Disruption of iron homeostasis and relevant pharmacotherapies in Alzheimer's disease / 药学学报

Iron is the most abundant metal element to support the body's physiological activities and play crucial roles in the central nervous system. Iron homeostasis is under strict control in normal circumstances, and some diseases will occur once the homeostasis was disrupted. Numerous researches suggest that iron homeostasis disruptes in Alzheimer's disease (AD) and the homeostasis disruption interacts with AD's hallmarks. Dispute still exists on how iron plays a role in AD despite of the great number of researches. This article will focus on iron metabolism, normal function in the brain and recent therapies of AD based on iron chelation.

Militarine alleviates white matter damage and cognitive impairment in rats with chronic cerebral hypoperfusion / 药学学报

Chronic cerebral hypoperfusion is a model for white matter lesions (WMLs) and cognitive impairment. In this study, we used the model in testing the protective effect of (-)-(2R)-1-[(4-β-D-glucopyranosyloxy) benzyl]-4-[4-(β-D-glucopyranosyloxy)benzyl]-2-isobutyl malate (militarine) on the white matter damaged. The model was established by bilateral common carotid ligation. Militarine (10 and 20 mg·kg-1·d-1) or saline was intragastrically administered daily for 30 days following the operation. Militarine (20 mg·kg-1·d-1)-treated rats exhibited significantly shorter escape latency, latency of the first time crossing and more numbers of platform crossings in Morris water maze task. Luxol fast blue (LFB) staining and Western blot analysis indicated that militarine promoted rehabilitation of white matter and increased levels of myelin basic protein (MBP) in the rats. Immunohistochemical staining for 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) revealed that militarine (20 mg·kg-1·d-1) markedly suppressed loss of CNPase-positive oligodendrocytes in the rat model. In conclusion, militarine can improve WMLs and cognitive impairment in the rat chronic hypoperfusion model.

A new multi-factor risk score system for predicting the outcome after allogenic hematopoietic stem cell transplantation / 中国实验血液学杂志

The aim of this study was to develop and investigate the significance of a new multi-factor risk score system to predict the outcome of patients with hematological malignancies received allogeneic hematopoietic stem cell transplantation (allo-HSCT). The impact of pre-, peri-, and post-transplant factors on the outcome including overall survival (OS), disease-free survival (DFS), relapse and transplant-related mortality (TRM) after allo-HSCT were retrospectively analyzed in 122 patients with hematological malignancies at our center. A new risk score system based on the independent risk factors was established and tested. The results showed that absolute monocyte count at day 30 after transplantation (AMC-30, ≥ 536 cells/µl) [hazard ratio (HR) = 0.313, 95% confidential interval (CI):0.156-0.63], WT1( ≥ 1.0%) (HR = 3.268, 95% CI:1.644-6.499), pre-transplant risk grouping (HR = 1.999, 95% CI = 0.993-4.023) were independent prognostic factors of OS and DFS. Patients were divided into 3 groups based on the risk scoring system:group A (no risk factor; score 0), group B (1 risk factor; score 1) and group C (2-3 risk factors; score 2-3). OS at 5 years were 95.1% ± 3.4%, 62.9% ± 6.6% and 36.1% ± 9.6%, respectively (P < 0.0001). DFS at 5 years were 92.6% ± 4.9%, 60.4% ± 6.8% and 15.4% ± 7.1%, respectively (P < 0.0001). The akaike information criterion(AIC) value of the new score system for OS was 331, less than those of AMC-30, WT1, and pre-transplant risk group (346, 343, 346), AIC value for DFS and relapse were 378 and 231, both less than the three single elements(417, 397, 411 and 268, 238, 257). It is concluded that the risk scoring system based on AMC-30, WT1, pre-transplant risk grouping is more highly predictive for clinical outcomes of allo-HSCT than any one of the three single elements.

Association of the ratio of regulatory and effector T cells with recurrence and chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the association of the ratio of regulatory and effector T cells with recurrence and chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT).</p><p><b>METHODS</b>Thirty patients with hematological malignancies who underwent allo-HSCT were classified as recurrence with cGVHD (n=4), non-recurrence with cGVHD (n=14), recurrence without cGVHD (n=5) and non-recurrence without cGVHD (n=7). The different percentage of CD4⁺CD25⁻CD69⁺ regulatory T cells in bone marrow and CD4⁺CD25⁺FoxP3⁺ regulatory T cells, Th1 cells and Th17 cells in peripheral blood were analyzed by flow cytometry.</p><p><b>RESULTS</b>There were no significant differences in all these T-cell subsets among different groups (P>0.05). While the ratio of CD4⁺CD25⁻CD69⁺ regulatory T cells and Th1 cells (0.211±0.177) in 9 recurrence patients was significant higher than that (0.133±0.160) in 21 non-recurrence patients (P=0.033). The ratio were also significance between recurrence without cGVHD and non-recurrence without cGVHD patients (0.167±0.073 vs 0.073±0.057, P=0.048), and between recurrence with cGVHD and non-recurrence without cGVHD patients (0.218±0.113 vs 0.073±0.057, P=0.024). Furthermore, the ratio of CD4⁺CD25⁺FoxP3⁺ regulatory T cells and Th17 cells was significant lower (1.975±2.045) in 18 cGVHD patients than that of 12 without cGVHD patients (3.198±1.132, P=0.010), and the ratio was also significant lower in non-recurrence patients with cGVHD (1.695±1.178) than that of without cGVHD (3.446±1.376, P=0.028).</p><p><b>CONCLUSION</b>Our results show that the ratio of CD4⁺CD25⁻CD69⁺ regulatory T cells and Th1 cells raise in recurrence patients, and the ratio of CD4⁺CD25⁺FoxP3⁺ regulatory T cells and Th17 decrease in cGVHD patients, which suggest that the ratio of regulatory and effector T cells had association with recurrence and cGVHD in patients with allo-HSCT.</p>

Reconstitution kinetics of T helper cells subsets post unmanipulated allogeneic blood and marrow transplantation / 中华血液学杂志

<p><b>OBJECTIVE</b>To compare the differences of the T helper cell reconstitution kinetics between HLA matched or HLA mismatched allo-HSCT through exploring the reconstitution kinetics of CD4+ CD25+Foxp3+ cells (CD4+ Treg), CD8+CD25+Foxp3+ cells (CD8+Treg), CD4+CD25-CD127+ conventional T cells (Tcon) and the secretion of IL-17a and IFN-γ in CD4+ T cells (Th17 and Th1 cells) or CD8+ T cells (Tc17 and Tc17 cells) post allogeneic hematopoietic stem cells transplantation (allo-HSCT).</p><p><b>METHODS</b>From December 2011 to October 2012, the peripheral blood (PB) of 20 patients undergoing HLA matched (10 patients) or mismatched (10 patients) allo- HSCT without acute graft-versus-host disease (aGVHD) and of 10 related healthy donors were collected to analyze the expression of CD25+Foxp3+, IL-17a, IFN-γ and CD127 expression through 8-colour Flow cytometer.</p><p><b>RESULTS</b>(1) The reconstitution kinetics of CD3+ T cells, CD4+ T cells, CD8+ T cells absolute numbers were comparable within 2 month post HLA matched and mismatched transplantation. (2)The absolute numbers of CD4+ Treg cells[+30 d, 8.46 (0.36-27.41) cells/μl 1.10 (0.04-8.03) cells/μl, P<0.05; +60 d, 8.50 (1.16-36.20) cells/μl vs 2.73 (0.34-6.84) cells/μl, P<0.05], Tcon cells[+30 d, 72.69 (3.85-211.73) cells/μl vs 13.41 (0.48-96.17) cells/μl, P<0.05; +60 d, 100.85 (16.28-267.20) cells/μl vs 47.75 (6.34-143.04) cells/μl, P<0.05], as well as Th17 cells[+30 d, 2.34 (0.02-6.87) cells/μl vs 0.20 (0.02-1.34) cells/μl, P<0.05; + 60 d, 1.90 (0.36- 7.82) cells/μl vs 0.46 (0.03-1.39) cells/μl, P<0.05]and Tc17 cells[+ 30 d, 1.08 (0.07-15.03) cells/μl vs 0.25 (0.01- 0.81) cells/μl, P<0.05;+60 d, 1.85 (0.63-26.57) cells/μl vs 0.46 (0.01-3.66) cells/μl, P<0.05]within 2 month post HLA matched HSCT were significantly higher than those post HLA- mismatched HSCT. However, the absolute numbers of Th1 cells or Tc1 cells within 2 month post HLA-matched or HLA-mismatched HSCT were comparable. (3) The ratio of Th1 and Th17 cells, or the ratio of Tc1 and Tc17 cells were significantly higher within 2 month post HLA-mismatched allo-HSCT compared to those post HLA-matched HSCT.</p><p><b>CONCLUSION</b>The reconstitution kinetics of T helper cells subset were different at early stage post HLA-matched or HLA-mismatched allo-HSCT, which might be help to explain the different rate or the different involved organ of the acute graft-versus-host diseases (aGVHD) post HLA-matched or -mismatched allo-HSCT.</p>

A comparison of NK cell subsets between rhG-CSF mobilized peripheral blood grafts and bone marrow grafts from healthy donors / 中华血液学杂志

<p><b>OBJECTIVE</b>To analyze the difference in NK cell subsets between recombination human granulocyte colony-stimulating factor (rhG-CSF) mobilized peripheral blood grafts (G-PB) and bone marrow grafts (G-BM) from healthy donors.</p><p><b>METHODS</b>From July 2009 to September 2009, G-PB and G-BM from 28 related donors were collected to analyze lymphocytes, NK cells and NK cell secretion of interferon-γ (IFN-γ, NK1), interleukin-13 (IL-13, NK2), transforming growth factor-β (TGF-β) and interleukin-10 (IL-10, NKr) by flow cytometry.</p><p><b>RESULTS</b>The percentage of lymphocytes in G-PB was significantly higher than that in G-BM (P < 0.01). The proportions of NK cells and NK1, NK2, NKr subsets among lymphocytes were significantly higher in G-BM than in G-PB (P < 0.05), and so were the percentage of NK2, NKr cells among NK cells (P < 0.01), but no significant difference in the percentage of NK1 cells among NK cells between G-PB and G-BM. The ratios of IL-13 and IFN-γ, of TGF-β and IFN-γ, or of IL-10 and IFN-γ in G-BM were significantly higher than those in G-PB (P = 0.010, 0.002, or 0.000, respectively).</p><p><b>CONCLUSION</b>The increased proportion of NK2 and NKr in G-BM might be helpful to explain the lower immunoreactivity of G-BM than that of G-PB, although the proportion of NK1 in G-BM and G-PB is similar.</p>

Effects of rhG-CSF mobilization on Th17 cells in donors' peripheral blood and bone marrow grafts / 中国实验血液学杂志

The study was aimed to explore the effects of recombination human granulocyte colony-stimulating factor (rhG-CSF) on Th17 cells in donors' peripheral blood (GPB) and bone marrow grafts (GBM). 25 healthy donors were injected subcutaneously with rhG-CSF 5 µg/(kg·d) for 5 consecutive days. GBM and GPB were harvested after injection on day 4 and 5 respectively. Some of these donors' steady-state bone marrow (SSBM) and steady-state peripheral blood (SSPB) were harvested before rhG-CSF injection. The changes of IL-17 secreted by T cells in donor BM and PB before and after mobilization were detected by flow cytometry. The results showed that the ability to secrete IL-17 from CD4(+) T cells and CD8(+) T cells in GBM was significantly lower than those in SSBM (GBM vs SSBM Th17/CD4(+) T, 0.74% ± 0.27% vs 1.78% ± 1.19%, p < 0.05; Tc17/CD8(+)T, 0.19% ± 0.16% vs 0.36% ± 0.37%, p < 0.05), changes in peripheral blood and bone marrow were same (GPB vs SSPB Th17/CD4(+) T, 1.82% ± 0.91% vs 3.26% ± 1.89%, p < 0.01; Tc17/CD8(+) T, 0.21% ± 0.17% vs 0.44% ± 0.28%, p < 0.01). The ratios of Th17/CD4(+) T and Tc17/CD8(+) T in GPB were higher than in GBM (p < 0.05, p < 0.01). It is concluded that rhG-CSF in vivo can inhibit the generation of Th17 cells both in bone marrow and peripheral blood grafts, and it may be partial reason for GPB/GBM mixed transplantation without increasing the GVHD incidence.

Determination of optimal time to second allogeneic peripheral blood stem cell harvest from healthy donors / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the optimal time for second allogeneic peripheral blood stem cell grafts (PBSC) harvest from healthy donors after in vivo recombinant human granulocyte colony-stimulating factor application (rhG-CSF).</p><p><b>METHODS</b>Thirty-eight healthy donors of second collection (group A) were treated with subcutaneous rhG-CSF \[5 microgxkg(-1)xd(-1)\] for five consecutive days and followed by leukapheresis on day 5 and 6. The control group (group B) was thirty-eight healthy donors who had received a first PBSC collection previously. Group A was reclassified as group C (< or = 9 months) and group D (> 9 months) according to the 75% quantile of interim time between first and second collection. The quantities of lymphocytes of CD3(+), CD3(+)CD4(+), CD3(+)CD8(+), CD14(+), CD34(+) cells and CD3(+)CD4(-)CD8(-) T cells were determined by multi-color flow cytometry.</p><p><b>RESULTS</b>The median number of CD3(+)CD8(+) (25.51 x 10(8)) and CD34(+) cells (0.51 x 10(8)) in group A were significantly lower than that (31.55 x 10(8) and 0.70 x 10(8) respectively) in group B (P < 0.05), and so did the CD3(+)CD8(+) (23.42 x 10(8)) and CD34(+) cells (0.42 x 10(8)) in group C than that in group B (P < 0.05). There was no statistical difference in median numbers of T cell subsets, monocytes, and CD34(+) cells between group B and group D (P > 0.05). The cell ratios of CD4(+)/CD8(+), CD14(+)/CD3(+) and CD3(+)CD4(-)CD8(-) T/CD3(+) in PBSC in group A, group C, and group D were similar to that in group B (P > 0.05). Sperman analysis showed a positive correlation between the total CD34(+) cells in second collection and the interval time from first to second collection (r = 0.357, P = 0.028).</p><p><b>CONCLUSION</b>Nine months after the first collection maybe an optimal time for the second PBSC collection. For those who undergo second PBSC collection within 9 months, more circulation blood should be extracted to ensure enough immunological and hematopoietic compositions.</p>

Peripheral monocyte counts at first collection of allo-grafts predicts amount of CD34(+) cells in mixture of rhG-CSF primed bone marrow and mobilized peripheral stem cell grafts / 中国实验血液学杂志

This study was purposed to investigate the relation of monocyte counts in peripheral blood (PB) at the first collection of allograft to the amount of CD34(+) cells in the mixture of recombinant human granulocyte colony-stimulating factor (rhG-CSF)-primed bone marrow graft (G-BM) and rhG-CSF mobilized peripheral stem cell grafts (G-PB). 70 healthy donors were treated with rhG-CSF [5 microg/(kg.d)] injected subcutaneously for 5 consecutive days. Bone marrow grafts and peripheral blood grafts were harvested on the 4th and 5th days respectively. Blood cell counts at the first collection of allografts were determined by blood analyzer XL2100, the amount of CD34(+) cells in G-BM and G-PB were determined by flow cytometry. The results showed that the monocyte counts in the PB of the 70 healthy donors were (1.15 +/- 0.60) x 10(9)/L. The amount of total CD34(+) cells in the G-BM, G-PB and mixture grafts were (5.85 +/- 2.93) x 10(7), (1.33 +/- 0.77) x 10(8), and (1.92 +/- 0.86) x 10(8) respectively. Pearson and Spearman correlation analysis indicated that the counts of monocyte at the first collection of allografts correlated positively with the amount of total CD34(+) cells in the G-BM (correlation coefficient, r = 0.265, p = 0.027), G-PB (r = 0.340, p = 0.004) and mixture grafts (r = 0.398, p = 0.001). Stepwise Linear Regression Model analysis also showed that the counts of monocytes in the PB correlated positively with the amount of CD34(+) cells in the G-BM, G-PB and mixture grafts (p = 0.027, 0.004 and 0.001 respectively). The sensitivity and specificity of the monocyte counts to predict the amount of CD34(+) cells in the mixture grafts were 71% and 70% respectively (p = 0.007). In conclusion, the monocyte counts in the PB at the first collection of allografts after rhG-CSF treatment of healthy donors may be a simple and practical indicator for harvest of CD34(+) cell amount in the mixture grafts.

Modulation of adhesion molecule expression on T cells in bone marrow after in vivo rhG-CSF application / 中国实验血液学杂志

The aim of study was to investigate the modulation effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on adhesion molecule expression of memory T lymphocyte in the bone marrow grafts. rhG-CSF was administered in 41 donors by subcutaneous injection for 5 consecutive days. Bone marrow grafts were collected on day 4. The percentages of CD4+ and CD8+, and the expressions of CD49d, CD54, CD62L and CD11a on donor T cells of steady state-bone marrow grafts (SS-BM, n=11) and rhG-CSF primed bone marrow (G-BM, n=30) were analyzed by using multi-color flow cytometry. The results indicated that the percentages of CD4+ and CD8+ T cells were significantly lower in G-BM than those in SS-BM (p<0.05). There were no significant differences in the percentages of memory CD4+ and CD8+ T cells between SS-BM and G-BM (p>0.05). The expressions of CD49d on CD4+ and CD8+T cells were significantly lower in G-BM than that in SS-BM (p<0.05). Compared with SS-BM, the expressions of CD54 on CD4+, memory CD4+ T cells and CD8+ T cells were significantly lower in G-BM (p<0.05). The expressions of CD62L on CD4+ and CD8+ T cells and memory T cells were all significantly lower in G-BM (p values were all less than 0.001). The expressions of CD11a on CD4+, memory CD4+ T cells were significantly lower in G-BM than that in SS-BM (p<0.05). There were no significant differences in the expression of CD11a on CD8+, memory CD8+ T cells between SS-BM and G-BM (p>0.05). It is concluded that the expression of cell adhesion molecules on the CD4+ and CD8+ T cells in G-BM is down-regulated after rhG-CSF treatment of healthy donors.

Comparative analysis of naive and memory CD4(+) and CD8(+) T-cell subsets in rhG-CSF mobilized peripheral blood and steady-state bone marrow / 中国实验血液学杂志

The study was aimed to analyze the difference of naive and memory CD4(+) and CD8(+) T-cell subsets between steady-state bone marrow (SS-BM) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) mobilized peripheral blood grafts (G-PB). Four CD4(+) and CD8(+) T-cell subsets classified according to the expression of CD45RA and CD62L were determined by three-color flow cytometry. The results showed that the percentage of CD4(+), CD8(+) T-cell subsets and the ratios of CD4/CD8 in G-PB were significantly higher than those in SS-BM (p < 0.05). The percentage of CD4(+) naive T-cells in G-PB was significantly lower than that in SS-BM (p < 0.001). As compared with SS-BM, the percentage of CD4(+) effector memory T-cells was significantly high in G-PB (p < 0.001). There were no significant differences in the percentages of the four CD8(+) T-cell subsets between SS-BM and G-PB (p > 0.05). The percentage of CD4(+)CD62L(+) T-cells in G-PB was significantly lower than that in SS-BM (p = 0.001). The absolute numbers of CD4(+) and CD8(+) T-cell subsets, the eight naive and memory CD4(+) and CD8(+) T-cell subsets were significantly higher in G-PB than those in SS-BM (p < 0.001). It is concluded that the difference of naive and memory CD4(+) and CD8(+) subsets between G-PB and SS-BM may partially explain why the incidence and severity of acute graft-versus-host disease (GVHD) was similar and the incidence of chronic GVHD was different after transplantation with SS-BM or G-PB.

Effect of bone marrow graft collection on composition of peripheral blood stem cell grafts from healthy donors after recombinant human granulocyte colony-stimulating factor application in vivo for mobilization / 中国实验血液学杂志

The study was purposed to investigate the effect of bone marrow graft collection on the composition of peripheral blood stem cell grafts in healthy donors after recombinant human granulocyte colony-stimulating factor (rhG-CSF) application in vivo. Sixty-two healthy donors were treated with rhG-CSF [5 microg/(kg.d)] injected subcutaneously for five consecutive days. Donors were divided into groups A and B, and 31 donors were there in each group. Bone marrow grafts and peripheral blood stem cell grafts were harvested on the day 4 and 5 respectively in group A. In group B, only peripheral blood grafts were collected on both the day 4 and 5. The quantities of the cell components, CD3(+), CD3(+)CD4(+), CD3(+)CD8(+), CD14(+), CD34(+) cells and CD3(+)CD4(-)CD8(-) T cells were determined by multi-color flow cytometry. The results showed that median counts of nuclear cells (1.56 x 10(5)), lymphocytes (8.56 x 10(4)), CD3(+) (6.12 x 10(4)), CD3(+)CD4(+) (3.38 x 10(4)), CD3(+)CD8(+) (2.27 x 10(4)), CD14(+) (3.83 x 10(4)), CD34(+) cells (744) and CD3(+)CD4(-)CD8(-) T cells (3588) per microliter of peripheral blood stem cell grafts in group A were similar to counts of nuclear cells (1.40 x 10(4)), lymphocytes (7.34 x 10(4)), CD3(+) (5.32 x 10(4)), CD3(+)CD4(+) (3.06 x 10(+)), CD3(+)CD8(+) (1.83 x 10(4)), CD14(+) (3.21 x 10(4)), CD34(+) cells (554) and CD3(+)CD4(-)CD8(-) T cells (3120) in group B (p > 0.05). There were no difference in the ratios of CD4(+) cells/CD8(+) cells, CD14(+) cells/CD3(+) cells and CD3(+)CD4(-)CD8(-) T cells/CD3(+) cells in peripheral blood stem cell grafts between group A [1.52 (0.54 - 2.87)], [0.57 (0.15 - 1.64)], [0.064 (0.018 - 0.673)] and group B [1.68 (0.31 - 3.35)], [0.59 (0.18 - 1.25)], [0.063 (0.021 - 0.136)] (p > 0.05). It is concluded that no effect of bone marrow graft collection on the composition of peripheral blood stem cell grafts in the same donor is found after rhG-CSF application in vivo, bone marrow grafts and peripheral blood stem cell grafts can be collected respectively or simultaneously.

Differential expression levels of killer immunoglobin-like receptor genotype in patients with hematological malignancies between high-risk and standard-risk groups / 中国实验血液学杂志

This study was purposed to investigate the killer immunoglobulin-like receptor (KIR) genotype in patients with hematological malignancies. The sequence specific primer-polymerase chain reaction (PCR-SSP) technique was performed for the amplification of six inhibitory KIR genes (KIR2DL1-2DL4, 3DL1-3DL2) and six activating KIR genes (KIR2DS1-S5, 3DS1). The methods of KIR-SSP was used to determine the KIR genotypes of 54 leukemia patients, including 14 patients with acute myeloid leukemia (AML), 16 with acute lymphoblastic leukemia (ALL), 20 with chronic myeloid leukemia (CML), 3 with myelodysplastic syndrome (MDS) and 1 with acute myeloid-lymphoblast leukemia (AMLL). 54 patients were classified as high risk group (n = 27) and standard risk group (n = 27). The expression of KIR in NK cells and T cells was detected by flow cytometry. The frequencies of activating KIR genes in standard risk group were higher than those in high risk group, especially 2DS1 (p = 0.014), or 2DS2 (p = 0.046), or 3DS1 (p = 0.027). However, the frequencies of inhibitory KIR genes in standard risk group were similar to those in high risk group (p > 0.05). The frequencies of activating KIR genes were also higher in standard risk patients with acute AML, as compared with those in high risk patients with acute AML, particularly 2DS1 (66.7% vs 29.4%, p = 0.022), 2DS2 (57.6% vs 17.6%, p = 0.013), and 2DS3 (33.3% vs 5.9%, p = 0.039). The percentages of patients in high-risk group who expressed more than two kinds of activating KIRs were lower that those in standard-risk group (p = 0.035). There was no difference in the expressions of CD158a, CD158b, and CD158e on NK cells and T cells between high-risk group and standard-risk group (p > 0.05). In conclusions, different expressions of activating KIR genes were found in patients between high-risk group and standard-risk group.

The prognostic analysis of KIR ligand mismatch in HLA-mismatched hematopoietic stem cell transplantation / 中华血液学杂志

<p><b>OBJECTIVE</b>To evaluate the prognostic implication of the killer-immunoglobulin like receptor (KIR) ligand mismatch in HLA mismatched hematopoietic stem cell transplantation (HSCT).</p><p><b>METHODS</b>Ninety-four leukemia patients undergoing unmanipulated HLA-mismatched/haploidentical blood and marrow HSCT enrolled this study.</p><p><b>RESULTS</b>Multivariate analysis showed that both KIR ligand mismatch (HR 2.833, CI, 1.286 - 6.241, P = 0.01) and doses of T cells (HR 3.059, CI, 1.292 - 7.246, P = 0.011) were independent risk factors for the acute graft versus host disease (aGVHD). In addition, compared to those without KIR ligand mismatch, patients with KIR ligand mismatch had the more adverse effect of 'high' dose T cells (> 1.48 x 10(5)/kg) on aGVHD (100% vs 63.3%, P = 0.036), and had more incidence of aGVHD with HLA-C mismatch (80.0% vs 57.4%, P = 0.056). Since multivariate analysis demonstrated that high risk leukemia was the only predictor for transplant related mortality (TRM), relapse and overall survival (OS), the effect of KIR ligand mismatch on prognosis in standard and high risk patients was further analyzed. The differences in TRM (50.0% vs 7.6%, P = 0.005) and OS (50.0% vs 88.4%, P = 0.014) between patients with and without KIR ligand mismatch were most striking for standard risk patients.</p><p><b>CONCLUSION</b>KIR ligand mismatch is a poor prognosis factor for patients underwent HLA mismatched HSCT, and is a useful parameter for donor selection.</p>

CD34 cells and T cell subsets in recombinant human granulocyte colony-stimulating factor primed bone marrow grafts from donors with different characteristics / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the cell composition in granulocyte colony-stimulating factor One (rhG-CSF) primed bone marrow grafts (G-BM) from donors with different characteristics.</p><p><b>METHODS</b>hundred and fifty healthy donors were injected subcutaneously rhG-CSF (5 microg x kg(-1) x d(-1)) in five consecutive days. Bone marrow and peripheral blood stem cells were harvested at day 4 and day 5. The number of CD3, CD3+ CD4+, CD3+ CD8+, CD14+ , CD34+ and CD3+ CD4- CD8- cells were determined by multicolor flow cytometry. Cell composition of G-BM from donors with different characteristics, including sex, age, weight, pregnancy were analysed.</p><p><b>RESULTS</b>The absolute number of nuclear cells (NCs), lymphocytes, CD3+, CD3+ CD4+, CD3+ CD8+, CD14+, CD34+ and CD3+ CD4- CD8- cells in G-BM were 31 050 (12 200 -58 100), 2122 (506 - 6618), 1344 (307 - 4791), 692 (145 - 3038), 616 (112 - 2575), 986 (265 -2958), 63 (11 -505) and 83 (9 -390) per microliter, respectively. The number of NCs [33 800 (18 600 - 57 100)], CD34+ cells [76 (22 -505)], and CD3+ CD4+ CD8- regulatory T cells [97 (11 - 380)] harvested from younger donors (aged < or = 38 years) were significantly higher than those from older ones (aged > 38) [28000 (12200-58100), 49 (11-220), and 65 (9 - 389) per microliter (P = 0.027, < 0.001 and = 0.001, respectively)]. Compared with that in donors with peripheral blood monocytes (PBMs) < or = 0.37 x 10(9)/L, higher number of NCs in G-BM [27 150 (13 800 - 58 100) vs 33 550 (12 200 - 57 100), P = 0.005] were collected in donors with PBMs > 0.37 x 10(9)/L. Multivariate analysis showed that donors age (< or = 38 vs > 38 years; P = 0.01) and monocyte number in peripheral blood (< or = 0.37 x 10(9)/L vs > 0.37 x 10(9)/L; P = 0. 003) were factors predicting for NC yields, and donors age ( < or = 38 vs > 38 years; P < 0.001) was factor predicting for yields of CD34+ cells (P < 0.001) and CD3+ CD4- CD8- regulatory T cells (P = 0.001) collection.</p><p><b>CONCLUSION</b>Donor age is a factor for the yields of NCs, CD34+ cells, and CD3+ CD4- CD8- regulatory T cells collection in G-BM, and donor's PBMs more than 0.37 x 10(9)/L, is another factor affecting NCs harvests.</p>

Effect of granulocyte colony-stimulating factor on immunological regulation and its application in allogenic hematopoietic stem cell transplantation / 中国实验血液学杂志

The granulocyte colony-stimulating factor (G-CSF) plays an important role in regulating function of immunocytes in process of mobilizing hematopoietic stem cells. The deep understanding of the immunoregulatory effects of G-CSF has important significance to improve the outcomes of patients with hematological malignancies after allogeneic hematopoietic stem cell transplantation, included alleviating acute graft-versus-host disease, maintaining or enhancing graft-versus-leukemia effects and decreasing the relapse rates. In this article, the immunoregulatory effect of G-CSF on graft of peripheral blood and bone marrow, the immunoregulation of G-CSF and allo-hematopoietic stem cell transplantation, as well as the prospective trend of research on immunoregulatory effects of G-CSF were reviewed.

Influence factors of reconstitution of killer cell immunoglobulin-like receptor on NK cells following non-T-cell-depleted haploidentical hematopoietic stem cell transplantation / 中华血液学杂志

<p><b>OBJECTIVE</b>To explore the influence factors of reconstitution of killer cell immunoglobulin-like receptor (KIR) on NK cells in the early stage after non-T cells depletion (non-TCD) HLA-mismatched hematopoietic stem cell transplantation (HSCT).</p><p><b>METHODS</b>The expression of KIR (CD158a, CD158b, CD158e) on NK cells from peripheral blood (PB) in 24 patients and their donors before and after HLA-mismatched non-TCD HSCT on day +30, +60, were detected by flow cytometry (FCM). Meanwhile the number of the CD3, CD4, CD8, CD14, CD34 positive cells in the allograft were also tested by FCM.</p><p><b>RESULTS</b>The high dose of CD4+ T cells in the allograft was positively correlated with increased aGVHD occurrence and inversely with the expression of CD158a, CD158aCD158b and CD158e on day +30 and +60. Furthermore, the expression of the CD158b [(19.27 +/- 9.40)% vs (28.92 +/- 10.59)%, P = 0.018 ] and CD158aCD158b [(7.30 +/- 4.73)% vs ( 14.26 +/- 9.71)%, P = 0.016] were higher in patients with 0 - I aGVHD than in patients with II - IV aGVHD.</p><p><b>CONCLUSION</b>Both of the T cells in the allograft and the occurrence of GVHD in the early stage after transplantation delayed the recovery of KIR on NK cells.</p>

Effects of rhG-CSF mobilization on immunological properties of grafts from peripheral blood and bone marrow / 中国实验血液学杂志

This study was aimed to investigate the difference of immunological properties between recombination human granulocyte colony-stimulating factor (rhG-CSF) mobilized peripheral blood grafts (G-PB) and rhG-CSF primed bone marrow grafts (G-BM). The lymphocyte proliferation ability and the quantities of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) secreted by T cells were determined by using MTT assays and sandwich ELISA; T cell subgroups, dendritic cells (DC), monocytes and the expression of CD28 costimulatory molecules on T cells were determined by multicolor flow cytometry. The results showed that the absolute numbers of lymphocytes, monocytes, CD3+, CD4+ and CD8+ T cells as well as DC1 and DC2, the ratios of CD4/CD8 in G-PB were significantly higher than those in G-BM, respectively (P < 0.001). T cell proliferation ability was significantly higher in G-PB than that in G-BM (P < 0.05). The quantities of IFN-gamma and IL-4 secreted by T cells per microliter of G-PB was significantly higher than those of G-BM, the ratios of IL-4/IFN-gamma were significantly lower in G-PB than that in G-BM (P < 0.001). As compared with G-BM, the ratio between DC2 and T-lymphocyte was significantly low in G-PB (P < 0.01), whereas the percentage and overall expression of CD28 on CD4+ and CD8+ cells were significantly high in G-PB (P < 0.05). It is concluded that T cell hyporesponsiveness of G-PB and G-BM induced by rhG-CSF in vivo were confirmed to be different, and the difference of immunological properties between G-PB and G-BM may explain the lower incidence of GVHD and lower relapse after G-BM and G-PB transplantation respectively.

Comparative study on the treatment effects with rhIL-11 and rhG-CSF in combination or alone on immune function / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the effect of in vivo administration of rhG-CSF and/or rhIL-11 on mice immune system function.</p><p><b>METHODS</b>T cell subgroups, suppressor T cells (CD8+ CD28-, CD4+ CD25+, CD3+ CD4- CD8- T cells), expression of CD28 on T cells, and spleen T cells intracellular IL4/IFN-gamma secretion were determined by multicolor flow cytometry. MTT was used to determine the T cell proliferation capacity and mixed lymphocyte reactions.</p><p><b>RESULTS</b>In vivo administration of cytokines decreased the percentage of lymphocytes (P < 0.05), rhIL-11 and rhG-CSF in combination significantly decreased the CD4+/CD8+ ratio and increased the percentage of CD8+ CD28- suppressor T cells compared to either cytokine alone (P < 0.01). There was no difference in the percentage of CD3+ CD4- CD8- and CD4+ CD25+ suppressor T cells between either of the cytokines. Furthermore, cytokines treatments significantly decreased the capacities of splenic T cells proliferation and the response to alloantigens compared with the PBS treatment (P < 0.05), the combination group being more significantly decreased (P < 0.01). And cytokines treatment significantly decreased the production of IFN-gamma and increased the production of IL-4 compared with the PBS treatment(P < 0.05). The ratio of IFN-gamma/IL-4 were significantly decreased after the combination compared with either of them alone.</p><p><b>CONCLUSION</b>The combination of rhIL-11 and rhG-CSF is potentially synergistic in the induction of immune tolerance by their effects on the proliferation capacity and function of T lymphocytes.</p>

In vivo effect of rhG-CSF on the CXCR-4 expression of hematopoietic progenitor or stem cells in bone marrow and peripheral blood / 中国实验血液学杂志

To investigate the effect of in vivo rhG-CSF on the CXCR-4 expression of hematopoietic progenitor or stem cells in bone marrow and peripheral blood, the expressions of CXCR-4 on CD34(+) cells and mononuclear cells of bone marrow and peripheral blood from healthy donor before and after mobilization were detected by three-color fluorescence analysis. The results showed that a significantly higher expression of CXCR4 on CD34(+) cells of bone marrow and mononuclear cells of peripheral blood, as compared to those before mobilization. There were no significant differences of CXCR-4 expression of CD34(+) cells in peripheral blood after mobilization, as compared with steady state bone marrow, and no dynamic change of mononuclear cells expressing CXCR-4 in bone marrow before and after mobilization. Significant positive correlation were found between the percentage of CD34(+) cells in bone marrow before mobilization and that in bone marrow and peripheral blood after mobilization; furthermore, the percentage of CD34(+) cells of bone marrow before mobilization had a positive correlation with both the count of CD34(+) cells per kilogram on the day of collection in bone marrow and peripheral blood after mobilization. It is concluded that the mobilization of hematopoietic cells may be involved in the signaling of SDF-1/CXCR-4 according to the increase of the surface expression of CXCR-4 on CD34(+) cells in bone marrow and on the MNC in peripheral blood after mobilization; meanwhile, the high surface expression of CXCR-4 may contribute to the MNC engraftment, monitoring the percentage of CD34(+) cells in bone marrow before mobilization can be regarded as a predictive factor for mobilization outcome.