Phenotypic and functional heterogeneity of human NK cells developing after umbilical cord blood transplantation: a role for human cytomegalovirus?

Blood ◽  
2012 ◽  
Vol 119 (2) ◽  
pp. 399-410 ◽  
Author(s):  
Mariella Della Chiesa ◽  
Michela Falco ◽  
Marina Podestà ◽  
Franco Locatelli ◽  
Lorenzo Moretta ◽  
...  
Keyword(s):  
Cord Blood ◽  
Nk Cells ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Nk Cell ◽  
Cord Blood Transplantation ◽  
Cell Subset ◽  
Hematologic Malignancies ◽  
Cell Development ◽  
Hematopoietic Stem

Abstract Natural killer (NK) cells play a crucial role in early immunity after hematopoietic stem cell transplantation because they are the first lymphocyte subset recovering after the allograft. In this study, we analyzed the development of NK cells after intrabone umbilical cord blood (CB) transplantation in 18 adult patients with hematologic malignancies. Our data indicate that, also in this transplantation setting, NK cells are the first lymphoid population detectable in peripheral blood. However, different patterns of NK-cell development could be identified. Indeed, in a group of patients, a relevant fraction of NK cells expressed a mature phenotype characterized by the KIR+NKG2A− signature 3-6 months after transplantation. In other patients, most NK cells maintained an immature phenotype even after 12 months. A possible role for cytomegalovirus in the promotion of NK-cell development was suggested by the observation that a more rapid NK-cell maturation together with expansion of NKG2C+ NK cells was confined to patients experiencing cytomegalovirus reactivation. In a fraction of these patients, an aberrant and hyporesponsive CD56−CD16+p75/AIRM1− NK-cell subset (mostly KIR+NKG2A−) reminiscent of that described in patients with viremic HIV was detected. Our data support the concept that cytomegalovirus infection may drive NK-cell development after umbilical CB transplantation.

Negative Effect of KIR Alloreactivity in Recipients of Umbilical Cord Blood Transplantation Depends on Transplantation Conditioning Intensity

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 152-152
Author(s):  
Claudio Brunstein ◽  
John E. Wagner ◽  
Daniel Weisdorf ◽  
Sarah Cooley ◽  
Harriet Noreen ◽  
...  
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Acute Gvhd ◽  
Nk Cell ◽  
Cord Blood Transplantation ◽  
Hematopoietic Stem ◽  
Risk Of Death ◽  
Increased Risk ◽  
Reduced Intensity

Abstract Transplant strategies involving natural killer (NK) cell alloreactivity (KIR-ligand mismatch [KIR-L mismatch]) have demonstrated superior outcomes for patients receiving T cell depleted HLA haploidentical hematopoietic stem cell allografts. It is unknown whether KIR-L mismatch has a similar effect in recipients of partially HLA-matched umbilical cord blood (UCB) grafts which contain comparatively few T-cells. We examined the clinical impact of KIR-L mismatch in 257 UCB recipients treated with either a myeloablative (n=155) or reduced intensity (n=102) regimen. After myeloablative conditioning, KIR-L mismatch had no demonstrable effect on grades III–IV acute GVHD (17% [CI, 6–28%] vs. 17% [CI, 10–24], p=.97), transplant-related mortality (TRM) (27% [CI, 14–40%] vs. 18% [CI, 11–25%], p=.19), relapse at 2 yrs (18% [95%CI, 6–30%] vs. 28% [95%CI, 19–27%], p=.37) and survival at 3 yrs (50% [CI, 32–68%] vs. 57% [CI, 47–67%], p=.46). In contrast, following reduced intensity conditioning when the engrafting unit was KIR-L mismatched there was a significantly higher incidence of grades III–IV acute GVHD (42% [CI, 27–59) vs. 13% [CI, 5–21], p < .01). Multivariate analysis confirmed NK cell alloreactivity as the only predictive factor associated with severe acute GVHD was (RR 1.8, CI [1.1–2.9]; p=.02). TRM was higher (27% [CI, 12–42%] vs. 12% [CI, 5–19%], p=.03) and three year survival was poorer (32% [CI, 15–59%] vs. 52% [CI, 47–67%], p=.03) when the engrafting unit was KIR-L mismatched, but relapse was unaffected (39% [95%CI, 21–57%] vs. 47% [95%CI, 34–60%], p=.72). KIR-L mismatch in recipients of a RIC UCB transplant was associated with a significant increased risk of death (RR 1.8, 95%CI, 1.0–3.1, p=.05). This data identify divergent effects of NK cell alloreactivity which are unmasked when comparing myeloablative versus RIC transplant platforms. We conclude that KIR-L mismatch should be avoided in recipients of a reduced intensity UCB transplant.

scholarly journals Development of Optimized Protocol for Generation of NK Cells Expressing Chimeric Antigen Receptors from Hematopoietic Stem Cells for Cancer Immunotherapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2044-2044
Author(s):  
Amie Patel ◽  
Laurel Christine Truscott ◽  
Satiro N. De Oliveira
Keyword(s):  
Stem Cells ◽  
Cord Blood ◽  
Nk Cells ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Large Scale ◽  
Nk Cell ◽  
Culture Media ◽  
Antigen Receptors ◽  
Hematopoietic Stem

Abstract Background : Natural Killer (NK) cells are innate immune cells that mediate cytotoxicity against tumor and virus-infected cells, and represent a very promising source for adoptive cellular approaches for cancer immunotherapy. Extensive research has been conducted, including clinical trials, attempting to harness their properties. Gene modification of NK cells can direct their specificity and enhance their function, but the efficiency of gene transfer in mature NK cells is very limited. We have previously published a protocol for generation of human NK cells from gene-modified hematopoietic stem cells (HSC) isolated from umbilical cord blood. Generation of NK cells from HSC provides the opportunity of generation of younger NK cells and expansion of specific gene-modified clones starting from a smaller number of previously isolated and cryopreserved initial cells, with added advantage of generation of multiple batches from the same donor. Chimeric antigen receptors (CAR) are engineered fusion proteins that combine the antigen specificity of antigen-binding moieties of monoclonal antibodies and intracellular activation motifs capable to activate immune cells. Preliminary evidence suggests that NK cells with specificity directed by second-generation CAR may have enhanced cytotoxicity. The goal is to develop a protocol with maximal generation of CAR-expressing NK cells from human HSC for clinical applications. We have evaluated the use of HSC isolated from G-CSF-mobilized apheresed peripheral blood mononuclear cells (PBSC), the elimination of serum in culture media and the elimination of feeder stroma. Significance : Development of a protocol for clinical translation and large-scale good manufacturing practice (GMP) compatibility, maximally generating functional CAR-expressing NK cells. G-CSF mobilized peripheral blood stem cells (PBSC) were used because of availability of larger HSC numbers, increasing safety and efficacy. Changes in culture media based on available literature were evaluated to promote generation of larger number of cells. Human AB serum and serum free media were tested to determine the cell yield for large-scale GMP-compatible protocol. Methods : A third-generation lentiviral vector co-delivering CD19-specific CAR and enhanced green fluorescent protein (EGFP) was used for gene modification of primary human PBSC. Gene-modified cells were then co-cultured with OP9-DL1 stromal cells over 35-40 days in six different culture media conditions for evaluation. Medium "A" was our previously published protocol and consisted of alpha-MEM enriched with 20% of fetal bovine serum and recombinant human cytokines SCF 5ng/mL, Flt3L 5ng/mL, IL-7 5ng/mL, and IL-15 10ng/mL. Medium "B" was AIM V enriched with 10% of human AB serum and cytokines SCF 5ng/mL, Flt3L 5ng/mL, IL-7 20ng/mL, and IL-15 50ng/mL. Medium "C" was similar to medium "B" excluding human AB serum. After 10 days of culture, IL-2 10ng/mL was added to all three media ("plus") creating six different conditions. Flow cytometry was used for detection of EGFP expression and NK cell surface markers. Digital droplet PCR was used for analysis of number of integrated viral copies. Feeder-free culture conditions were developed with the addition of recombinant human IGF-1 100ng/mL to AIM V culture media enriched with SCF, Flt-3 and IL-15. Results : NK cell differentiation was achieved in all conditions. Feeder-free conditions seemed to present mature NK cells earlier (days 25-30) than stromal co-culture (days 35-45), but lower cell yield. As previously reported, PBSC had lower yields of NK differentiation as compared to umbilical cord blood, but higher concentrations of IL-7 and IL-15 rescued the differentiation. Total cell yields were 100-220-fold expansions, with highest counts recovered from conditions with higher IL-7 and IL-15. The removal of serum and addition of IL-2 did not seem to affect differentiation or proliferation. CD56+/CD16+/CD94+ NK cells were present in 10-40% of all CD56+ cells. Conclusions : Large-scale GMP-compatible generation of clinically-relevant numbers of gene-modified NK cells from HSC is feasible. Higher doses of cytokines IL-7 and IL-15 successfully increase the yield of NK cells from PBSC. Absence of serum did not decrease differentiation or proliferation. PBSC showed folds of expansion and NK cell differentiation comparable to those obtained from umbilical cord blood. Disclosures No relevant conflicts of interest to declare.

scholarly journals Minimal change glomerulopathy after unrelated umbilical cord blood transplantation for the treatment of children：case report

2021 ◽  
Author(s):  
Liangliang Ren ◽  
Ling Li ◽  
Lei Zhang ◽  
Xin Li ◽  
xiaorui Fu ◽  
...  
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Cell Lymphoma ◽  
Cord Blood Transplantation ◽  
Blood System ◽  
Minimal Change ◽  
Hematopoietic Stem ◽  
Blood Transplantation ◽  
Child Patient

Umbilical cord blood allogeneic hematopoietic stem cell transplantation(UCBT) has been gradually applied in the treatment of patients with blood system diseases. This paper reports a case of a child patient with highly invasive T-cell lymphoma who underwent UCBT after chemotherapy and developed minimal change glomerulopathy after transplantation.

Successful engraftment after reduced-intensity umbilical cord blood transplantation for myelofibrosis

Blood ◽  
2010 ◽  
Vol 116 (4) ◽  
pp. 649-652 ◽  
Author(s):  
Shinsuke Takagi ◽  
Yasunori Ota ◽  
Naoyuki Uchida ◽  
Koichi Takahashi ◽  
Kazuya Ishiwata ◽  
...  
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Cord Blood Transplantation ◽  
Donor Cell ◽  
Umbilical Cord Blood Transplantation ◽  
Hematopoietic Stem ◽  
Blood Transplantation ◽  
Marrow Fibrosis ◽  
Reduced Intensity

Abstract Although allogeneic hematopoietic stem cell transplantation has recently been applied to patients with myelofibrosis with reproducible engraftment and resolution of marrow fibrosis, no data describe the outcomes of umbilical cord blood transplantation. We describe 14 patients with primary (n = 1) and secondary myelofibrosis (n = 13) who underwent reduced-intensity umbilical cord blood transplantation. Conditioning regimens included fludarabine and graft-versus-host disease prophylaxis composed cyclosporine/tacrolimus alone (n = 6) or a combination of tacrolimus and mycophenolate mofetil (n = 8). Thirteen patients achieved neutrophil engraftment at a median of 23 days. The cumulative incidence of neutrophil and platelet engraftment was 92.9% at day 60 and 42.9% at day 100, respectively. Posttransplantation chimerism analysis showed full donor type in all patients at a median of 14 days. The use of umbilical cord blood could be feasible even for patients with severe marrow fibrosis, from the viewpoint of donor cell engraftment.

scholarly journals INFECTIOUS COMPLICATIONS AFTER UMBILICAL CORD-BLOOD TRANSPLANTATION FROM UNRELATED DONORS

2016 ◽  
Vol 8 ◽  
pp. 2016051 ◽  
Author(s):  
Juan Montoro ◽  
Jaime Sanz
Keyword(s):  
Stem Cell ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Cord Blood Transplantation ◽  
Infectious Complications ◽  
Unrelated Donor ◽  
Alternative Source ◽  
Hematopoietic Stem ◽  
Blood Transplantation

Umbilical cord-blood (UCB) is a well-recognized alternative source of stem cells for unrelated donor hematopoietic stem cell transplantation (HSCT). As compared with other stem cell sources from adult donors, it has the advantages of immediate availability of cells, absence of risk to the donor and reduced risk of graft-versus-host disease despite donor-recipient HLA disparity. However, the use of UCB is limited by the delayed post-transplant hematologic recovery due, at least in part, to the reduced number of hematopoietic cells in the graft and the delayed or incomplete immune reconstitution. As a result, severe infectious complications continue to be a leading cause of morbidity and mortality following UCB transplantation (UCBT). We will address the complex differences in the immune properties of UCB and review the incidence, characteristics, risk factors, and severity of bacterial, fungal and viral infectious complications in patients undergoing UCBT.

Umbilical Cord Blood Stem Cell Transplantation

1993 ◽  
Vol 16 (5_suppl) ◽  
pp. 113-115 ◽  
Author(s):  
R. Miniero ◽  
U. Ramenghi ◽  
N. Crescenzio ◽  
L. Perugini ◽  
A. Busca ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Cord Blood Transplantation ◽  
Human Umbilical Cord Blood ◽  
Human Umbilical Cord ◽  
Alternative Source ◽  
Hematopoietic Stem

Human umbilical cord blood as an alternative source of hematopoietic stem cells for bone marrow reconstitution, has recently been demonstrated to yield successful HLA-matched placental blood grafts in children. It has been shown that cord blood contains sufficient progenitor cells to effect hematological reconstitution. Since then, more than 25 cord blood stem cells (CBSCs) transplants have been performed worldwide for the treatment of a variety of malignant and nonmalignant diseases. The majority of the grafts performed thus far have utilized CBSCs from HLA-identical siblings. However, much of the interest in this setting is devoted to the potential use of CBSCs for HLA-mismatched and unrelated transplants. Preliminary results suggest that allorecognition and graft-versus-host disease may be less intense in CBSCs transplants than in recipients of similarly compatible bone marrow. This review summarizes the results and potential future applications of cord blood transplantation.

Analysis of Mismatched Umbilical Cord Blood Transplants for Adults Patients 45 Years or Older.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5067-5067
Author(s):  
Seah H. Lim ◽  
Willaim V. Esler ◽  
Yana Zhang ◽  
Jian Zhang ◽  
Colleen Burris ◽  
...  
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Older Patients ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Hematopoietic Stem ◽  
Secondary Aml ◽  
Leukemia Relapse ◽  
Older Populations

Abstract Although hematopoietic stem cell (HSC) transplants are curative for some patients with hematologic malignancies, they have been applied primarily to younger patients. Yet, hematologic malignancies are commoner in the older populations. Therefore, despite advances in HSC transplants, many patients, especially older patients, still die of their disease. Umbilical cord blood (UCB) transplants have been shown to produce comparable results to those obtained from unrelated bone marrow transplants for adults with hematologic malignancies. UCB transplants may be particularly suitable for older patients needing unrelated HSC transplants since the incidence of GVHD is lower despite the less stringent HLA-matching requirement. Furthermore, UCB procurement is fast and can be accomplished in two weeks. However, data on the applicability of UCB transplants in older adult patient is lacking. The outcome of 14 consecutive adult patients (9 males and 5 females), 45 years or older, needing HSC transplants but without matched sibling donors in a single institution was analyzed. The median age was 55.5 years (range 45–78). The median weight was 72 kg (range 60–105). The median CD34 cells infused were 2.3 x 105/kg. Four patients received one-antigen mismatched, five patients two-antigen mismatched and five patients three-antigen mismatched transplants. Conditioning regimens consisted of Bu/Cy with (n=5) or without (n=1) ATG, Flu/Mel (n=7) and BEAM (n=1). GVHD prophylaxis consisted of cyclosporin A and methylprednisone. Five patients received double UCB transplants. The diagnosis: AML (n =8; 2 untreated secondary AML, 2 primary refractory AML, 2 secondary AML in CR1, 1 secondary AML in CR2 and 1 AML in CR3 and has failed a previous autologous transplant), CML (n=3; 2 in BC and 1 in CP1), CLL (n =2; both with advanced refractory disease) and SAA due to Hep C (n=1). Despite the age of these patients, Grade I–II acute GVHD occured in 10 patients and Grade III–IV in only 2 patients. Three patients died, all from septicemia, before engraftment could be documented. Other deaths include severe GVHD (n=2), VOD (n=1), stroke (n=1), septicemia (n=1) and leukemia relapse (n=1). Five patients are alive and disease-free. As of August 1, 2007, the 5-year actuarial DFS and OS are both 31% for the group and 50% for those <65 years (Figure 1). All five patients >65 years died within 100 days of transplants. In conclusion, some older patients needing HSC transplants may benefit from mismatched UCB transplants if they are not candidates for autologous transplants and do not have HLA-matched siblings. Obviously longer follow-up is needed in these patients to better determine the long-term effect of this approach in older patients. However, further optimization of the conditioning regimen is needed for patients older than 65 years to reduce early TRM due to toxicities. Figure Figure

HHV-6 Encephalitis in Pediatric Unrelated Umbilical Cord Blood Transplantation: Role for Ganciclovir Prophylaxis?

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4667-4667
Author(s):  
Frankie Wai Tsoi Cheng ◽  
Vincent Lee ◽  
Wing Kwan Leung ◽  
Paul Kay Sheung Chan ◽  
Ting Fan Leung ◽  
...  
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Conflicts Of Interest ◽  
Rare Complication ◽  
Cord Blood Transplantation ◽  
The Other ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Before And After

Abstract Abstract 4667 Background The role of ganciclovir as HHV-6 prophylaxis in unrelated hematopoietic stem cell transplant (HSCT) setting remains controversial. Methods We performed a 8-year retrospective review of patients received unrelated HSCT from January 2000 to September 2008. From January 2002, ganciclovir prophylaxis 5mg/kg twice daily for 7 days for all unrelated HSCT before transplant was adopted. The other transplant policies including antibacterial, antifungal, antiviral and graft-versus-host disease control policies remained unchange in that period. The prevalence of HHV-6 encephalitis was studied before and after the change in policy. Result Fifty-four unrelated HSCT were performed from January, 2000 to September, 2008. Total four cases (7.4%) of HHV-6 encephalitis were diagnosed. Two cases out of 16 cases (12.5%) diagnosed before adoption of the policy; 2 cases out of 38 cases (5.3%) diagnosed afterward. All of them were unrelated umbilical cord blood (UCB) transplant recipients. Two cases had significant residual neurological deficit and refractory seizure. The other two cases died of other transplant-related mortalities. Conclusion We conclude that HHV-6 encephalitis is still a rare complication of unrelated HSCT and may be more common in unrelated UCB transplantation. Routine use of ganciclovir as HHV-6 prophylaxis in all unrelated HSCT recipients may not be justified. Disclosures: No relevant conflicts of interest to declare.

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