scholarly journals Spatio-Temporal Bone Remodeling after Hematopoietic Stem Cell Transplantation

2020 ◽  
Vol 22 (1) ◽  
pp. 267
Author(s):  
Constanze S. Schwarz ◽  
Christian H. Bucher ◽  
Claudia Schlundt ◽  
Sarah Mertlitz ◽  
Katarina Riesner ◽  
...  

The interaction of hematopoietic cells and the bone microenvironment to maintain bone homeostasis is increasingly appreciated. We hypothesized that the transfer of allogeneic T lymphocytes has extensive effects on bone biology and investigated trabecular and cortical bone structures, the osteoblast reconstitution, and the bone vasculature in experimental hematopoietic stem cell transplantations (HSCT). Allogeneic or syngeneic hematopoietic stem cells (HSC) and allogeneic T lymphocytes were isolated and transferred in a murine model. After 20, 40, and 60 days, bone structures were visualized using microCT and histology. Immune cells were monitored using flow cytometry and bone vessels, bone cells and immune cells were fluorescently stained and visualized. Remodeling of the bone substance, the bone vasculature and bone cell subsets were found to occur as early as day +20 after allogeneic HSCT (including allogeneic T lymphocytes) but not after syngeneic HSCT. We discovered that allogeneic HSCT (including allogeneic T lymphocytes) results in a transient increase of trabecular bone number and bone vessel density. This was paralleled by a cortical thinning as well as disruptive osteoblast lining and loss of B lymphocytes. In summary, our data demonstrate that the adoptive transfer of allogeneic HSCs and allogeneic T lymphocytes can induce profound structural and spatial changes of bone tissue homeostasis as well as bone marrow cell composition, underlining the importance of the adaptive immune system for maintaining a balanced bone biology.

2006 ◽  
Vol 6 ◽  
pp. 246-253 ◽  
Author(s):  
Elizabeth Hexner

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.


Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3189 ◽  
Author(s):  
Maite Alvarez ◽  
Cordelia Dunai ◽  
Lam T. Khuat ◽  
Ethan G. Aguilar ◽  
Isabel Barao ◽  
...  

The failure of autologous hematopoietic stem cell transplantation (HSCT) has been associated with a profound immunodeficiency that follows shortly after treatment, which renders patients susceptible to opportunistic infections and/or cancer relapse. Thus, given the additional immunosuppressive pathways involved in immune evasion in cancer, strategies that induce a faster reconstitution of key immune effector cells are needed. Natural killer (NK) cells mediate potent anti-tumor effector functions and are the first immune cells to repopulate after HSCT. TGF-β is a potent immunosuppressive cytokine that can impede both the development and function of immune cells. Here, we evaluated the use of an immunotherapeutic regimen that combines low dose of IL-2, an NK cell stimulatory signal, with TGF-β neutralization, in order to accelerate NK cell reconstitution following congenic HSCT in mice by providing stimulatory signals yet also abrogating inhibitory ones. This therapy led to a marked expansion of NK cells and accelerated NK cell maturation. Following HSCT, mature NK cells from the treated recipients displayed an activated phenotype and enhanced anti-tumor responses both in vitro and in vivo. No overt toxicities or adverse effects were observed in the treated recipients. However, these stimulatory effects on NK cell recovery were predicated upon continuous treatment as cessation of treatment led to return to baseline levels and to no improvement of overall immune recovery when assessed at later time-points, indicating strict regulatory control of the NK cell compartment. Overall, this study still demonstrates that therapies that combine positive and negative signals can be plausible strategies to accelerate NK cell reconstitution following HSCT and augment anti-tumor efficacy.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 927-927
Author(s):  
Joseph H. Chewning ◽  
Charlotte N. Gudme ◽  
Bo Dupont

Abstract The role of Natural Killer (NK) cells in host protection against viral infection and malignant transformation has been well described. NK cells may also lead to a reduction in post-transplant relapse and improved survival in hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML). It has been hypothesized that the genotype for the inhibiting killer immunoglobulin-like receptor (KIR) of the hematopoietic stem cell donor in combination with the HLA class I genotype of the recipient could control NK alloreactivity leading to a reduction in post-transplant complications. The KIR gene family encodes however both activating and inhibiting receptors. Here we test the hypothesis that activating KIRs with ligand specificity for HLA class I may contribute to alloreactivity, and potentially could be a genetic factor of significance in allogeneic HSCT. We tested this hypothesis in studies of two pairs of inhibiting and activating KIRs with highly homologous codon sequences in the extracellular domain, namely KIR2DL2/3-KIR2DS2 and KIR2DL1-KIR2DS1. Both the inhibitory 2DL1 and activating 2DS1 have ligand specificity for HLA-Cw group 2, and 2DL2 and 2DL3, have ligand specificity for HLA-Cw group 1, while the activating 2DS2 does not bind in vitro to C1 group. Using an EBV-transformed B-lymphoblastoid cell line (EBV-BLCL) target cell panel homozygous for HLA Class I alleles, we found that NK cells from donors with KIR haplotypes lacking KIR2DS1 or 2DS2 were not cytotoxic to allogeneic EBV-BLCL, independent of the target HLA class I genotype. Polyclonal NK cells obtained from KIR2DS1 positive and C1 group positive donors mediated NK cytotoxicity against C2 positive targets. In contrast, NK cells from KIR2DS1 positive, C2 group homozygous donors displayed minimal cytotoxicity against the C2 group targets (p<0.01). NK clones generated from 2DS1 positive, C2-group negative individuals were cytotoxic to C2-group target cells, while such NK clones could not be obtained from individuals positive for 2DS1 and cognate ligands. Similar findings were made for the relationship between 2DS2, 2DL2/3 and cognate ligand C1 group. Both polyclonal IL-2 propagated NK cells and NK clones from individuals positive for 2DS2 and homozygous for C2 group displayed specific cytotoxicity against C1 positive target cells. The cytotoxicity of 2DS2 positive, C1 group positive NK cells against the C1 positive BLCLs was minimal (p<0.01). These studies demonstrate that 2DS1 and 2DS2 are activating receptors that can induce an alloantigen response. We also present a model for combinations of KIR and HLA genotypes in which the allogeneic function of KIR2DS1 and 2DS2 is consistently seen in donor NK cells. Activating KIR may therefore play a role in allogeneic HSCT, and could contribute to the balance between activating and inhibiting signals for NK cells in HLA-Cw incompatible donor-recipient combinations. Activating KIR interactions with cognate ligand could potentially also play a role in the innate immune response. In the normal host, the increased affinity of the inhibiting KIR isoforms for HLA class I may prevent auto-reactivity, while the activating isoforms may only function in an HLA restricted pattern in context of specific pathogens or transformed cells. It is possible that the low affinity activating KIR may require additional co-stimulating signals that are up-regulated during cellular stress.


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5493-5493
Author(s):  
Falk Heidenreich ◽  
Elke Rücker-Braun ◽  
Sebastian Tuve ◽  
Marc Schmitz ◽  
Rebekka Wehner ◽  
...  

Abstract Introduction Greiner et al. demonstrated data suggesting a promising link between CD8+ T cell responses with a specificity of NPM1mut and graft versus leukemia effect (GvL). In patients with acute myeloid leukemia (AML) who underwent hematopoietic stem cell (HSC) transplantation, effector cells of the newly established immune system are thought to elicit a potent graft versus leukemia (GvL) effect eradicating residual leukemic cells. Cytotoxic T-lymphocytes (CTLs) specific for leukemia associated MHC-presented peptides may play a crucial role in the anti-tumor reaction and in achieving complete molecular remission. Leukemic cells are detectable after allogeneic HSCT in AML at least at the level of minimal residual disease (MRD). Malignant cells could therefore be identified and targeted by effector cells of the new immune system and stimulation of CTLs by antigen is assured. Detectable leukemia-specific CTLs will allow studies which address the correlation of the course of CTLs and clinical events. Further, it could allow for an assessment of the functional properties of these cells with respect to GvL effects. Methods We screened HLA-A0201 positive patients with AML and chronic lymphocytic leukemia (CLL) biweekly from day 28 after transplantation until day 112 for antileukemic CTLs applying streptamer technology. For AML a panel of 7 MHC peptide complexes was used to label CTLs from peripheral blood: phycoerythrin-(PE)-labeled streptamers refolded with peptides (number of different peptides) derived from the amino acid sequence of the proteins WT1 (1), PR3 (1), RHAMM (1), mutated NPM1 (2), and survivin (2). For CLL peptides derived from RHAMM (1), survivin (2) and fibromodulin (4) were chosen for screening. Peptides from cytomegalovirus (CMV) protein pp65 and from Influenza matrix protein M1 were used as positive controls. A peptide of the HIV reverse transcriptase served as negative control. Results Up to now neither for AML (n = 9) nor for CLL (n = 1), leukemia specific CTLs were detected according to the respective panel at any time point. However, it was possible to detect CMV-specific CTLs in most of the CMV seropositive patient-recipient pairs and frequencies increased when CMV reactivation occurred. Increasing frequencies of CMV-specific CTLs were even measured in CMV seropositive patients who received allogeneic HSC grafts from CMV seronegative donors, proving the adequacy of the method and reflecting the stimulation and proliferation of CMV-specific CTLs. Discussion Different reasons may account for our negative results so far: the limited numbers of selected peptides, which may not be immunodominant or the small number of screened patients are two of them. It must be considered that the CTL immune response to virus infection and concomitant CMV clearance may not represent a proper model for the GvL effect, which possibly is characterized only by a weak proliferation of CTLs resulting in cell counts below the detection limit of the applied flowcytometric measurements. We will further extend our screening approach to a minimum of 18 individuals per specificity. If frequencies above the limit of detection will not be detected in at least one out of 18 patients the 95 % confidence interval of the true percentage of patients with measurable CTLs of this specificity should be < 15 %. Conclusions This study highlights the difficulties to study leukemia-specific CTLs. So far, leukemia-specific CTLs have only been measured in single patients after allogeneic HSCT. Information on cohorts of patients who have been monitored longitudinally for specific CTLs is very rare. The kinetics of leukemia-specific CTLs which mediate GvL effects are almost unknown. Further research on delineating T-cell mediated GvL-effects and realistic estimates for frequencies of specific CTLs at well defined time-points are urgently needed. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3653-3653
Author(s):  
Josefina Perez-Nuñez ◽  
Antonio Jimenez-Velasco ◽  
Katy Hurst ◽  
Manuel Barrios-Garcia ◽  
MJ Moreno ◽  
...  

Abstract Philadelphia positive acute lymphoblastic leukemia (Ph + ALL) accounts for approximately 20% -30% of all adult ALL. The prognosis of patients with Phi + ALL is unfavorable when treated with standard chemotherapy schemes, presenting a long-term survival of 15% -20%. Since the introduction of Imatinib (IM) to treatment regimens the survival of these patients has improved, although allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option. We conducted a retrospective analysis of Ph + ALL patients before and after IM became available in order to analyze the impact of IM on survival in adult Phi + ALL. Patients and methods Between April 1997 and April 2013 we diagnosed 120 over 15 year old patients with ALL (B and T lineage), 31 (25.8%) of which were Phi +, all B lineage. Of these 31 cases, 30 were treated with protocols from Spanish group PETHEMA with curative intent. 14 of them (47%) were treated with chemotherapy and Imatinib (IM cohort) and 16 (53%) with chemotherapy (pre-IM cohort). In 17 of the 30 cases allogeneic HSCT was performed, 7 in the pre-IM cohort and 10 in the IM cohort. In the post-transplant period, two patients were treated with Dasatinib due to positive minimal residual disease (BCR-ABL1 positive). The probabilities of overall survival (OS) (death) and event free survival (EFS) (no response, relapse or death) were estimated using the Kaplan-Meier product limit method. Differences between groups were tested using the X2 test. Univariate analysis was performed using Cox regression models or log-rank test. Multivariate analysis was performed using Cox proportional hazards regression model. The study was conducted in accordance with the Declaration of Helsinki. Results The median age was 38 years (range, 15-66 years), 17 patients were males and 13 females. The whole series survival was 32.4 ± 9.2%. The OS mean of the pre-IM cohort was 3.1 years (CI 95%, 0.5-5.7) and 6.9 years (CI 95%, 4.4-9.4) in the IM cohort (figure 1). The main characteristics of both groups are reflected in Table 1. When we analyzed the EFS, the variables that influenced it were being treated with IM (48% in the IM cohort versus 12.5% in the pre-IM cohort, p = 0.03), having received an allogeneic HSCT (45% versus 8%, p = 0.004) and being in first complete remission before allogeneic HSCT (51% versus 0%, p <0.001). In the analysis of OS, the only variables with prognostic significance were: treatment with IM (63% in the IM cohort versus 12.5% in the pre-IM cohort, p = 0.01) and having received an allogeneic HSCT (55 % versus 0%, p <0.001). When the 17 patients that received allogeneic HSCT were analyzed separately, OS in the pre-IM cohort was 29 ± 17% versus 79 ± 13% in the IM cohort (p = 0.057). Table 1. Patient characteristics (N=30) Characteristic Pre-IM cohort(N=16) IM cohort(N=14) P Female/Male 7/9 6/8 0.96 Age ² 40 years 12 (75%) 10 (71%) 0.82 ³ 50 x109/L WBC 8 (50%) 4 (29%) 0.23 Transcript type: e1a2 b2a2/b3a2 12 (75%) 4 (25%) 11 (79%) 3 (21) 0.83 Morphological CR after induction 13/15 (88%) 13/13 (100%) 0.17 No. of Allo-HSCT 7 (44%) 10 (71%) 0.13 CR pre Allo-HSCT: 1CR 2CR 5 (71%) 2 (29%) 10 (100%) 0 (0%) 0.07 Relapse 8/13 (61.5%) 4/13 (31%) 0.12 Exitus 14 (87.5%) 5 (36%) 0.003 Abbreviations: IM, imatinib. WBC, white blood cells. CR, complete remision. Allo-HSCT, allogenetic hematopoietic stem cell transplantation. Figure 1 Figure 1. Conclusions In our study we show how adult Phi + ALL patients who are treated with chemotherapy associated with IM and subsequently receive an allogeneic HSCT exhibit a higher overall survival rate than those treated in the pre-IM era. Although Phi + ALL is still considered of very high risk, in our series of patients treated in the IM era, with a follow-up of over 7 years, overall survival was of 63%, higher than that of historical series of adults with Phi negative ALL. This work has been financed by a grant from the Malaga Association for Research in Leukemia "AMPILE" and the FIS 11-01966 project. Disclosures No relevant conflicts of interest to declare.


2013 ◽  
Vol 31 (30) ◽  
pp. 3782-3790 ◽  
Author(s):  
Rafijul Bari ◽  
Piya Rujkijyanont ◽  
Erin Sullivan ◽  
Guolian Kang ◽  
Victoria Turner ◽  
...  

Purpose Killer-cell immunoglobulin-like receptors (KIRs) that regulate natural-killer cells are highly polymorphic. Some KIR2DL1 alleles encode receptors that have stronger signaling function than others. We tested the hypothesis that the clinical outcomes of allogeneic hematopoietic stem-cell transplantation (HSCT) could be affected by donor KIR2DL1 polymorphism. Patients and Methods All 313 pediatric patients received allogeneic HSCT at a single institution. Donor KIR2DL1 functional allele typing was retrospectively performed using single nucleotide polymorphism assay. Results Patients who received a donor graft containing the functionally stronger KIR2DL1 allele with arginine at amino acid position 245 (KIR2DL1-R245) had better survival (P = .0004) and lower cumulative incidence of disease progression (P = .001) than those patients who received a donor graft that contained only the functionally weaker KIR2DL1 allele with cysteine at the same position (KIR2DL1-C245). The effect of KIR2DL1 allelic polymorphism was similar in patients with acute myeloid leukemia or acute lymphoblastic leukemia among all allele groups (P ≥ .71). Patients who received a KIR2DL1-R245–positive graft with HLA-C receptor-ligand mismatch had the best survival (P = .00003) and lowest risk of leukemia progression (P = .0005) compared with those who received a KIR2DL1-C245 homozygous graft. Conclusion Donor KIR2DL1 allelic polymorphism affects recipient outcomes after allogeneic HSCT. These findings have substantial implications for prognostication and donor selection.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1910-1910 ◽  
Author(s):  
Midori Nakagaki ◽  
Michael Barras ◽  
Cameron Curley ◽  
Jason P Butler ◽  
Glen A Kennedy

Abstract Background: Despite routine antiemetic administration during conditioning for hematopoietic stem cell transplantation (HSCT), breakthrough chemotherapy induced nausea and vomiting (CINV) can still be problematic. Recent studies in solid tumor therapy have demonstrated effectiveness of both olanzapine and the second generation 5HT3 receptor antagonist palonosetron in management of CINV. However, there remains little comparative data on efficacy of these agents, especially within HSCT. Aims: To compare the effectiveness of olanzapine and palonosetron to an ondansetron infusion (standard of care) for the treatment of breakthrough CINV in patients undergoing HSCT. Method: A randomized open-label prospective study was performed in HSCT patients suffering breakthrough CINV during conditioning despite standard prophylaxis with IV ondansetron 8mg TDS plus a single dose of oral aprepitant 165mg. Patients were randomised on a 1:1:1 basis to receive either ondansetron 32mg in 250ml normal saline as a continuous infusion over 24 hours, an olanzapine wafer 10mg once daily, or a single dose of palonosetron 0.25mg IV. All groups were allowed prn metoclopramide IV and / or lorazepam SL as rescue anti-nausea medication. Nausea score was graded from 0 (no nausea) to 100 (worst nausea) and recorded using a visual analogue scale (VAS). The primary endpoint was a composite outcome of no emesis, no use of rescue medication, and nausea score reduction of >50%. The secondary endpoint was nausea score reduction of >50%. Both endpoints were measure at 24 and 48hrs after initiation of the study treatment. Statistical analysis was conducted using a double-sided Fisher's exact test. Results: In total, 18, 22 and 22 patients were randomized to the ondansetron, olanzapine and palonosetron arms respectively. Overall 53% of patients had undergone autologous and 47% allogeneic HSCT. Conditioning regimens included high dose melphalan (200mg/m2) and BEAM for autologous HSCT and Cy / TBI and fludarabine / melphalan (melphalan 120mg/m2) for allogeneic protocols. A similar proportion of patients randomized to ondansetron versus olanzapine versus palonosetron received autologous versus allogeneic HSCT, with similar ratios of individual conditioning regimens included within each arm (p=NS for all comparisons). Patients' age, gender and other risk factors such as history of CINV were also similar between arms (p=NS for all comparisons). The primary endpoint was achieved in 6%, 45% and 18%, and 6%, 64% and 18% of ondansetron versus olanzapine versus palonosetron patient groups at 24 and 48hrs respectively. Overall olanzapine was significantly more effective at controlling breakthrough CINV compared to ondansetron at both 24 and 48hrs (p=0.011 and 0.0002 respectively). Olanzapine was also more effective than palonosetron at 48hrs (p=0.005). The secondary outcome was observed in 17%, 60% and 62%, and 35%, 71% and 43% of ondansetron versus olanzapine versus palonosetron patient groups at 24 and 48hrs respectively. Again, olanzapine was superior to ondansetron at controlling nausea at both 24 and 48hrs (p=0.0009 and p=0.048 respectively). However, there was no significant difference between olanzapine and palonosetron in reduction of nausea score >50% at either time point. Palonosetron was superior to ondansetron at nausea control at 24 (p=0.008) but not at 48hrs. Serious adverse drug reactions were not reported in any arms, and median duration from stem cell infusion to the engraftment was 13 days, 13 days and 14 days for ondansetron, olanzapine and palonosetron arms respectively (p=NS). Conclusions: When compared to ondansetron infusion and a single dose of palonosetron, daily olanzapine is superior treatment of breakthrough CINV in patients undergoing HSCT. A single dose of palonosetron does not significantly reduce emesis but is effective for the treatment of nausea up to 24 hours. Further studies are required to determine the ideal dosing frequency of palonosetron. Disclosures Off Label Use: Olanzapine is used as an antiemetic, which is widely accepted..


Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1608-1609
Author(s):  
Maria Concetta Renda ◽  
Emanuela Fecarotta ◽  
Aurelio Maggio ◽  
Francesco Dieli ◽  
Guido Sireci ◽  
...  

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