/ granulocytic/ promyelocytic MDSCs were:3.43(0.31-10.65)×106/kg, 8.23(0.85-16.2 )×106/kg , 1.11(0.51-3.53)×107/kg ,respectively in G-BM and these of monocytic/ granulocytic MDSCs were:1.64(0.28-4.3)×107/kg , 1.96(0.62-6.2)×107/kg , respectively in G-PBPC. The incidence of grades II-IV aGVHD was 29.6%, and there was no difference between the HLA-matched and haploidentical transplantation group. Patients who received a higher dose of promyelocytic MDSCs(&gt;0.82×107/kg, p&lt;0.001) in G-BM or a higher total dose of monocytic MDSCs in G-BM and G-PBPC (&gt;1.23×107/kg, p&lt;0.001) exhibited a lower incidence of grades II-IV aGVHD. Conclusion: Our results suggest that a high number of MDSCs infused were associated with decreased risk of aGVHD in allogeneic blood and marrow transplantation, which may reflect the immune suppressive function of MDSCs in allogeneic transplantation.
Calcineurin inhibitor (CNI) use in pediatric liver and kidney transplant (Tx) patients is associated with increased risk of obesity and impaired T-regulatory (Treg) cell function. (126.19)
Authors: Akimova Tatiana , Kamath Binita , Goebel Jens , Meyers Kevin , Rand Elizabeth , Hawkins Andre , Bucuvalas John , Hancock Wayne 
Published: January 2023

Abstract
CNI use can cause hyperlipidemia and new onset diabetes, and obesity may have adverse effects on allograft and patient survival, but the mechanisms are unclear. Design: We assessed if CNI or rapamycin (Rapa) use correlated with the metabolic status of children (n = 62) with stable, long-term liver (26 M, 27 F) or kidney (6 M, 3 F) allografts, and if being overweight or obese (Ow/Ob) was associated with impaired Treg phenotype or function. Results: Most patients had CNI (39) or Rapa (9) monotherapy, though 12 received CNI (8) or Rapa (4) plus MMF, Aza or steroids. 45 children had normal weight, but 7 were overweight and 10 were obese. The CNI group had more Ow/Ob patients (p=0.045) and higher BMI-for age percentile (BMI) than the Rapa group (61.7 vs. 42.9, p=0.047). CNI dose correlated with BMI (0.521, p=0.013), while Rapa use negatively correlated with BMI (-0.888, p=0.044). Also, Ow/Ob patients had reduced Treg suppressive function compared to patients with normal weight (153 vs. 100 units for autologous CD4 responders, 166 vs. 92 for standard CD4 responders, 114 vs. 43 for CD8 responders, p=0.031), and BMI was negatively correlated with CTLA-4 expression in Tregs (-0.555, p=0.011). Conclusions: CNI use is associated with being overweight or obese post-Tx, and the latter are associated with impaired Treg function and phenotype. The metabolic consequences of being overweight or obese post-Tx may include disruption of immune regulation and favor a pro-inflammatory phenotype.
Implication of CD4+ NKG2D+ T cells in the outcome of graft after kidney transplantation. (126.20)
Authors: López-Larrea Carlos , Schlangen Karin , Fernandez-Sanchez Alba , Carbajal Palo Reyes , Garcia-Melendreras Susana , Gómez-Huertas Ernesto , Ortega-Suarez Francisco , Aransay Bañares Ana , Suarez-Alvarez Beatriz 
Published: January 2023

Abstract
The activating receptor NKG2D is mainly expressed on γδ T, αβ CD8+ T, NKT and NK cells but an unusual NKG2D+ CD4+ T subset has been detected in certain pathologies. In this work, we analyzed the presence of CD4+ NKG2D+ T cells in peripheral blood samples from kidney transplanted patients and healthy donors by flow cytometry. Furthermore, whole genome microarray expression studies (Human HT-12 v3, Illumina) and TCR Vβ repertory (TCR Landscape technology) were performed in order to determinate its phenotypic and functional characteristics. We showed that 41% of the patients have a subset of CD4+ NKG2D+ T lymphocytes, which maintains stable during time. These cells presented a phenotype of memory cells with downregulation of costimulatory molecules and an increased expression of cytotoxic markers specific of NK cells. Several pathways associated with immune response, apoptosis, inflammatory response and cellular catabolic process were significant affected. CD4+ NKG2D+ T cells showed resistance to apoptosis and restricted TCR repertoire with oligoclonal expansion of one or two Vβ families, suggesting a limited capacity to respond to different antigens. In short, presence of this subset in kidney transplanted patients could be favorable for the graft acceptance but compromise the immune response against diverse antigens. It could be used as a biomarker to determine the outcome of the allograft and predict the immune response in these patients.
Graft versus host disease impairs vaccine responses via decreased CD4+ and CD8+ T cell proliferation and increased CD8+ T cell apoptosis through the perforin pathway (126.27)
Authors: Nasholm Nicole , Duncan Brynn , Capitini Christian , Fry Terry 
Published: January 2023

Abstract
Graft versus leukemia (GVL) responses contribute to the curative potential of allogeneic blood or marrow transplantation (alloBMT) but can be associated with graft versus host disease (GVHD). Tumor-targeted vaccines have the potential to enhance the potency and specificity of GVL, but we have shown that GVHD can limit responses. Using a minor histocompatibility-mismatched BMT (B6 -&gt;C3H.SW) with donor lymphocyte infusions (DLI), we examined the mechanism of reduced vaccine responses. The proliferative capacity, persistence and survival of vaccine-responding T cells were monitored following adoptive transfer of HY-specific T cells and HY-expressing dendritic cells in mice with GVHD. Both CD4+ and CD8+ HY specific T cells undergo less vaccine-driven proliferation in recipients with GVHD. Furthermore, HY-specific CD8+ T cells demonstrated increased apoptosis, whereas HY-specific CD4+ T cells did not. To determine a mechanism of apoptosis, we used a Fas Ligand-, TRAIL-, or perforin-deficient DLI to induce GVHD. Fas ligand- and TRAIL-deficient DLI did not affect apoptosis of the CD8+ HY-specific T cell population. However, a perforin-deficient DLI resulted in significantly less apoptosis. Finally, perforin-deficient DLI allowed for enhanced HY-expressing tumor protection. Thus, diminished vaccine responses seen during GVHD result from reduced proliferation and perforin-mediated CD8+ T cell apoptosis, factors to be considered when optimizing vaccine strategies following alloBMT.
Tolerance-promoting regimens permit extensive T cell activation but alter differentiation in vivo (126.29)
Authors: Wang Szu-I , Gill Ronald 
Published: January 2023

Abstract
Short-term perturbation of the costimulatory molecule CD154 and/or the adhesion molecule LFA-1 can induce allograft tolerance. However, the effect of these agents on antigen-specific T cells is unclear. Therefore, we determined how anti-CD154 or anti-LFA-1 monoclonal antibody (mAb) therapy impacted the reactivity of CD4 and CD8 T cells in vivo. We monitored both antigen-specific responses of ovalbumin (OVA)-specific CD8 (OT-I) or CD4 (OT-II) TCR transgenic T cells and alloreactivity by polyclonal T cells (C57BL/6 anti-BALB/c). CD45.1 OT-I, OT-II or B6 T cells were transferred into CD45.2 B6 hosts locally challenged with mAct-OVA or BALB/c APCs, respectively, in the presence of mAb therapy. Anti-CD154 and anti-LFA-1 each inhibited the magnitude of OT-I and OT-II responses but permitted extensive proliferation and conversion to an antigen-experienced CD44hiCD62Llo phenotype. Both treatments decreased expression of Gzm B in OT-I T cells and IFN-gamma in OT-II T cells. Polyclonal alloreactivity also was markedly inhibited by either anti-LFA-1 or anti-CD154 therapy, though activation and proliferation still occurred in both cases. Importantly, anti-LFA-1 but not anti-CD154 treatment resulted in a striking increase in Treg/ Teff cell ratio in the reactive lymph node. Overall, neither blocking CD154 nor LFA-1 prevented T cell recognition/activation in vivo. However, LFA-1 blockade exhibited a more pronounced ability to skew alloreactivity towards a Treg phenotype in vivo.
Reconstitution of protective immune responses against CMV and VZV does not require disease development in paediatric recipients of umbilical cord blood transplantation. (126.4)
Authors: Soudeyns Hugo , Salem Fourati Insaf , Brito Rose-Marie , Charrier Emily , Cordeiro Paulo , Caty Martine , Mezziani Samira , Malette Brigitte , Duval Michel , Alfieri Carolina , Ovetchkine Philippe , Le Deist Françoise , Merindol Natacha 
Published: January 2023

Abstract
Cytomegalovirus (CMV) and varicella-zoster virus (VZV) are significant causes of morbidity and mortality following umbilical cord blood transplant (UCBT). Yet the kinetics of reconstitution and protective potential of antiviral cell-mediated immune responses following UCBT remain poorly characterized. Here, the reconstitution of CMV and VZV-specific T cell responses was assessed from 1 to 36 months post-transplant using IFN-γ ELISpot and MHC-peptide tetramers in 28 children who underwent UCBT to treat haematological or inherited disorders. Barely detectable in the first 3 months post-UCBT, antiviral T cell responses directed against CMV and VZV were observed in 30.4% and 40.3% of subjects after 36 months. Four CMV-seronegative subjects developed IFN-γ responses against CMV, and 4 subjects developed VZV-specific IFN-γ responses without clinical signs of VZV infection. No CMV- or VZV-related events were observed in subjects following the development of CMV- or VZV-specific responses &gt;150 SFU per 10E6 PBMC, consistent with T cell-mediated protection. Famciclovir prophylaxis did not strictly prevent the reconstitution of the VZV-specific T cell repertoire. Lastly, the magnitude of VZV- and CMV-specific responses was correlated with the frequency of naïve CD8+ T cells, underlining the importance of immune reconstitution to achieve antiviral protection. Monitoring of cell-mediated immunity during the post-transplant period could guide the tailoring of antiherpetic prophylaxis.
Allogeneic inducible regulatory T cells allow the generation of mixed chimerism via nonmyeloablative conditioning in mice models (126.5)
Authors: Ruiz Paulina , Maldonado Paula , Hidalgo Yessia , Silva Cinthia , Ramirez Valerie , Rosemblatt Mario , Bono Maria 
Published: January 2023

Abstract
It has been demonstrated that the generation of mixed chimerism induces stable tolerance in allogeneic transplant organs. Current protocols require myeloablative or nonmyeloablative conditioning, both involving physical, pharmacological and/or cellular conditioning in order to produce general immunosuppression. Here, we have successfully developed a protocol that produces mixed chimerism using inducible allogeneic regulatory T cells (iTreg), low dose irradiation (3 Gy) and the FDA approved immunosuppressive drugs Rapamycin and Abatacept. Under experimental conditions, allogeneic iTreg treated mice produced mixed chimerism whereas, control mice lacking iTreg, rejected allogeneic bone marrow transplantation. Additionally, chimeric mice are able to accept secondary allogeneic skin transplants. Therefore we propose that generation of mixed chimerism is an improved specific therapy designed for stable alloinjert tolerance induction.
TNF but not IL-12 or interferon-alpha (IFN-a) plays a critical signal 3 role in in vivo CD8 cytotoxic T lymphocyte (CTL) maturation in the parent-into-F1 (P→F1) model. (126.7)
Authors: Via Charles , Soloviova Kateryna , Puliaiev Maksym 
Published: January 2023

Abstract
In addition to TcR signaling and costimulation, CD8 T cells require a third signal to mature into CTL. In pathogen models, IFN-a and IL-12 serve as signal 3 however in the P→F1 model, B6→B6D2F1 mice exhibit robust donor anti-host CD8 CTL in the absence of exogenous pathogens resulting in &gt;90% elimination of host splenocytes i.e. acute graft-vs.host disease (GVHD). Selective inhibition of donor CD8 (but not donor CD4) activation converts acute GVHD to chronic GVHD with splenocyte expansion. To determine whether signal 3 molecules IL-12 or IFN-a are required to directly act on donor T cells in signal 3 manner, we transferred IL-12 or IFN-a receptor defective B6 donor cells into normal B6D2F1 mice. In neither transfer was acute GVHD phenotype significantly impaired compared to wild type (WT) B6→F1 mice. Moreover, peak CD8 CTL effectors were not impaired quantitatively or qualitatively. Similarly, blocking of WT B6→F1 with anti-IL-12 mAb did not alter phenotype. Significant IL-12 or IFN-a related gene expression was not detected by RT-PCR in WT B6→F1 mice prior to day 7. By contrast, TNF receptor 2 KO (TNFR2KO)→F1 but not TNFR1KO→F1 mice convert phenotype from acute to chronic GVHD. Thus, in the absence of pathogens, IFN-a and IL-12 play no significant signal 3 role alone. Instead, endogenous TNF signaling through TNFR2 plays a critical signal 3 role. These results have implications for CTL formation in the non-pathogen setting i.e. tumors, autoantigens and transplantation.
Infiltration of mixture of immune cells is associated with good prognosis in patients with differentiated thyroid cancer. (127.1)
Authors: Cunha Lucas , Morari Elaine , Razolli Daniela , Nonogaki Suely , Soares Fernando , Vassallo José , Ward Laura 
Published: January 2023

Abstract
Immune responses against differentiated thyroid carcinomas (DTC) have long been recognized but its effect on patients prognosis is a matter of debate. In order to investigate the role of immune cell infiltration in the progression of DTC, we studied 398 patients - 253 with papillary and 13 with follicular thyroid cancers, as well as 132 with nonmalignant tissues. Immune cell infiltration was identified using CD3, CD4, CD8, CD20, CD68, and FoxP3 immunohistochemical markers. We colocalized CD4/IL-17 in order to identify Th17 lymphocytic infiltration. We also colocalized CD33/CD11b in order to identify myeloid derived suppressor cells (MDSCs) infiltration. Immune cells infiltrated malignant tissues more often than benign lesions. We observed a close correlation among CLT, tumor infiltrating lymphocytes, tumor-associated macrophages and cell molecular profile, suggesting this profile may be related to antitumor immune response. The presence of chronic lymphocytic thyroiditis (CLT), CD68+, CD4+, CD8+, CD20+, FoxP3+, Th17 and MDSCs was associated with clinical and pathological features of lower tumor aggressiveness and a more favorable patient outcome. A log-rank test confirmed an association between CLT, tumor-associated macrophage infiltration, and CD8+ lymphocytes and an increased disease-free survival. In conclusion, immune cell infiltration and the presence of concurrent CLT helped characterize specific tumor histotypes and were associated with favorable prognostic features.
Inducible costimulator (ICOS) regulates the immune response in a mouse brain tumor model (127.12)
Authors: Nigam Pragati , Auffinger Brenda , Han Yu , Lesniak Maciej 
Published: January 2023

Abstract
Glioblastoma multiforme (GBM) is the most invasive form of brain tumors and average survival less than 14.6 months. Tumors in the central nervous system (CNS) are thought to be poorly immunogenic due to compartmentalization and immune specialization. However, presence of CD4+IL-17+ (Th17) and CD4+Foxp3+ regulatory T cells (Tregs) in GBM indicates that immune responses occur within the context of CNS-resident tumors. Inducible costimulator (ICOS) belongs to the CD28 family of costimulatory molecules. ICOS is upregulated on the surface of activated T cells and its interaction with ICOS ligand can shape diverse immune responses, such as differentiation of helper T cells and IL-10-secreting Tregs. Here, we hypothesized that ICOS plays a role in regulating T cell responses involved in tumor progression. To study the role of ICOS in tumor progression, wild-type (WT) and ICOS-deficient (ICOS-/-) mice were intracranially-implanted with murine GL261 glioma cells. The median survival of tumor-bearing ICOS-/- mice was reduced to 25 days from 30 days in WT mice. The data shows a two-fold reduction in frequency of intracranial Tregs in tumor-bearing ICOS-/- mice (p&lt;0.01). Additionally, the frequency of intracranial CD4+IFN-g+ T cells increased 3-fold (p&lt;0.02), accompanied by a trend for increased in Th17 cells in tumor-bearing ICOS-/- mice. Collectively this indicates a role for ICOS in regulation of brain tumor-specific immune response and provides rationale for further investigation.
Characterization of human monocyte-derived dendritic cells in the presence of leukemic cell soluble products (127.14)
Authors: Motta Juliana , Castelo-Branco Morgana , Rumjanek Vivian 
Published: January 2023

Abstract
Professional antigen-presenting cells, dendritic cells (DCs) play an important role in controlling tumors, since they are able to initiate an antitumoral immune response. Some works demonstrate that products secreted by solid tumor cells can modulate DCs, however, leukemic cell products are not well studied. Considering that leukemic cells are present in the same place as monocytes (DCs precursor), we analyzed a possible influence of leukemic cell products on DC development and function. For this, monocytes from healthy donors were separated by density gradient and cultured, for 5 days, in the presence of IL-4 and GM-CSF and also with K562 supernatant (SN). In another experiment, immature DCs were cultured with TNF-α for a further 2 days. During a control differentiation, monocytes down regulate CD14, CD16 and CD68 expression and start to express CD1a. In this stage, immature DCs present high endocytic ability. In the presence of SN K562, CD14, CD16 and CD68 expression remained high and CD1a expression was low. However, the addition of SN K562 did not interfere with dextran endocytosis. If activated, DCs increase CD83, CD80 and CD86 expression. It was observed that monocytes differentiated in the presence of SN K562 and then activated expressed less CD83, although CD80 and CD86 expression were not modulated. Finally, these results suggest that products released by leukemic cells affect DC differentiation and these cells become unable to complete their development.
A novel p56lck-interacting protein expressed in CD8+ memory cells and tumor infiltrating T cells that inhibits proximal TCR-mediated signaling (127.16)
Authors: Frey Alan , Burns Jeremy , Vazquez-Cintron Edwin 
Published: January 2023

Abstract
The presence of tumor infiltrating CD8+ T cells (‘TIL’) demonstrates that cancers elicit immune response, however, TIL lack lytic function demonstrating tumor-induced suppression. In MCA38 adenocarcinoma, defective TIL lytic function is due to blockade of TCR signal transduction in turn due to inactivation of p56lck. We have identified an interacting partner for p56lck in nonlytic TIL: Protocadherin-18 (‘pcdh18’). In the hematopoietic system long-term, antigen-specific central memory CD8+ T cells all express pcdh18 protein. pcdh18 gene is robustly transcribed upon activation of CD8+CD44+CD62LhiCD127+ cells in vitro coincident with conversion into Em cells (CD44+CD62LloCD127+). After pcdh18 transfection into primary CD8+ effector T cells, activation causes defective: proximal TCR signaling, cytokine secretion, and lytic function, and also enhanced AICD, a phenotype that mimics that of freshly-isolated nonlytic TIL. pcdh18 has a motif at Y842 (QGQY*QP) which is highly homologous to the inhibitory tyrosine motif found in p56lck at Y505 (EGQY*QP). Y842 is phosphorylated in nonlytic TIL upon activation, but not in lytic TIL implying an association between Y842 phosphorylation and lytic function. Y842 was shown by site-directed mutagenesis to be required for the pcdh18 inhibitory phenotype in transfected T cells. Thus, we have identified an activation marker of CD8+ central memory T cells which functions as a TCR inhibitory signaling receptor and therein effector phase function.
IL-17-producing CD8+ T cells induce myeloid-derived suppressor cell chemotaxis and correlate with human cancer progression (127.2)
Authors: Zou Quanming , Zhuang Yuan , Zhao Yongliang , Chen Weisan , Pang Ken C. 
Published: January 2023

Abstract
Tumor progression is a multistage process involving cross-talk between tumor-infiltrating immune cells and tumor cells within the tumor microenvironment. IL-17-producing CD8+ T cells (Tc17 cells) represent a newly discovered T-cell subset, but their nature, regulation, function, and clinical relevance in human tumors are presently unknown. We found that Tc17 cells accumulated in tumors of 103 gastric cancer patients, and that increased Tc17 cell percentage independently predicted reduced overall survival. Tumor-activated macrophages secreted IL-6, IL-1β, and IL-23, which together favored Tc17 cell polarization, and this process was negatively regulated by tumor-infiltrating regulatory T cells (Tregs) through a cell contact-dependent mechanism. Supernatants from Tc17 cell cultures induced CXCL12 chemokine production by tumor cells, which in turn promoted CXCR4-dependent migration of myeloid-derived suppressor cells (MDSCs) and subsequent impairment of anti-tumor CD8+ cytotoxic T cell (CTL) function via a cell contact-dependent mechanism. Collectively, this study identifies a novel regulatory network involving Tc17 cells, which in conjunction with Macrophage, tumor cells, and MDSCs exert an immunosuppressive effect within the tumor microenvironment. Efforts to inhibit Tc17 cell activity might therefore prove a valuable strategy in anti-cancer therapy.
A new potential target for enhancing the anti-tumor T cell response: Lysophosphatidic acid signaling inhibits CD8+ T cell activation (127.29)
Authors: Oda Shannon , Fujiwara Yuko , Oravecz Tamas , Tigyi Gabor , Pelanda Roberta , Torres Raul 
Published: January 2023

Abstract
Lysophosphatidic acid (LPA) is a lysophospholipid that is present at low nanomolar concentrations in the plasma of healthy individuals. It has been well documented that many cancers aberrantly produce LPA and the increased level of LPA has been shown to be beneficial to the tumor, promoting tumorigenesis, invasion, metastases, and vascularization. However the effects of elevated levels of LPA on the adaptive immune response to the tumor have not been addressed. The immune system, and T cells in particular, are important for their ability to recognize and eliminate nascent tumors in cancer immunosurveillance and tumor rejection. However multiple inhibitory mechanisms within the tumor microenvironment have been described that protect the tumor from T cells. Work in our laboratory has found that LPA inhibits CD8+ T cell activation in vitro and in vivo. Specifically, we have demonstrated that CD8+ T cells express an LPA receptor that, in the presence of LPA, is able to inhibit T cell receptor (TCR) signaling and subsequent cell activation, proliferation and function. These data document that LPA is able to negatively regulate T cell activation and function. We have preliminary data that increased LPA production by tumors functions to protect the tumor from CD8+ T cell-mediated eradication. If true, these findings would represent the first report of lysophospholipid-mediated protection of tumor from adaptive immunity and highlight a potential target for cancer treatment.