Effect of KGF (Palifermin) On Immune Reconstitution After Autologous Transplantation for Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1152-1152
Author(s):  
Emmanuel Clave ◽  
Corinne Douay ◽  
Claire Rabian ◽  
Maryvonnick Carmagnat ◽  
Helene Moins ◽  
...  
Keyword(s):  
Immune Deficiency ◽  
Multiple Myeloma ◽  
T Cell ◽  
Clinical Application ◽  
Peripheral Blood ◽  
Immune Reconstitution ◽  
Autologous Transplantation ◽  
Effector Memory ◽  
Memory Cells ◽  
Effector Memory Cells

Abstract Abstract 1152 Poster Board I-174 Introduction Human-keratinocyte growth factor 1(KGF) is currently being evaluated in clinical trials for its safety and efficacy in preventing mucosal damage from irradiation and after bone marrow transplantation (BMT). It has been suggested that, besides having preventive effects on oral mucositis, it may also have immunomodulating effects by uniquely protecting thymic epithelial cells. A potential clinical application of KGF is the amelioration of prolonged post BMT-immune deficiency in BMT recipients. In animal models of autologous and allogeneic BMT, KGF administration during BMT resulted in enhanced thymopoiesis and increased peripheral T-cell numbers. Therefore, a potential clinical application of KGF is the improvement of prolonged post BMT-immune deficiency in BMT recipients. Thymopoiesis can be assessed by analysis of T-cell receptor excision circles (TREC). This marker for recent thymic emigrants might be a novel prognostic factor for outcome after transplantation in multiple myeloma patients. We investigated the potential influence of KGF on immune reconstitution after autologous transplantation for myeloma using this marker. Materials and Methods Twenty-four myeloma patients from a single institution were treated homogeneously with the induction combination bortezomib (Velcade®) plus dexamethasone (DXM), followed by high dose melphalan (140-200 mg/m2) and an autologous transplantation with peripheral blood stem cells. Patients were randomized for KGF treatment in 2 groups, 11 having received three doses of palifermin (Kepivance®) (60 μg/kg once daily i.v.) pre- and post-conditioning regimen (total six doses). Blood samples were drawn at diagnosis, before BMT, and at 1, 3, 6, 9, 12 and 18 months post BMT. We analysed signal joint (sj) TREC in peripheral blood lymphocytes using quantitative RT-PCR. The percentage and absolute numbers of lymphocyte populations were monitored by flow cytometry. Values were expressed as means ± SEM. Patient groups were compared by the Mann-Whitney test. Results Both CD4+ and CD8+ naïve T cells (CD45RA+ CCR7+) were strongly decreased by pretransplantation bortezomib plus DXM treatment. SjTREC decreased sharply after transplantation and returned to baseline after 1 year without differences between the two groups of patients. Natural regulatory T lymphocytes (phenotypically assessed as CD4+ CD25 high, CD127 low) were not modified by KGF treatment either. Notably, the CD3+ cell population was significantly higher during the first 3 months post BMT in KGF treated patients (1518 ± 380 vs 821 ± 105 CD3+/blood mL, p = 0.032 at 1 month post BMT). This was related to a higher CD8+ cell counts, specifically in the CD8 effector memory cells (assessed as CD45 RA- CCR7-) (790 ± 320 vs 292 ± 55, p< 0.05 at 1 month post BMT). No correlation was found with documented infectious complications, relapse or survival. Conclusions These data suggest that, unexpectedly, the main effect of KGF on immunity in that autologous BMT setting, is not to be accounted by changes in thymic function but rather by the peripheral expansion of CD8+ effector memory cells which could be favoured by the treatment prior BMT and/or by the post-BMT lymphopenia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Prostate Cancer: Early Detection and Assessing Clinical Risk Using Deep Machine Learning of High Dimensional Peripheral Blood Flow Cytometric Phenotyping Data

2021 ◽  
Vol 12 ◽  
Author(s):  
Georgina Cosma ◽  
Stéphanie E. McArdle ◽  
Gemma A. Foulds ◽  
Simon P. Hood ◽  
Stephen Reeder ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Specific Antigen ◽  
Effector Memory ◽  
Memory Cells ◽  
Prostate Disease ◽  
Clinical Risk ◽  
High Risk Disease ◽  
Effector Memory Cells ◽  
Benign Prostate ◽  
Asymptomatic Men

Detecting the presence of prostate cancer (PCa) and distinguishing low- or intermediate-risk disease from high-risk disease early, and without the need for potentially unnecessary invasive biopsies remains a significant clinical challenge. The aim of this study is to determine whether the T and B cell phenotypic features which we have previously identified as being able to distinguish between benign prostate disease and PCa in asymptomatic men having Prostate-Specific Antigen (PSA) levels &lt; 20 ng/ml can also be used to detect the presence and clinical risk of PCa in a larger cohort of patients whose PSA levels ranged between 3 and 2617 ng/ml. The peripheral blood of 130 asymptomatic men having elevated Prostate-Specific Antigen (PSA) levels was immune profiled using multiparametric whole blood flow cytometry. Of these men, 42 were subsequently diagnosed as having benign prostate disease and 88 as having PCa on biopsy-based evidence. We built a bidirectional Long Short-Term Memory Deep Neural Network (biLSTM) model for detecting the presence of PCa in men which combined the previously-identified phenotypic features (CD8+CD45RA-CD27-CD28- (CD8+ Effector Memory cells), CD4+CD45RA-CD27-CD28- (CD4+ Effector Memory cells), CD4+CD45RA+CD27-CD28- (CD4+ Terminally Differentiated Effector Memory Cells re-expressing CD45RA), CD3-CD19+ (B cells), CD3+CD56+CD8+CD4+ (NKT cells) with Age. The performance of the PCa presence ‘detection’ model was: Acc: 86.79 ( ± 0.10), Sensitivity: 82.78% (± 0.15); Specificity: 95.83% (± 0.11) on the test set (test set that was not used during training and validation); AUC: 89.31% (± 0.07), ORP-FPR: 7.50% (± 0.20), ORP-TPR: 84.44% (± 0.14). A second biLSTM ‘risk’ model combined the immunophenotypic features with PSA to predict whether a patient with PCa has high-risk disease (defined by the D’Amico Risk Classification) achieved the following: Acc: 94.90% (± 6.29), Sensitivity: 92% (± 21.39); Specificity: 96.11 (± 0.00); AUC: 94.06% (± 10.69), ORP-FPR: 3.89% (± 0.00), ORP-TPR: 92% (± 21.39). The ORP-FPR for predicting the presence of PCa when combining FC+PSA was lower than that of PSA alone. This study demonstrates that AI approaches based on peripheral blood phenotyping profiles can distinguish between benign prostate disease and PCa and predict clinical risk in asymptomatic men having elevated PSA levels.

Predictive value of circulating B cells and T cell subsets in melanoma patients treated with neoadjuvant ipilimumab and interferon.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15036-e15036
Author(s):  
Arjun Khunger ◽  
Ghanashyam Sarikonda ◽  
Jenn Tsau ◽  
Zeni Alfonso ◽  
Jane Gao ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Peripheral Blood ◽  
Post Treatment ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Memory Cells ◽  
Color Flow ◽  
Time Points ◽  
Effector Memory Cells

e15036 Background: Patients with locally/regionally advanced melanoma were treated on a clinical trial with a neoadjuvant combination of ipilimumab (ipi) and high dose IFNα2b (HDI) (Tarhini et al, JITC 2018). In this study, immune cell composition in peripheral blood samples collected at various time points was measured to determine any correlation with clinical outcomes and investigate the immune modulating effect of the combination therapy. Methods: Patients were randomized to neoadjuvant ipi at 3 mg/kg or 10 mg/kg, both given in combination with HDI. Tumor radiologic responses were designated as complete (CR), partial (PR), stable disease (SD) or disease progression (PD). Pathologic complete response (pCR) was defined as absence of viable tumor on histologic assessment. Peripheral blood mononuclear cells (PBMC) from treated patients (N = 28) were tested at baseline (before initiating ipi-HDI), then at 6-weeks, 3-months and 12-months (following neoadjuvant ipi-HDI). High complexity (14-color) flow cytometry analysis was performed to detect key immunological biomarkers including myeloid derived suppressor cells (MDSCs), B cells, regulatory T cells (Tregs), PD-1 and TIM3 expression on T-cells, and differentiation of T-cells into Th1, Th2 or Th17 phenotype at different time points during systemic immunotherapy. Statistical significance was determined using R-package employing Kruskal’s test. Results: Lower levels of peripheral Tregs (p = 0.02), MDSCs (p = 0.05), and CD4 effector memory cells (p = 0.04) at 3-months post treatment correlated with radiologic response. In addition, lower change from baseline at 3 months in CD4/CD8 ratio (p = 0.04), levels of Tregs (p = 0.01) and CD4 effector memory cells (p = 0.02) was associated with radiologic response. Patients exhibiting pCR had significantly lower Tregs (p = 0.04) at 6-months post treatment and significantly higher CD8 central memory cells at both 3 months (p = 0.04) and 12 month time-points (p = 0.01) as compared to patients without pCR. Finally, patients without pCR had significantly lower change from baseline in CD19 B cells at 6 months (p = 0.01) and 12 months (p = 0.04) as compared to patients with pCR. Conclusions: Our data demonstrates that the levels of immunosuppressive cells including Tregs and MDSCs in periphery are negatively associated with response. Higher levels of CD8 memory cells and B cells on-treatment are associated with clinical benefit.

TCR-transgenic lymphocytes specific for HMMR/Rhamm limit tumor outgrowth in vivo

Blood ◽  
2012 ◽  
Vol 119 (15) ◽  
pp. 3440-3449 ◽  
Author(s):  
Stefani Spranger ◽  
Irmela Jeremias ◽  
Susanne Wilde ◽  
Matthias Leisegang ◽  
Lilian Stärck ◽  
...  
Keyword(s):  
T Cell ◽  
Effector Memory ◽  
Memory Cells ◽  
Lymphoid Leukemia ◽  
Hematopoietic Stem ◽  
Transgenic Expression ◽  
Effector Memory Cells ◽  
Tumor Outgrowth

Abstract The hyaluronan-mediated motility receptor (HMMR/Rhamm) is overexpressed in numerous tumor types, including acute lymphoid leukemia and acute myeloid leukemia (AML). Several studies have reported the existence of T-cell responses directed against HMMR in AML patients that are linked to better clinical outcome. Therefore, we explored the use of HMMR-specific TCRs for transgenic expression in lymphocytes and their in vivo impact on HMMR+ solid tumors and disseminated leukemia. We obtained TCRs via an in vitro priming approach in combination with CD137-mediated enrichment. Recipient lymphocytes expressing transgenic TCR revealed the specific tumor recognition pattern seen with the original T cells. Adoptive transfer experiments using a humanized xenograft mouse model resulted in significantly retarded solid tumor outgrowth, which was enhanced using IL-15–conditioned, TCR-transgenic effector memory cells. These cells also showed an increased potency to retard the outgrowth of disseminated AML, and this was further improved using CD8-enriched effector memory cells. To define a safe clinical setting for HMMR-TCR gene therapy, we analyzed transgenic T-cell recognition of hematopoietic stem cells (HSCs) and found on-target killing of HLA-A2+ HSCs. Our findings clearly limit the use of HMMR-TCR therapy to MHC- mismatched HSC transplantation, in which HLA-A2 differences can be used to restrict recognition to patient HSCs and leukemia.

scholarly journals Increasing CD28-FOXP3+CD8+ Treg and Senescent CD8+NK2GA+Eomes+ NK-like T Cells in Peripheral Blood of Patients with Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1125-1125 ◽  
Author(s):  
Dimitri Kasakovski ◽  
Xiangbo Zeng ◽  
Ling Xu ◽  
Yangqiu Li
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Peripheral Blood ◽  
Cd8 T Cell ◽  
Regulatory Function ◽  
Effector Memory ◽  
Significant Difference ◽  
Hematological Cancers

Abstract Immune dysfunction in patients with multiple myeloma (MM) includes TGF-β induced dendritic cell dysfunction, regulatory T cell (Tregs)/Th17 cell imbalance, accumulation of Tregs and myeloid derived suppressor cells. These tumor-induced dysfunctions may contribute to immune escape and even suppress immune cells introduced in adoptive cellular immunotherapy. CD28 independent T cells of the effector memory (TEM) and CD45RA+ effector memory (TEMRA) population were shown to accumulate with age and contribute to the immunosuppressive tumor microenvironment in several solid tumors and hematological cancers. Especially in the CD8+ population, the loss of CD28 is associated with high cytotoxicity and regulatory function while showing high diversity and defective antigen-induced proliferation. In the CD4 subset, regulatory and senescent T cells were studied extensively, while in the CD8 positive subset their heterogeneity is still not clearly defined. Their potential immunosuppressive role and distribution in healthy individuals (HI) as well as patients with multiple myeloma (MM) remains to be observed. Furthermore, a recently characterized CD8+CD28- NK-like T cell subset showing expression of NK-related inhibitory receptors and TCR independent effector function is potentially of interest in the progression of MM. In the present study, we compared the changes of distribution of CD8+CD25+ and CD8+FOXP3+ regulatory T cells (Treg), CD28-CD57+ senescent T cells (Tsen), and CD8+KIR/NK2GA+EOMES+ NK-like T in peripheral blood (PB) between HI and patients with MM by multicolour flow cytometry (Gating strategy shown in Figure 1A). When comparing 35 HIs (Median age is 54) and 14 MM patients (Median age is 52), it was shown that there is no significant change in the proportion of senescent T cells in CD8 (P = 0.2452), TEM/CD8 (P = 0.1686) and TEMRA/CD8 (P = 0.4861) between HIs and the MM group, while both the CD25+FOXP3+ regulatory T cells of the CD4 population (P = 0.0031) and CD28-FOXP3+ regulatory T cells of the CD8 population (P = 0.0014) were shown to increase. There is no significant difference in the percentages of KIR/NK2GA+EOMES+ in the CD8 T cell and TEMRA/CD8 T cell population between HIs and the MM group. Remarkably, although there was no overall increase in senescent T cell in MM patients, senescent CD8+NK2GA+EOMES+ NK-like T cells increased in MM patients in comparison to HIs (P = 0.0068) (Figure 1B). In conclusion, the increase of regulatory T cells of both the CD4 and CD8 population as well as the increase of senescent NK-like T cells in the CD8 population potentially contributes to cancer progression through creation of suppressive microenvironments. Moreover, we found that regulatory CD8 T cells and CD8 NK-like T cells only contribute to a small part of the overall CD28- senescent T cell pool. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Plant microRNAs from Moringa oleifera Regulate Immune Response and HIV Infection

2021 ◽  
Vol 11 ◽  
Author(s):  
Antonella Minutolo ◽  
Marina Potestà ◽  
Valentina Roglia ◽  
Marco Cirilli ◽  
Federico Iacovelli ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Hiv Infection ◽  
Traditional Medicine ◽  
Moringa Oleifera ◽  
Cell Activation ◽  
Local Community ◽  
Effector Memory ◽  
Memory Cells ◽  
Effector Memory Cells

Traditional medicine is often chosen due to its affordability, its familiarity with patient’s cultural practices, and its wider access to the local community. Plants play an important role in providing indispensable nutrients, while specific small RNAs can regulate human gene expression in a cross-kingdom manner. The aim of the study was to evaluate the effects of plant-enriched purified extract microRNAs from Moringa oleifera seeds (MO) on the immune response and on HIV infection. Bioinformatic analysis shows that plant microRNAs (p-miRs) from MO belonging to 18 conserved families, including p-miR160h, p-miR166, p-miR482b, p-miR159c, p-miR395d, p-miR2118a, p-miR393a, p-miR167f-3p, and p-miR858b are predicted to target with high affinity BCL2, IL2RA, TNF, and VAV1, all these being involved in the cell cycle, apoptosis, immune response and also in the regulation of HIV pathogenesis. The effects of MO p-miRs transfected into HIV+ PBMCs were analyzed and revealed a decrease in viability associated with an increase of apoptosis; an increase of T helper cells expressing Fas and a decrease of intracellular Bcl2 protein expression. Meanwhile no effects were detected in PBMCs from healthy donors. In CD4+ T cells, transfection significantly reduced cell activation and modified the T cell differentiation, thereby decreasing both central and effector memory cells while increasing terminal effector memory cells. Interestingly, the p-miRs transfection induces a reduction of intracellular HIV p24 protein and a reduction of viral DNA integration. Finally, we evaluated the effect of synthetic (mimic) p-miR858b whose sequence is present in the MO p-miR pool and predicted to target VAV1, a protein involved in HIV-Nef binding. This protein plays a pivotal role in T cell antigen receptor (TCR) signaling, so triggering the activation of various pathways. The transfection of HIV+ PBMCs with the synthetic p-miR858b showed a reduced expression of VAV1 and HIV p24 proteins. Overall, our evidence defines putative mechanisms underlying a supplementary benefit of traditional medicine, alongside current antiretroviral therapy, in managing HIV infection in resource-limited settings where MO remains widely available.

scholarly journals Identification of Pertussis-Specific Effector Memory T Cells in Preschool Children

2015 ◽  
Vol 22 (5) ◽  
pp. 561-569 ◽  
Author(s):  
Lia de Rond ◽  
Rose-Minke Schure ◽  
Kemal Öztürk ◽  
Guy Berbers ◽  
Elisabeth Sanders ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Booster Vaccination ◽  
T Cell Memory ◽  
Effector Memory ◽  
Memory Cells ◽  
Cell Memory ◽  
Cell Responses ◽  
Specific Effector ◽  
Effector Memory Cells

ABSTRACTWhooping cough remains a problem despite vaccination, and worldwide resurgence of pertussis is evident. Since cellular immunity plays a role in long-term protection against pertussis, we studied pertussis-specific T-cell responses. Around the time of the preschool acellular pertussis (aP) booster dose at 4 years of age, T-cell memory responses were compared in children who were primed during infancy with either a whole-cell pertussis (wP) or an aP vaccine. Peripheral blood mononuclear cells (PBMCs) were isolated and stimulated with pertussis vaccine antigens for 5 days. T cells were characterized by flow-based analysis of carboxyfluorescein succinimidyl ester (CFSE) dilution and CD4, CD3, CD45RA, CCR7, gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α) expression. Before the aP preschool booster vaccination, both the proliferated pertussis toxin (PT)-specific CD4+and CD8+T-cell fractions (CFSEdim) were higher in aP- than in wP-primed children. Post-booster vaccination, more pertussis-specific CD4+effector memory cells (CD45RA−CCR7−) were induced in aP-primed children than in those primed with wP. The booster vaccination did not appear to significantly affect the T-cell memory subsets and functionality in aP-primed or wP-primed children. Although the percentages of Th1 cytokine-producing cells were alike in aP- and wP-primed children pre-booster vaccination, aP-primed children produced more Th1 cytokines due to higher numbers of proliferated pertussis-specific effector memory cells. At present, infant vaccinations with four aP vaccines in the first year of life result in pertussis-specific CD4+and CD8+effector memory T-cell responses that persist in children until 4 years of age and are higher than those in wP-primed children. The booster at 4 years of age is therefore questionable; this may be postponed to 6 years of age.

scholarly journals CHARACTERIZATION OF CENTRAL AND EFFECTOR CD4⁺ MEMORY CELLS IN PSORIASIS

2021 ◽  
Vol 23 (4) ◽  
pp. 969-974
Author(s):  
A. V. Kolerova ◽  
D. A. Mikailova ◽  
M. A. Beimanova ◽  
E. A. Blinova
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Central Memory ◽  
Effector Memory ◽  
Memory Cells ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Central Memory Cells ◽  
Effector Memory Cells ◽  
Severity Of The Disease

Psoriasis is a chronic autoimmune disease in which the skin and joints are involved in the pathological process. It was found that the recurrence of rashes in this disease occurs due to the resident memory cells of the skin. The number of CD4+CCR3+ effector memory cells in peripheral blood correlates with the severity of the disease. Therefore, the aim of our work is to study the phenotype of peripheral blood memory cells in patients with psoriasis.The study included 6 healthy donors: average age – 45.4 (min – 29, max – 55), women – 3, men – 3; 10 patients with psoriasis: women – 4, men – 6, average age – 37.3 (min – 23, max – 57), of which 5 patients with PASI > 10 and 5 patients with PASI < 10. The exclusion criteria for the study were the presence of autoimmune, oncological and hematological diseases, systemic therapy with immunosuppressive drugs for 1 month. Patients signed informed consent to participate in the study. Isolation of peripheral blood mononuclear cells was performed in a density gradient of ficoll-urographin (p = 1.082 g/L). Then cells were stained with fluorochrome-conjugated monoclonal antibodies to surface markers of central (Tcm) and effector (Tem) CD4+ memory cells (CD4, CD45RO, CD197), the α-chain of the IL-7 receptor (CD127), and the γ-chain of the IL-7 receptor (CD132). Statistical analysis of the data obtained was performed using the Statistica 6.0 software package.The percent of Tcm in the peripheral blood of donors was 33.4% (in – 18.2, max – 43.7), Tem – 28.7% (min – 13.6, max – 38.9), in patients with psoriasis: Tcm – 28.65% (min – 13.3, max – 59.6), Tem – 21.5% (min – 9.3, max – 38.6). In the peripheral blood of patients with psoriasis, among the central CD4+ memory cells, the proportion of CD127+CD132- -cells is 26.00%, CD127+CD132+ – 1.69%, CD127+CD132- – 69.00%, CD127- CD132+ – 1.94%. Among effector CD4+ memory cells, the proportion of CD127+CD132- -cells is 23.58%, CD127+CD132+ – 1.18%, CD127+CD132- – 69.84%, CD127- CD132+ – 0.70%. A direct correlation was found between the number of CD127- CD132+ central memory cells and the PASI value (r = 0.639, p < 0.05).In patients with psoriasis, the proportion of central memory cells is higher than in healthy donors, while the number of effector memory cells is lower. A direct correlation was found between the number of central cells expressing the γ-chain of the IL-7 receptor and the severity of the disease. Activated memory cells are characterized by high expression of CD132. It can be assumed that this population of memory cells plays a role in maintaining autoimmune inflammation in patients with this disease, and also participates in the repopulation of skin resident memory cells. 

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