scholarly journals Immunosenescent Characteristics of T Cells in Young Patients Following Haploidentical Stem Cell Transplantation from Parental Donors

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3283-3283
Author(s):  
Ga Hye Lee ◽  
Kyung Taek Hong ◽  
Jung Yoon Choi ◽  
Hee Young Shin ◽  
Won-Woo Lee ◽  
...  
Keyword(s):  
Dna Damage ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Telomere Length ◽  
Cell Transplantation ◽  
Cd8 T Cells ◽  
Hematopoietic Stem

Introduction: Pediatric and adolescent patients in need of allogeneic hematopoietic stem cell transplantation generally receive stem cells from older, unrelated or parental donors when a sibling donor is not available. Despite encouraging clinical outcomes, it has been suggested that immune reconstitution accompanied by increased replicative stress and a large difference between donor and recipient age may worsen immunosenescence in pediatric recipients. Therefore, in this study paired samples were collected at the same time from donors and recipients of haploidentical hematopoietic stem cell transplantation (HaploSCT). Methods: We conducted flow cytometry-based phenotypic and functional analyses and telomere length measurements of 21 paired T-cell sets from parental donors and children who received T cell-replete HaploSCT with post-transplant cyclophosphamide (PTCy) at Seoul National University Children's Hospital between February 2014 and January 2017. The conditioning regimen was comprised of targeted busulfan (total target area under the curve, 75,000 mg•h/L) with intensive pharmacokinetic monitoring, fludarabine and cyclophosphamide. Results: Fourteen pediatric, adolescent, and young adult patients with malignant disease and seven with nonmalignant disease were included with a median post-transplantation period of 16.9 months (range, 12.4-38.8). Senescent T cells, CD28- or CD57+ subsets of both CD4+ and CD8+ T cells, were significantly expanded in patients compared with parental donors. Further, not only CD4+CD28- T cells, but also CD4+CD28+ T cells showed reduced cytokine production capacity and impaired polyfunctionality compared with parental donors, whereas their TCR mediated proliferation capacity was comparable. Of note, the telomere length in patient T cells was preserved, or even slightly longer, in senescent T cells compared with donor cells. We also found that the patients had a higher level of γ-H2AX-expressing CD28- senescent T cells compared with the donors, which is used as a DNA damage marker. Regression analysis showed that senescent features of CD4+ and CD8+ T cells in patients were influenced by donor age and the frequency of CD28- cells, respectively. Conclusions: Our data suggest that T cells undergo premature immunosenescent changes and exhibit functional defects in pediatric HaploSCT recipients. Further, there is an increased level of DNA damage in patient CD4+ T cells compared to those of parental donors. Therefore, long-term, comprehensive immune monitoring of these patients is necessary. Disclosures No relevant conflicts of interest to declare.

Generation of Human T/NK Cell Precursors for Adoptive Transfer To Enhance Immune Reconstitution in Allogeneic Hematopoietic Stem Cell Transplantation Recipients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3209-3209
Author(s):  
Sonali Chaudhury ◽  
Johannes Zakarzewski ◽  
Jae-Hung Shieh ◽  
Marcel van der Brink ◽  
Malcolm A.S. Moore
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem ◽  
Serum Free ◽  
Cd34 Cells

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with significant post-transplant immunoincompetence which affects in particular the T cell lineage and results in an increased susceptibility to infections. Novel strategies to enhance immune recovery after HSCT could prevent malignant relapse and immune deficiency and improve the overall outcome of this therapy. We have established a serum free culture system using murine bone marrow stroma expressing the Notch ligand Delta-like 1 (DL1) to obtain high numbers of human pre-T cells from CD34+ cells. Human cord blood CD34+ cells were plated on OP9 DL1 stroma transduced with adenovirus expressing thrombopoietin (ad-TPO) at an MOI of 30. Media used was QBSF-60 (Serum free media prepared by Quantity Biologicals) supplemented with Flt-3 ligand and IL-7 (10ng/ml). At 4–5 weeks we obtained a 10 5–10 7 fold expansions of cultured cells of which about 70–80% were CD5, CD7 positive pre T cells (Fig 1). We then developed an optimal system to study human lymphohematopoiesis using mouse models (NOD/SCID/IL2rϒnull and NOD/SCIDβ2null) and established an adequate pre T cell number (4 × 10 6) and radiation dose (300 Rads). We injected CD34 and pre-T cells (CD45 +, CD4−, CD5+, CD7+) derived from OP9 DL1 cultures into these mice and achieved ~50%engraftment of NK in the bone marrow and spleen of the mice at 2 weeks following transplant. The thymus from the same mice showed evidence of about 12–15% CD7+ pre T cells. We are currently studying the function of the generated NK and T cells both in vivo and in vitro studies. Figure Figure

New Interleukin-15 Superagonist (IL-15 SA) Significantly Enhances Graft-Versus-Tumor Activity After Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3254-3254
Author(s):  
Cavan P Bailey ◽  
Christopher Sauter ◽  
Michelle M Panis ◽  
Tulin Budak-Alpdogan ◽  
Hing Wong ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cd8 T Cells ◽  
T Cell Proliferation ◽  
Hematopoietic Stem ◽  
Interleukin 15 ◽  
And Function

Abstract Interleukin-15 (IL-15) is a pleiotropic cytokine, which plays various roles in the innate and adaptive immune system, including the development, activation, homing and survival of immune effector cells. IL-15 has been previously shown to increase CD8+ T and NK cells number and function in normal mice and recipients of stem cell transplantation. However, obstacles remain in using IL-15 therapeutically, specifically its low potency and short in vivo half-life. To overcome this, a new IL-15 mutant (IL-15N72D, J. Immunol, 2009; 183:3598) has been developed, with increased biological activity. Co-expressing IL-15N72D, in conjunction with IL-15RαSu/Fc produced a biologically active and highly potent IL-15 superagonist complex (IL-15SA, also known as ALT-803, Cytokine, 2011; 56:804). We evaluated the effects of IL-15-SA on immune reconstitution and graft-versus-tumor (GVT) activity in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Lethally irradiated BALB/c recipients were transplanted with T-cell depleted (TCD) bone marrow (BM) cells from B6 mice. IL-15 SA was administered via IP injection in two doses on days +17 and +24 after transplant. Animals were sacrificed at day 28. Administration of IL-15 significantly increased the numbers of CD8+ T cells and NK cells. IL-15 SA also augmented interferon-γ secretion from CD8+ T cells. We observed similar activity in B6CBA→CB6F1 transplant model. Interestingly IL-15 SA upregulates NKG2D and CD107a expression on CD8+ T cells. IL-15 SA administration also specifically increased slow-proliferative CD8+ T-cell proliferation in conjunction with robust IFN-γ and TNF-α secretion in CD8+ T cells in recipients of CFSE (carboxyfluorescein succinimidyl ester) labeled-T-cell infusion, whereas there was no effect on CD4+ T-cell proliferation. We then tested the anti-tumor activity of IL-15 SA in three different tumor models; murine mastocytoma (P815), murine B cell lymphoma (A20) and murine renal cell carcinoma (Renca). We found that IL-15 SA administration enhanced GVT activity against P815 and A20 in recipients of allogeneic HSCT though this activity required a low-dose T cell infusion with HSCT. Interestingly, augmented GVT activity against to Renca after IL-15 SA administration in recipients of allogeneic HSCT did not require T cell infusion. We conclude that IL-15 SA is a very potent cytokine complex for enhancing CD8+ and NK cell reconstitution and function after HSCT, which would be a candidate for post-transplant immunotherapy. Disclosures: Wong: Altor Bioscience: Employment.

Dual Production of IL-2 and IFN-Gamma by CMV-Specific CD8+ T-Cells Is a Hallmark of Their Ability to Control CMV Reactivation in Patients After Hematopoietic Stem Cell Transplantation,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4081-4081
Author(s):  
Tomas Kalina ◽  
Ladislav Krol ◽  
Jan Stuchly ◽  
Petra Keslova ◽  
Petr Hubacek ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Cd8 T Cells ◽  
Antiviral Treatment ◽  
Hematopoietic Stem ◽  
Cmv Reactivation

Abstract Abstract 4081 Introduction: Depletion of cellular immunity as a consequence of conditioning before allogeneic hematopoietic stem cell transplantation (HSCT) frequently results in CMV reactivation, which may in turn lead to life-threatening infections and require timely antiviral treatment. Methods: We have investigated the ex vivo response of CMV-specific CD4+ and CD8+ T-cells to CMV antigen (combined CMV total lysate, pp65 and IE-1 peptide mix) in 191 samples from 118 individuals. We included patients with either high or undetectable viral loads, and those who controlled or did not control their CMV reactivations. All patient subsets were compared to healthy donors. Polychromatic flow cytometric measurements of CD154 (CD40L), intracellular cytokines (IFNγ, IL2), and a degranulation marker (CD107a) revealed the functional status of various T-cells simultaneously. Results: We found that dual IFNγ/IL2 producing CD8+ T-cells were significantly increased in patients controlling their CMV reactivations (average 0.33%, SD=0.4%) compared to non-controllers (average=0.02%, SD=0.07%). In contrast, CD8+ T-cells that produced IFNγ only were the most abundant subtype but they were present in a substantial number of both, controllers (average 4.36%, SD=4.8%) and non-controllers (average 1.64%, SD=3.7%). Hierarchical clustering of distinct functional signatures revealed that polyfunctional CD8+ T-cells were acting in concert with other subsets, whereas the isolated production of IFNγ by CD8+ T cells heralds insufficient collaboration with others. On a subset of patients with reactivation of CMV post HSCT, we have evaluated the sensitivity and specificity of functional signature test (n=64 samples) to predict reactivation control. When dual IFNγ/IL2 producing cells above 0.1% cut-off were considered protective, sensitivity of 75% and specificity 93% was achieved, while IFNγ-only production by more 0.3% cells had sensitivity of 88% but specificity of 73% only. Conclusions: Our study revealed functional signatures that are useful readout of immune monitoring. Furthermore, our data may modify the interpretation of previous studies that assessed only IFNγ. Supported by the Czech Ministry of Health grant NS/9996-4, MZØFNM2005 and Czech Ministry of Education MSMT21620813 Disclosures: No relevant conflicts of interest to declare.

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