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Nowak J.,Institute of Hematology and Transfusion Medicine | Koscinska K.,Lower Silesian Center for Cellular Transplantation with National Bone Marrow Donor Registry | Mika-Witkowska R.,Institute of Hematology and Transfusion Medicine | Rogatko-Koros M.,Institute of Hematology and Transfusion Medicine | And 34 more authors.
Biology of Blood and Marrow Transplantation | Year: 2015

Some cancers treated with allogeneic hematopoietic stem cell transplantation (HSCT) are sensitive to natural killer cell (NK) reactivity. NK function depends on activating and inhibitory receptors and is modified by NK education/licensing effect and mediated by coexpression of inhibitory killer-cell immunoglobulin-like receptor (KIR) and its corresponding HLA I ligand. We assessed activating KIR (aKIR)-based HLA I-dependent education capacity in donor NKs in 285 patients with hematological malignancies after HSCT from unrelated donors. We found significantly adverse progression-free survival (PFS) and time to progression (TTP) in patients who received transplant from donors with NKs educated by C1:KIR2DS2/3, C2:KIR2DS1, or Bw4:KIR3DS1 pairs (for PFS: hazard ratio [HR], 1.70; P = .0020, Pcorr = .0039; HR, 1.54; P= .020, Pcorr= .039; HR, 1.51; P= .020, Pcorr= .040; and for TTP: HR, 1.82; P= .049, Pcorr= .096; HR, 1.72; P= .096, Pcorr= .18; and HR, 1.65; P= .11, Pcorr= .20, respectively). Reduced PFS and TTP were significantly dependent on the number of aKIR-based education systems in donors (HR, 1.36; P= .00031, Pcorr= .00062; and HR, 1.43; P= .019, Pcorr= .038). Furthermore, the PFS and TTP were strongly adverse in patients with missing HLA ligand cognate with educating aKIR-HLA pair in donor (HR, 3.25; P= .00022, Pcorr= .00045; and HR, 3.82; P= .027, Pcorr= .054). Together, these data suggest important qualitative and quantitative role of donor NK education via aKIR-cognate HLA ligand pairs in the outcome of HSCT. Avoiding the selection of transplant donors with high numbers of aKIR-HLA-based education systems, especially for recipients with missing cognate ligand, is advisable. © 2015 American Society for Blood and Marrow Transplantation.


Spolnicka M.,Central Forensic Laboratory of the Police | Piekarska R.Z.,Central Forensic Laboratory of the Police | Jaskula E.,Polish Academy of Sciences | Jaskula E.,Lower Silesian Center for Cellular Transplantation with National Bone Marrow Donor Registry | And 13 more authors.
Clinical Epigenetics | Year: 2016

Background: Our recent study demonstrated that DNA methylation status in a set of CpGs located in ELOVL2, C1orf132, TRIM59, KLF14, and FHL2 can accurately predict calendar age in blood. In the present work, we used these markers to evaluate the effect of allogeneic hematopoietic stem cell transplantation (HSCT) on the age-related methylation signature of human blood. Methods: DNA methylation in 32 CpGs was investigated in 16 donor-recipient pairs using pyrosequencing. DNA was isolated from the whole blood collected from recipients 27–360 days (mean 126) after HSCT and from the donors shortly before the HSCT. Results: It was found that in the recipients, the predicted age did not correlate with their calendar age but was correlated with the calendar age (r = 0.94, p = 4 × 10−8) and predicted age (r = 0.97, p = 5 × 10−10) of a respective donor. Despite this strong correlation, the predicted age of a recipient was consistently lower than the predicted age of a donor by 3.7 years (p = 7.8 × 10−4). This shift was caused by hypermethylation of the C1orf132 CpGs, for C1orf132 CpG_1. Intriguingly, the recipient-donor methylation difference correlated with calendar age of the donor (r = 0.76, p = 6 × 10−4). This finding could not trivially be explained by shifts of the major cellular factions of blood. Conclusions: We confirm the single previous report that after HSCT, the age of the donor is the major determinant of age-specific methylation signature in recipient’s blood. A novel finding is the unique methylation dynamics of C1orf132 which encodes MIR29B2C implicated in the self-renewing of hematopoietic stem cells. This observation suggests that C1orf132 could influence graft function after HSCT. © 2016, The Author(s).


Lange A.,Polish Academy of Sciences | Lange A.,Lower Silesian Center for Cellular Transplantation with National Bone Marrow Donor Registry | Dlubek D.,Polish Academy of Sciences | Dlubek D.,Lower Silesian Center for Cellular Transplantation with National Bone Marrow Donor Registry | And 7 more authors.
Journal of Immunotoxicology | Year: 2014

A Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) case was maintained in remission with the use of chemo-immunotherapy. The latter involved sibling bone marrow transplant (BMT) (three procedures) followed by intravenous (IV) donor lymphocyte infusion (DLI). The third relapse responded to routine chemotherapy and again DLI was employed. During hematological and molecular remission verified at the level of iliac crest aspiration, extra-medullary relapse in the bones was apparent. A novel procedure of donor lymphocyte injection to the bone leukemic lesions was developed and employed. A dose of 106 donor lymphocytes/kg body weight (BW) of the recipient were each time injected to the plane of the right and left tibia, the head of the humerus, and the calcaneus, which resulted in healing of the destructive process. In consequence of this novel approach, in addition to the healing of bone lesions, an accumulation of cytotoxic activated T-cells in the marrow was documented, which was mirrored by an increase in the number of transcripts for interferon (IFN)-γ, interleukin (IL)-17, as well as RORγt. The local administration of DLI directly to the leukemic lesions requires a lower dose that diminishes the toxicity due to the general immune system activation. © 2014 Informa Healthcare USA, Inc.


Jaskula E.,Polish Academy of Sciences | Lange A.,Polish Academy of Sciences | Lange A.,Lower Silesian Center for Cellular Transplantation with National Bone Marrow Donor Registry | Kyrcz-Krzemien S.,Silesian Medical University | And 14 more authors.
Biology of Blood and Marrow Transplantation | Year: 2014

Three NOD2 polymorphisms (single nucleotide polymorphism [SNP]8 [2104C≥T, Arg702Trp], SNP12 [2722G≥C, Gly908Arg], and SNP13 [3020insC, Leu1007 fsins C]), identified as disease-associated variants in Crohn's disease, have recently been suggested as gene markers of the outcome of hematopoietic stem cell transplantation (HSCT). In the present multicenter study of 464 donor-recipient pairs, we focused on the effect of NOD2 mutation(s) on the risk of infections and acute graft-versus-host disease (aGVHD). The presence of SNP13 in recipients, donors, or both was more frequently seen in patients having sepsis than in those lacking sepsis (9 of 48 versus 33 of 386, P= .046). The presence of SNP8 (recipient and/or donor positive) was associated with a higher rate of Herpes viruses reactivation (17 of 21 versus 86 of 173, P= .007). In the SNP8-positive group, a trend for a higher rate of bacteremia well controlled by antibiotics was found (9 of 10 versus 47 of 81, P= .106). In contrast, the presence of SNP13 in recipient and/or donor resulted in a poor response to antibiotics (5 of 11 versus 9 of 10, P= .042). A statistically significant association between the presence of NOD2 SNPs and acute grade ≥ II GVHD was found in a subgroup of HSCT patients who received transplants from unrelated donors with a myeloablative conditioning regimen that included antithymocyte globulin (ATG). In this subgroup of patients, donor positivity for any SNPs investigated (7 of 18 versus 17 of 113, P= .036) and, independently, only the presence of SNP8 (4 of 8 versus 20 of 123, P= .055) were associated with severe grade ≥ II aGVHD. In conclusion, SNP8 positivity in donors or recipients makes patients more prone to Herpes viruses reactivation and bacteremia but not to sepsis. Septic complications were associated with SNP13 polymorphism. SNP8 in donors constitutes a risk factor of severe aGVHD, but only if patients received transplants from unrelated donors and received ATG as part of a conditioning regimen. © 2014.


Jaskula E.,Polish Academy of Sciences | Lange A.,Polish Academy of Sciences | Lange A.,Lower Silesian Center for Cellular Transplantation with National Bone Marrow Donor Registry | Dlubek D.,Polish Academy of Sciences | And 13 more authors.
Tissue Antigens | Year: 2013

Four hundred and ninety-five patients (390 and 105 grafted from unrelated and sibling (SIB) donors, respectively) and their donors were analyzed for the impact of interleukin-10 (IL-10) promoter genotype [rs18000896 (-1082 G/A), rs18000871 (-819 C/T) and rs18000872 (-592 C/A)] on the outcome of hematopoietic stem cell transplantation (HSCT). Patients having ACC haplotype were at a lower risk of acute graft versus host disease (aGvHD, grade>I) if transplanted from human leukocyte antigen (HLA) well-matched (10/10) unrelated donors (20/135 vs 39/117, P<0.001, Pcorr=0.002), which was not seen if patients were transplanted from either sibling (SIB) or poorly matched (<10/10) unrelated donors (MUD). In addition, GCC haplotype positive recipients of unrelated donor transplants tended to be more susceptible to aGvHD (68/199 vs 39/169, P=0.019, Pcorr=0.057). Multivariate logistic regression analysis in the MUD transplanted group showed that donor-recipient human leukocyte antigen (HLA) mismatch [odds ratio (OR)=3.937, P=0.001] and a lack of ACC haplotype in recipients (OR=0.417, P=0.013) played a significant role as independent risk factors of aGvHD grade>I. ACC carriers had higher proportions of FoxP3+ lymphocytes gated in CD4+ lymphocytes as compared with patients with other IL-10 haplotypes. It was seen at the time of hematological recovery (mean±SEM: 3.80±0.91% vs 2.06±0.98%, P=0.012) and 2weeks later (5.32±0.87% vs 2.50±0.83%, P=0.013); -592 C/A polymorphism was separately analyzed and it was found that AA homozygotes tended to have a higher incidence of aGvHD (8/15 vs 116/456, P=0.034) and low proportions of FoxP3 CD4+ lymphocytes in blood (0.43±0.22% vs 4.32±0.71%, P=0.051) measured 2weeks after hematological recovery. Functional IL-10 polymorphism associated features influenced the risk of aGvHD with a positive effect of ACC on the pool of Treg in blood. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


PubMed | Institute of Hematology and Transfusion Medicine, Medical University of Warsaw, Silesian Medical University, Medical University of Gdańsk and 4 more.
Type: Journal Article | Journal: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation | Year: 2014

Three NOD2 polymorphisms (single nucleotide polymorphism [SNP]8 [2104C>T, Arg702Trp], SNP12 [2722G>C, Gly908Arg], and SNP13 [3020insC, Leu1007 fsins C]), identified as disease-associated variants in Crohns disease, have recently been suggested as gene markers of the outcome of hematopoietic stem cell transplantation (HSCT). In the present multicenter study of 464 donor-recipient pairs, we focused on the effect of NOD2 mutation(s) on the risk of infections and acute graft-versus-host disease (aGVHD). The presence of SNP13 in recipients, donors, or both was more frequently seen in patients having sepsis than in those lacking sepsis (9 of 48 versus 33 of 386, P = .046). The presence of SNP8 (recipient and/or donor positive) was associated with a higher rate of Herpes viruses reactivation (17 of 21 versus 86 of 173, P = .007). In the SNP8-positive group, a trend for a higher rate of bacteremia well controlled by antibiotics was found (9 of 10 versus 47 of 81, P = .106). In contrast, the presence of SNP13 in recipient and/or donor resulted in a poor response to antibiotics (5 of 11 versus 9 of 10, P = .042). A statistically significant association between the presence of NOD2 SNPs and acute grade > II GVHD was found in a subgroup of HSCT patients who received transplants from unrelated donors with a myeloablative conditioning regimen that included antithymocyte globulin (ATG). In this subgroup of patients, donor positivity for any SNPs investigated (7 of 18 versus 17 of 113, P = .036) and, independently, only the presence of SNP8 (4 of 8 versus 20 of 123, P = .055) were associated with severe grade II aGVHD. In conclusion, SNP8 positivity in donors or recipients makes patients more prone to Herpes viruses reactivation and bacteremia but not to sepsis. Septic complications were associated with SNP13 polymorphism. SNP8 in donors constitutes a risk factor of severe aGVHD, but only if patients received transplants from unrelated donors and received ATG as part of a conditioning regimen.


PubMed | Institute of Hematology and Transfusion Medicine, Polish Academy of Sciences and Lower Silesian Center for Cellular Transplantation with National Bone Marrow Donor Registry
Type: | Journal: Archivum immunologiae et therapiae experimentalis | Year: 2016

Natural killer (NK) cell licensing status depends on clonal expression of inhibitory killer cell immunoglobulin-like receptors (iKIR) and short term HLA environment. Licensed NK cells are more efficient in tumor killing than unlicensed NK cells. Cognate KIR-HLA pairs in hematopoietic stem cell transplant (HSCT) donor and recipient are decisive for the possible change in the NK cell licensing status after HSCT. We assessed clinical outcomes in 297 patients with lymphoproliferative or myeloproliferative malignancies, or myelodysplastic syndrome in a model with upward licensing, downward resetting, and unchanged licensing genetics status after T cell replate HSCT from unrelated donors. We found extremely low (0%) relapse/progression incidence (RI), and better (59%) event-free survival (EFS) in recipients with upward licensing status and highly increased RI (37.5%), and reduced EFS (8%) among patients with the downward resetting status of repopulated donor NK cells after HSCT, as compared with unchanged NK cell licensing (RI 23%, EFS 47%). These trends were confirmed in adjusted multivariable models (for RI p=6.66E-09, OR=1.47, 95% CI 1.29-1.66 and for EFS p=3.79E-13, OR=1.67, 95% CI 1.50-1.84). Differences in the incidence of acute graft versus host disease (GvHD 62, 69, and 47%) and chronic GvHD (24, 44, and 15%, respectively) in three groups were insignificant. It would be rationale the preferential selection of the donors with upward licensing over downward resetting inhibitory KIR:HLA constellation and inclusion of the KIR genotyping in the donor selection algorithm for malignant patients. Further studies using enlarged cohorts of patients with more homogenous diagnosis are essential to reliably verify these preliminary data.

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