scholarly journals Clinical Factors Influencing Phenotype of HCMV-Specific CD8+ T Cells and HCMV-Induced Interferon-Gamma Production after Allogeneic Stem Cells Transplantation

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Inmaculada Gayoso ◽  
Sara Cantisán ◽  
Carolina Cerrato ◽  
Joaquín Sánchez-García ◽  
Carmen Martin ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Stem Cell ◽  
Interferon Gamma ◽  
Cd8 T Cells ◽  
Hematopoietic Stem ◽  
Stem Cell Source ◽  
Cell Source ◽  
Hcmv Replication ◽  
Two Parameters

Human cytomegalovirus (HCMV) infection causes significant morbidity and mortality after hematopoietic stem cell transplantation (HSCT). In this work, we characterized the phenotype and interferon-gamma (INF-γ) production of HCMV-specific T cells using QuantiFERON-HCMV assay in 26 patients 6 months after HSCT. We analysed whether these two parameters were associated with clinical variables. Our results showed that the patients receiving stem cells from donors ≥40 years old were 12 times more likely to have HCMV-specific CD8+ T cells with “differentiated phenotype” (CD45RA+CCR7+ ≤6.7% and CD28+ ≤30%) than patients grafted from donors <40 years old (OR=12;P=0.014). In addition, a detectable IFN-γproduction in response to HCMV peptides (cutoff 0.2 IU/mL IFN-γ; “reactive” QuantiFERON-HCMV test) was statistically associated with HCMV replication after transplantation (OR=11;P=0.026), recipients ≥40 versus <40 years old (OR=11;P=0.026), and the use of peripheral blood versus bone marrow as stem cell source (OR=17.5;P=0.024). In conclusion, donor age is the only factor significantly associated with the presence of the “differentiated phenotype” in HCMV-specific CD8+ T cells, whereas HCMV replication after transplantation, recipient age, and stem cell source are the factors associated with the production of IFN-γin response to HCMV epitopes.

Pre-/Post-HSCT Imatinib Improves Survival of Childhood with BCR/ABL+ Acute and Chronic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5248-5248
Author(s):  
Fuyu Pei ◽  
Qi Li ◽  
Wenfeng Xu ◽  
Zhiyong Peng ◽  
Xuedong Wu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Myelogenous Leukemia ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Stem Cell Source ◽  
Significant Difference ◽  
Cell Source

Abstract Objective:To evaluate the effect of hematopoietic stem cell transplantation (HSCT) for children with leukemia in our center in recent years. Methods: We retrospectively analyzed data of 87 patients with leukemia underwent HSCT at a median age of 8 years from February 2006 to December 2013 in our center. The median follow-up time was 28 months (range, 2-96), the ratio of male to female patients was 59:28. Conditioning regimen included cyclophosphamide, fludarabine, busulfan with or without (w/o) thiotepa. Anti-thymocyte globulin and cytarabine were individually used for the patients with lymphoid leukemia and myeloid leukemia. GVHD prophylaxis included tacrolimus, mycophenolate mofetil w/o post-transplant cyclophosphamide. Median nucleated cells: 3.75 (1.16`7.56) × 107/Kg. Patients with BCR/ABL+ acute lymphoblastic leukemia (ALL) received imatinib before and after transplant over 6 months per each one. Twenty-six patients received transplant from sibling donors, 31 from haploidentical donor, 30 from unrelated donors; Status before transplant were grouped as CR1 (n= 57), CR 2 (n=13), CR 3 (n=1) and NR (n=16). Source of stem cells included PBSC in 40 cases, UCB in 3 cases, BM in 24 cases, BM+PBSC in 9 cases, and mixed stem cells (BM /PBSC+ UCB) in 11 cases. Results: The estimated 5-year overall survival (OS) was 56.8 ± 5.8% in total.Among them, OS was 54.3 ± 8.0% in 45 patients with ALL; 85.7 ± 13.2% in 8 patients with BCR/ABL+ALL; 48.6 ± 8.7% in 37 patients with BCR/ABL-ALL. 32.8 ± 15% in 29 patients with acute myeloid leukemia and 82.5 ± 11.3% in 13 patients with chronic myelogenous leukemia, respectively. Single factor analysis showed there was no significant difference for OS in comparison of BCR/ABL+ALL, BCR/ABL-ALL, AML and CML (P=0.057), but patients with BCR/ABL+ALL had higher OS compared to those with BCR/ABL-ALL (P=0.048) and to AML (P=0.040). In comparison of difference status before transplant, OS were 55.2 ± 11.6%, 54.9 ± 15.6%, 0,and 27.5 ± 11.6% in CR1, CR2, CR3 and NR, respectively (P=0.025). OS was higher in CR1 than NR (P=0.005). When comparing stem cell source, OS was 65.5 ± 8.5%, 0%, 41.7 ± 11.4%, 33.3 ± 15.7%, and 72 ± 17.8% in PBSC, unrelated CB (UCB), BM, BM+PBSC, and BM/PBSC+UCB transplants, respectively (P=0.003); PBSC transplant associated with higher OS than BM (P=0.049) and BM+PBSC (P=0.009); and BM/PBSC+UCB mixed transplant had highest OS (P=0.026). Multivariate analysis showed Risk factors for OS only remained stem cell source (P=0.046) and status before transplantation (P=0.048). the transplant types (P=0.023), and follow up time(P=0.017). Conclusion: Comparing with data reported in literature we have similar outcomesin total for childhood with leukemia. Use of imatinib pre-/post-transplant for patients with BCR/ABL+ALL conduces to the highest OS in current study. Stem cell sources and the status before transplant have a significant effect on OS. Disclosures No relevant conflicts of interest to declare.

Development of Novel Stem Cell Transplantation and Gene-Immunotherapy Using WT1-Specific T-Cell Receptor Gene.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3028-3028
Author(s):  
Toshiki Ochi ◽  
Hiroshi Fujiwara ◽  
Kozo Nagai ◽  
Toshiaki Shirakata ◽  
Kiyotaka Kuzushima ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Hematopoietic Stem Cells ◽  
Cell Transplantation ◽  
Clinical Efficacy ◽  
Cd8 T Cells ◽  
Hematopoietic Stem

Abstract Abstract 3028 Poster Board II-1004 Purpose The Wilms' tumor 1 (WT1) is one of the zinc-finger transcriptional regulators, and its expression level is very low in most tissues of adults. In contrast, various kinds of leukemia and solid tumors express WT1 abundantly, and high expression level of WT1 is correlated with disease aggressiveness and poor prognosis. These findings indicate that WT1 is a promising target antigen for anti-cancer cellular immunotherapy. Following identification of immunogenic epitopes derived from WT1 which are recognized by HLA class I-restricted and HLA class II-restricted T cells, phase I/II WT1 peptide vaccination trials have been conducted. Although the positive correlation between the clinical efficacy and vaccine-induced WT1-specific T-cell response has been reported, the clinical efficacy is not satisfactory. Adoptive transfer of WT1-specific T cells seems to be the promising approach to achieve marked improvement in clinical efficacy of WT1-targeting immunotherapy, however, it still remains difficult to expand WT1-specific T cells sufficiently ex vivo. To overcome these problems, we attempted to establish gene-immunotherapy targeting WT1 using T-cell receptor (TCR) gene isolated from the WT1-specific T-cell clone. We also verified the feasibility of novel stem cell transplantation by transducing WT1-specific TCR gene into hematopoietic stem cells. Methods We cloned the full length TCR-αa and -β genes from a WT1235-243-specific and HLA-A*2402-restricted cytotoxic T lymphocyte (CTL) clone. The WT1-specific TCR gene-repressing retroviral and lentiviral vectors were constructed. Retroviral vector was transduced to human peripheral T cells in retronectin-coated plate. WT1-specific functions of TCR gene-transduced CD8+ T cells and CD4+ T cells were examined by evaluating WT1 peptide-specific cytotoxicity by 51Cr-release assay and WT1 peptide-specific Th1 cytokine production, respectively. To improve the efficacy of WT1-specific TCR expression, we developed the novel retroviral vector which can inhibit selectively intrinsic TCR expression (si-TCR vector). Finally, we transduced the WT1-specific TCR lentiviral vector into human cord blood CD34+ cells, and transplanted them to NOD/SCID/common-γnull mice. Then, we examined whether WT1-specific human mature T cells can differentiate in mice. The presence of WT1-specific human T cells in mice was determined by tetramer assay and IFN-γ production in response to stimulation with WT1 peptide. Results Following transfer of WT1-specific TCR gene into peripheral blood lymphocytes, WT1 peptide-specific CD8+ and CD4+ T cells could be expanded easily in vitro. TCR gene-transduced CD8+ T cells exerted cytotoxicity against WT1 peptide-pulsed target cells and human leukemia cells in an HLA-A*2402-restricted manner. Similarly, TCR gene-transduced CD4+ T cells showed WT1-specific Th1 cytokine production in response to stimulation with human leukemia cells in HLA-A*2402-restricted fashion depending on the interaction of CD4 and HLA class II molecules. The newly developed si-TCR vector appeared to inhibit expression of endogenous TCR efficiently and improved the efficacy of WT1-specific TCR expression 3 to 5-fold higher as compared to the conventional vector. Three months after transplantation of WT1-specific TCR gene-transduced human hematopoietic stem cells in NOD/SCID/common-γnull mice, differentiation of WT1-specific human T cells in murine spleen was evaluated. Tetramer assay revealed that human mature T cells expressing WT1-specific TCR on their cell surface were clearly detected. Furthermore, these WT1-specific CD8+ T cells appeared to produce IFN-γ in response to stimulation with WT1 peptide-loaded HLA-A*2402-positive cells. Conclusion The adoptive gene-immunotherpay using WT1-specific TCR gene against leukemia seems to be promising. Moreover, the novel stem cell transplantation using WT1-specific TCR gene-transduced hematopoietic stem cells might open the door to induce long-lasting anti-leukemic cellular immunity in patients with leukemia. Disclosures No relevant conflicts of interest to declare.

Peripheral blood stem cell versus bone marrow allotransplantation: does the source of hematopoietic stem cells matter?

Blood ◽  
2001 ◽  
Vol 98 (10) ◽  
pp. 2900-2908 ◽  
Author(s):  
Martin Körbling ◽  
Paolo Anderlini
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Peripheral Blood ◽  
Fetal Liver ◽  
Hematopoietic Stem ◽  
Stem Cell Source ◽  
Number Of Patients ◽  
Cell Source

Abstract Hematopoietic stem cells from 4 different sources have been or are being used for the reconstitution of lymphohematopoietic function after myeloablative, near-myeloablative, or nonmyeloablative treatment. Bone marrow (BM)–derived stem cells, introduced by E. D. Thomas in 1963,1 are considered the classical stem cell source. Fetal liver stem cell transplantation has been performed on a limited number of patients with aplastic anemia or acute leukemia, but only transient engraftment has been demonstrated.2 Peripheral blood as a stem cell source was introduced in 1981,3 and cord blood was introduced as a source in 1988.4 The various stem cell sources differ in their reconstitutive and immunogenic characteristics, which are based on the proportion of early pluripotent and self-renewing stem cells to lineage-committed late progenitor cells and on the number and characteristics of accompanying “accessory cells” contained in stem cell allografts.

Long-Lasting HHV-6 Reactivation and Immune Recovery In Adult Long-Survivors After Umbilical Cord Blood (UCB) Allo-SCT: A Comparison With PBSC As Stem-Cell Source

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2065-2065
Author(s):  
Marina Illiaquer ◽  
Florent Malard ◽  
Thierry Guillaume ◽  
Berthe-Marie Imbert-Marcille ◽  
Jacques Delaunay ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Viral Load ◽  
Nk Cells ◽  
B Lymphocytes ◽  
Cd8 T Cells ◽  
Immune Reconstitution ◽  
Stem Cell Source ◽  
Cell Source

Abstract HHV-6 reactivation and HHV-6 encephalitis have been identified as significant complications in the post allo-SCT setting, especially in patients receiving UCB as the stem cell source (Scheurer et al, BMT, 2012). It is known that HHV-6 reactivations occur mainly within the first month post-transplant and may persist few months after allo-SCT (Chevallier et al, BMT, 2010). At our knowledge, no study has evaluated the long-term persistence of HHV-6 infection and its consequences in patients after allo-SCT. Here we have compared long-term HHV-6 reactivation and immune reconstitution (T, B and NK cells, CD3+, CD4+ and CD8+ T cells, gammaglobulin) between two cohorts of patients who received either double UCB units (n=23) or PBSC (n=25) as stem cells source for allo-SCT between February 2006 and January 2012. Patients were collected prospectively between October 2012 and June 2013. The median time between the graft and the time of analysis were 4 years for the UCB group vs 3.8 years for the PBSC group (p=NS). All patients were fit and in persistent complete remission at time of analyses. There were no differences between UCB vs PBSC groups in term of sex (male: 56% vs 55%), type of disease (myeloid: 52% vs 55%), disease status at diagnosis (high-risk: 89% vs 71%), conditioning regimen (RIC: 83% vs 84%) or median year of transplant (2008 vs 2009). The use of ATG was significantly higher in the PBSC group: 93% of cases vs 10%, p<0.0001. Half of the patients (52%, n=11) showed long-lasting HHV-6 reactivation in the UCB group (median viral load: 2.7 log10copies/mL (range: 2-3.4) compared to only 4% of the patients (n=1, viral load: 2 log10copies/mL) in the PBSC group (p<0.0001). Except a significant higher long-lasting B lymphocytes recovery in the UCB group (median: 740 vs 490 Giga/L, normal range: 100-400 Giga/L, p=0.03), there were no significant differences regarding immune reconstitution between both groups, where total lymphocytes, CD3+, CD4+ and CD8+ T cells, NK cells counts and gammaglobulin rates were in the normal ranges. In the UCB group, patients with higher B lymphocytes count (>740 Giga/L) showed no higher incidence of HHV6 reactivation (56% v 67%, p=1). Furthermore no statistically significant correlation was observed between B lymphocyte count and HHV6 reactivation. The persistence of HHV-6 reactivation has no clinical impact in this cohort. In conclusion, HHV-6 infection persists for a very long time in half of the patients after UCB allo-SCT but is not clinically relevant. Long-term immune reconstitution does not explain this event. The cause of long-lasting HHV-6 reactivation after CBT allo-SCT in adults remains to be elucidated. Disclosures: Moreau: CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau.

scholarly journals Failure of Effector Function of Human CD8+ T Cells in NOD/SCID/JAK3−/− Immunodeficient Mice Transplanted with Human CD34+ Hematopoietic Stem Cells

PLoS ONE ◽  
2010 ◽  
Vol 5 (10) ◽  
pp. e13109 ◽  
Author(s):  
Yoshinori Sato ◽  
Hiroshi Takata ◽  
Naoki Kobayashi ◽  
Sayaka Nagata ◽  
Naomi Nakagata ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Hematopoietic Stem Cells ◽  
Cd8 T Cells ◽  
Effector Function ◽  
Hematopoietic Stem ◽  
Immunodeficient Mice ◽  
Human Cd34

scholarly journals CD34+ Hematopoietic Stem Cells Exert Accessory Function in Lipopolysaccharide-induced  T Cell Stimulation and CD80 Expression on Monocytes

1999 ◽  
Vol 189 (4) ◽  
pp. 693-700 ◽  
Author(s):  
Taila Mattern ◽  
Gundolf Girroleit ◽  
Hans-Dieter Flad ◽  
Ernst T. Rietschel ◽  
Artur J. Ulmer
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cells ◽  
Cell Stimulation ◽  
Hematopoietic Stem ◽  
Accessory Function ◽  
T Cell Stimulation ◽  
Blood Stem Cells

CD34+ hematopoietic stem cells, which circulate in peripheral blood with very low frequency, exert essential accessory function during lipopolysaccharide (LPS)-induced human T lymphocyte activation, resulting in interferon γ production and proliferation. In contrast, stimulation of T cells by “conventional” recall antigens is not controlled by blood stem cells. These conclusions are based on the observation that depletion of CD34+ blood stem cells results in a loss of LPS-induced T cell stimulation as well as reduced expression of CD80 antigen on monocytes. The addition of CD34-enriched blood stem cells resulted in a recovery of reactivity of T cells and monocytes to LPS. Blood stem cells could be replaced by the hematopoietic stem cell line KG-1a. These findings may be of relevance for high risk patients treated with stem cells or stem cell recruiting compounds and for patients suffering from endotoxin-mediated diseases.

scholarly journals The Role of T Cells in Hematopoietic Stem Cell Engraftment

2006 ◽  
Vol 6 ◽  
pp. 246-253 ◽  
Author(s):  
Elizabeth Hexner
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Immune Cells ◽  
Immune Reconstitution ◽  
Host Immune System ◽  
Hematopoietic Stem ◽  
Cell Engraftment ◽  
Donor T Cells

Much attention has focused on the immune recovery of donor T cells following hematopoietic stem cell transplantation (HSCT). Termed immune reconstitution, a better understanding of the dynamics of the functional recovery of immune cells following HSCT has important implications both for fighting infections and, in the allogeneic setting, for providing antitumor activity while controlling graft-vs.-host disease (GVHD). The immune cells involved in immune reconstitution include antigen-presenting cells, B lymphocytes, natural killer cells, and, in particular, T lymphocytes, the immune cell that will be the subject of this review. In addition, T cells can play an important role in the process of engraftment of hematopoietic stem cells. The evidence for a T cell tropic effect on hematopoietic engraftment is both direct and indirect, and comes from the clinic as well as the research lab. Animal models have provided useful clues, but the molecular mechanisms that govern the interaction between donor stem cells, donor T cells, the host immune system, and the stem cell niche remain obscure. This review will describe the current published clinical and basic evidence related to T cells and stem cell engraftment, and will identify future directions for translational research in this area.

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