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1.
Giorgia Serafini Marco Andreani Manuela Testi MariaRosa Battarra Andrea Bontadini Eika Biral Katharina Fleischhauer Sarah Marktel Guido Lucarelli Maria Grazia Roncarolo Rosa Bacchetta 《Haematologica》2009,94(10):1415-1426
Background
Thalassemia major can be cured with allogeneic hematopoietic stem cell transplantation. Persistent mixed chimerism develops in around 10% of transplanted thalassemic patients, but the biological mechanisms underlying this phenomenon are poorly understood.Design and Methods
The presence of interleukin-10-producing T cells in the peripheral blood of eight patients with persistent mixed chimerism and five with full donor chimerism was investigated. A detailed characterization was then performed, by T-cell cloning, of the effector and regulatory T-cell repertoire of one patient with persistent mixed chimerism, who developed stable split erythroid/lymphoid chimerism after a hematopoietic stem cell transplant from an HLA-matched unrelated donor.Results
Higher levels of interleukin-10 were produced by peripheral blood mononuclear cells from patients with persistent mixed chimerism than by the same cells from patients with complete donor chimerism or normal donors. T-cell clones of both host and donor origin could be isolated from the peripheral blood of one, selected patient with persistent mixed chimerism. Together with effector T-cell clones reactive against host or donor alloantigens, regulatory T-cell clones with a cytokine secretion profile typical of type 1 regulatory cells were identified at high frequencies. Type 1 regulatory cell clones, of both donor and host origin, were able to inhibit the function of effector T cells of either donor or host origin in vitro.Conclusions
Overall these results suggest that interleukin-10 and type 1 regulatory cells are associated with persistent mixed chimerism and may play an important role in sustaining long-term tolerance in vivo. These data provide new insights into the mechanisms of peripheral tolerance in chimeric patients and support the use of cellular therapy with regulatory T cells following hematopoietic stem cell transplantation. 相似文献2.
Relationship between mixed chimerism and rejection after bone marrow transplantation in thalassaemia
Marco Andreani Manuela Testi Mariarosa Battarra Paola Indigeno Annalisa Guagnano Paola Polchi Giorgio Federici Guido Lucarelli 《Trasfusione del sangue》2008,6(3):143-149
Background
Thalassaemia is a genetic disease that requires a hypertransfusion regimen to treat the anaemia caused by enhanced red blood cell destruction. The only radical cure for thalassaemia is to correct the genetic defect by bone marrow transplantation from an HLA-identical donor capable of producing and maintaining a normal haemoglobin level in the recipient. Complete donor haematopoiesis is not essential for sustained engraftment and the simultaneous presence of haematopoietic cells of both donor and recipient origin is not a rare event after a transplant.Patients and methods
The evolution of marrow engraftment of 93 transplanted thalassaemic patients, all from Middle East or Asian countries, was monitored by analysis of short tandem repeats.Results
Forty-three of 93 (46%) patients experienced a status of mixed chimerism early after bone marrow transplantation. Results of further engraftment analysis in these patients showed in 27 complete donor engraftment; rejection occurred in seven, while eight maintained the presence of both host and donor-derived cells. Interestingly, five out of the seven patients who rejected their transplant showed more than 25% residual host cells early after transplantation.Discussion and conclusion
Our study confirmed that the presence of large amounts of residual host cells within the first 2 months after a transplant is a risk factor for graft rejection also in a group of patients with wide ethnic heterogeneity, irregular transfusion regimens and/or poor chelation treatment. Ten percent of the transplanted thalassaemic patients maintained coexistence of donor and recipient cells, showing a stable functional graft, characterized by normal production of beta globin chains and high levels of haemoglobin. A mechanism responsible for peripheral tolerance induction, such as the production of specific regulatory T-cell clones, seems to play a key role in the induction of long-term tolerance after the transplant. 相似文献3.
Federico Moscard�� Jaime Sanz Leonor Senent Susana Cantero Javier de la Rubia Pau Montesinos Dolores Planelles Ignacio Lorenzo Jose Cervera Javier Palau Miguel A. Sanz Guillermo F. Sanz 《Haematologica》2009,94(6):827-832
Background
Cord blood transplant is a feasible treatment alternative for adult patients with hematologic malignancies lacking a suitable HLA-matched donor. However, the kinetics of myeloid recovery is slow, and primary graft failure cannot be detected easily early after transplantation. We investigated the impact of hematopoietic chimerism status from unselected marrow cells 14 days after transplantation on predicting engraftment after a cord blood transplant.Design and Methods
Seventy-one adult patients with hematologic malignancies undergoing single-unit unrelated donor cord blood transplantation after a myeloablative conditioning regimen were included in the study. All patients received conditioning regimens based on busulfan, thiotepa and antithymocyte globulin. Chimerism status was assessed analyzing short tandem repeat polymorphisms.Results
The cumulative incidence of myeloid engraftment at 1 month was significantly lower in patients with mixed chimerism than in those with complete donor chimerism (55% vs. 94%; p<0.0001). For patients achieving myeloid recovery, the median time of engraftment was 16 days when donor chimerism at day + 14 was higher than 90%, compared with 24 days when donor chimerism was below this level (p<0.001). A donor chimerism level of 65% was found to be the best cut-off point for predicting primary graft failure, with a sensitivity of 97% and a specificity of 80%. The incidence of primary graft failure was 67% for patients with less than 65% donor chimerism at day +14 as compared to only 2% for those with more than 65% donor chimerism (p<0.001). Patients with mixed chimerism also had a lower cumulative incidence of platelet engraftment than those with complete chimerism (62% vs. 89%; p=0.01).Conclusions
Donor-recipient chimerism status at day +14 predicts engraftment after a single-unit cord blood transplant in adults. 相似文献4.
Mueller RJ Stussi G Puga Yung G Nikolic M Soldini D Halter J Meyer-Monard S Gratwohl A Passweg JR Odermatt B Schanz U Biedermann BC Seebach JD 《Haematologica》2011,96(1):119-127
Background
The possibility that allogeneic hematopoietic stem cell transplantation performed across the ABO blood group-barrier is associated with an increase of graft-versus-host disease, in particular endothelial damage, has not been elucidated so far. For this reason, we investigated the level of endothelial cell chimerism after allogeneic hematopoietic stem cell transplantation in order to delineate the role of hematopoietic stem cells in endothelial replacement.Design and Methods
The frequency of donor-derived endothelial cells was analyzed in 52 hematopoietic stem cell transplant recipients, in 22 normal skin biopsies, in 12 skin samples affected by graft-versus-host disease, various tissues from five autopsies and four secondary solid tumors by ABH immunohistochemistry, XY fluorescence in situ hybridization and short tandem repeat analysis of laser captured endothelial cells.Results
Skin biopsies from two patients transplanted with minor ABO-incompatible grafts (i.e. O in A) showed 3.3% and 0.9% H antigen-positive donor-derived endothelial cells by ABH immunohistochemistry. Tumor biopsies from two recipients showed 1.2% and 2.5% donor-derived endothelial cells by combined immunohistochemistry/ fluorescence in situ hybridization. All other skin samples, heart, liver, bone-marrow, and tumor tissues failed to reveal donor-type endothelial cells up to several years after ABO-incompatible hematopoietic stem cell transplantation.Conclusions
Endothelial cell replacement by bone marrow-derived donor cells after allogeneic hematopoietic stem cell transplantation is a rare event. It does not seem to represent a major mechanism of physiological in vivo blood vessel formation, tumor neoangiogenesis, vascular repair after graft-versus-host disease episodes or acceptance of ABO-incompatible grafts. 相似文献5.
H��l��ne Lapillonne Ladan Kobari Christelle Mazurier Philippe Tropel Marie-Catherine Giarratana Isabelle Zanella-Cleon Laurent Kiger Marie Wattenhofer-Donz�� H��l��ne Puccio Nicolas Hebert Alain Francina Georges Andreu St��phane Viville Luc Douay 《Haematologica》2010,95(10):1651-1659
Background
Ex vivo manufacture of red blood cells from stem cells is a potential means to ensure an adequate and safe supply of blood cell products. Advances in somatic cell reprogramming of human induced pluripotent stem cells have opened the door to generating specific cells for cell therapy. Human induced pluripotent stem cells represent a potentially unlimited source of stem cells for erythroid generation for transfusion medicine.Design and Methods
We characterized the erythroid differentiation and maturation of human induced pluripotent stem cell lines obtained from human fetal (IMR90) and adult fibroblasts (FD-136) compared to those of a human embryonic stem cell line (H1). Our protocol comprises two steps: (i) differentiation of human induced pluripotent stem cells by formation of embryoid bodies with indispensable conditioning in the presence of cytokines and human plasma to obtain early erythroid commitment, and (ii) differentiation/maturation to the stage of cultured red blood cells in the presence of cytokines. The protocol dispenses with major constraints such as an obligatory passage through a hematopoietic progenitor, co-culture on a cellular stroma and use of proteins of animal origin.Results
We report for the first time the complete differentiation of human induced pluripotent stem cells into definitive erythrocytes capable of maturation up to enucleated red blood cells containing fetal hemoglobin in a functional tetrameric form.Conclusions
Red blood cells generated from human induced pluripotent stem cells pave the way for future development of allogeneic transfusion products. This could be done by banking a very limited number of red cell phenotype combinations enabling the safe transfusion of a great number of immunized patients. 相似文献6.
In vivo selection may provide a means to increase the relative number of cells of donor origin in recipients with hemopoietic chimerism. We have tested whether in vivo selection using chemical inducers of dimerization (CIDs) can direct the expansion of transduced normal donor erythrocytes in recipients with chimerism using a mouse model of pyruvate kinase deficiency. Marrow cells from normal CBA/N mice were transduced with a vector (F36Vmpl(GFP)) that promotes cell growth in the presence of CIDs. Transduced cells were then transplanted into minimally conditioned, pyruvate kinase-deficient recipients (CBA-Pk-1(slc)/Pk-1(slc)) to establish stable chimerism. CID administration resulted in expansion of normal donor erythrocytes and improvement of the anemia. The preferential expansion of normal erythrocytes also resulted in a decrease in erythropoietin levels, reducing the drive for production of pyruvate kinase-deficient red blood cells. CID-mediated expansion of genetically modified erythrocytes could prove a useful adjunct to transplantation methods that achieve erythroid chimerism. 相似文献
7.
De Somer L Sprangers B Fevery S Rutgeerts O Lenaerts C Boon L Waer M Billiau AD 《Haematologica》2011,96(3):424-431
Background
Challenge of MHC-mismatched murine bone marrow chimeras with recipient-type lymphocytes (recipient lymphocyte infusion) produces antileukemic responses in association with rejection of donor chimerism. In contrast, MHC-matched chimeras resist eradication of donor chimerism by recipient lymphocyte infusion. Here, we investigated lymphohematopoietic host-versus-graft reactivity and antileukemic responses in the MHC-matched setting, which is reminiscent of the majority of clinical transplants.Design and Methods
We challenged C3H→AKR radiation chimeras with AKR-type splenocytes (i.e. recipient lymphocyte infusion) and BW5147.3 leukemia cells. We studied the kinetics of chimerism using flowcytometry and the mechanisms involved in antileukemic effects using in vivo antibody-mediated depletion of CD8+ T and NK cells, and intracellular cytokine staining.Results
Whereas control chimeras showed progressive evolution towards high-level donor T-cell chimerism, recipient lymphocyte infusion chimeras showed a limited reduction of donor chimerism with delayed onset and long-term preservation of lower-level mixed chimerism. Recipient lymphocyte infusion chimeras nevertheless showed a significant survival benefit after leukemia challenge. In vivo antibody-mediated depletion experiments showed that both CD8+ T cells and NK cells contribute to the antileukemic effect. Consistent with a role for NK cells, the proportion of IFN-γ producing NK cells in recipient lymphocyte infusion chimeras was significantly higher than in control chimeras.Conclusions
In the MHC-matched setting, recipient lymphocyte infusion elicits lymphohematopoietic host-versus-graft reactivity that is limited but sufficient to provide an antileukemic effect, and this is dependent on CD8+ T cells and NK cells. The data indicate that NK cells are activated as a bystander phenomenon during lymphohematopoietic T-cell alloreactivity and thus support a novel type of NK involvement in anti-tumor responses after post-transplant adoptive cell therapy. 相似文献8.
Ya-Li Zhou Xin-Hua Zhang Tie-Niu Liu Li Wang Xiao-Lin Yin 《Trasfusione del sangue》2014,12(4):471-478
Background
Splenectomy is reported to increase the haemoglobin level in patients with haemoglobin H Constant Spring (HbH CS) disease; however, its impact on iron burden and the underlying mechanism remains unclear.Materials and methods
From March through to May 2013, a total of 50 adults with HbH CS disease (25 cases splenectomised and 25 cases non-splenectomised) were enrolled. The patients’ general conditions, history of blood transfusion and iron chelator treatment were investigated. Levels of haemoglobin, nucleated red blood cell counts, and serum ferritin were measured. The percentage of apoptotic erythroid precursor cells in bone marrow, an index representing ineffective erythropoiesis, was determined in some cases.Results
There were no significant differences in age, blood transfusion volume, and use of iron chelator drugs between the splenectomised group and the non-splenectomised group. Significantly higher haemoglobin levels, serum ferritin levels and nucleated red blood cell counts as well as a higher percentage of apoptotic erythroid progenitor cells were detected in the splenectomised group. Regression analysis revealed that age and nucleated red blood cell counts were independent risk factors affecting the serum ferritin level.Discussion
Despite improving the haemoglobin level, splenectomy is associated with greater iron burden in HbH CS disease. A high nucleated red blood cell count is predictive of the risk of severe iron overload. 相似文献9.
Kremer Hovinga IC Koopmans M Baelde HJ de Heer E Bruijn JA Bajema IM 《Annals of the rheumatic diseases》2007,66(12):1568-1573
Background
Chimerism indicates the presence of cells from one individual in another individual, and has been associated with several autoimmune diseases. Although this finding may point towards a role for chimerism in the induction of SLE, it could also indicate that chimerism is the result of repair mechanisms after injury.Objective
To perform a post‐mortem investigation for the presence of chimerism in 48 organs from seven women with SLE and establish whether there was a relationship between chimerism and injury.Methods
Chimeric male cells in female tissue specimens were identified by in situ hybridisation of the Y‐chromosome. Organs were categorised into four different groups according to injury experienced. Results were compared with those for unaffected control organs.Results
Chimerism was found in all seven patients with SLE. Y‐chromosome‐positive cells were present in 24 of 48 organs from women with SLE, which was significantly more than in control organs (p<0.001). Chimerism occurred more often in organs from patients with SLE who had experienced injury than in normal control organs, irrespective of whether the injury experienced was SLE‐related, non‐SLE‐related or both.Conclusions
This is the first report of the distribution of chimerism in a large number of organs from women with SLE. It shows that the occurrence of chimerism is related to injury. The data support the hypothesis that tissue chimerism is the result of a repair process.Chimerism is the presence of cells from one individual in another individual. The involvement of chimerism in the pathogenesis of autoimmune diseases has been addressed in several studies.1,2,3 We recently investigated the occurrence of chimerism in kidneys of women with the autoimmune disease systemic lupus erythematosus (SLE) and found that chimerism occurs twice as often in lupus nephritis as in normal kidneys.4 SLE is an immune‐mediated disease that affects several organs and has a variety of clinical symptoms.5 This disease is characterised by the presence of autoantibodies, particularly autoantibodies against nuclear components.6 Despite extensive research, the aetiology of SLE is still unknown, but is probably multifactorial. Chimerism is a candidate factor that may be responsible for the development of SLE.SLE occurs in women and men at a ratio of approximately 10:1. In women, the first symptoms most often occur during their fertile years.7 This is interesting in terms of whether chimerism plays a role in SLE, because pregnancy is thought to be the most likely source of chimeric cells. During pregnancy, fetal cells enter the maternal circulation, making the mother chimeric. These circulating fetal cells have been reported to be haematopoietic progenitor cells, trophoblast cells, nucleated erythrocytes and leucocytes.8,9,10,11 We have shown that, in kidneys with lupus nephritis, both CD3 and CD34 positive chimeric cells are present.4The presence of chimeric cells in tissues affected by SLE may indicate the pathogenic potential of chimeric cells. For example, their presence could be interpreted as a graft‐versus‐host or a host‐versus‐graft reaction.12 In these scenarios, chimeric cells are involved in the initiation of disease. However, recent publications have stressed the importance of chimeric cells in repair, showing in experimental designs that fetal cells migrate to sites of injury in the mother.13Organ injury in autoimmune diseases such as SLE can be extensive. If chimeric cells indeed have repair capabilities, the amount of tissue chimerism would be expected to be high in organs from women with SLE, especially in those that show histological signs of injury. Moreover, it is possible that specifically SLE‐related injury leads to the presence of chimerism, in contrast with other forms of injury. In an autopsy case study of one patient with SLE, Johnson et al14 showed that chimerism was present in the heart, lung, kidney, intestines and skin. However, Khosrotehrani et al15 found no chimerism in skin specimens from seven patients with mild SLE. Apart from the 57 kidney specimens with lupus nephritis that we previously studied, there have been no other data gathered on either the occurrence of chimerism in organs from women with SLE or the relationship between tissue chimerism and injury.Therefore, we investigated the association of chimerism and injury in a large number of tissue samples from patients with SLE, categorising whether these tissues had an SLE‐related injury, a non‐SLE‐related injury, a combination of the two, or were histologically normal. 相似文献10.
Wu CJ Krishnamurti L Kutok JL Biernacki M Rogers S Zhang W Antin JH Ritz J 《Blood》2005,106(10):3639-3645
Peripheral destruction of sickled erythrocytes is a cardinal feature of sickle cell disease (SCD). Less well established is the potential contribution of ineffective erythropoiesis to the pathophysiology of this hemoglobinopathy. Since patients with SCD frequently develop mixed hematopoietic chimerism after allogeneic nonmyeloablative stem cell transplantation, we used this opportunity to directly compare the differentiation and survival of SCD and donor-derived erythropoiesis in vivo. Donor and recipient erythropoiesis was compared in 4 patients with SCD and 4 without SCD who developed stable mixed hematopoietic chimerism following transplant. Molecular analysis of chimerism in peripheral blood and bone marrow demonstrated higher expression of donor-derived beta-globin RNA relative to the level of donor-derived genomic DNA in patients with SCD. Analysis of chimerism in immature (glycophorin A-positive [GYPA(+)], CD71(hi)) and mature (GYPA(+), CD71(neg)) erythroblasts confirmed the intramedullary loss of SS erythroblasts with progressive maturation. In patients with SCD, relative enrichment of donor erythroid precursors began to appear at the onset of hemoglobinization. Ineffective erythropoiesis of homozygous hemoglobin S (SS) progenitors thus provides a maturation advantage for homozygous hemoglobin A (AA) or heterozygous hemoglobin S/hemoglobin A (SA) donor erythroid precursor cells that results in greater donor contribution to overall erythropoiesis following stem-cell transplantation and improvement of clinical disease. 相似文献
11.
Bacher U Haferlach C Alpermann T Kern W Schnittger S Haferlach T 《Haematologica》2011,96(9):1284-1292
Background
The World Health Organization separates acute erythroid leukemia (erythropoiesis in ≥50% of nucleated bone marrow cells; ≥20% myeloblasts of non-erythroid cells) from other entities with increased erythropoiesis – acute myeloid leukemia with myelodysplasia-related changes (≥20% myeloblasts of all nucleated cells) or myelodysplastic syndromes – and subdivides acute erythroid leukemia into erythroleukemia and pure erythroid leukemia subtypes. We aimed to investigate the biological/genetic justification for the different categories of myeloid malignancies with increased erythropoiesis (≥50% of bone marrow cells).Design and Methods
We investigated 212 patients (aged 18.5–88.4 years) with acute myeloid leukemia or myelodysplastic syndromes characterized by 50% or more erythropoiesis: 108 had acute myeloid leukemia (77 with acute erythroid leukemia, corresponding to erythroid/myeloid erythroleukemia, 7 with pure erythroid leukemia, 24 with acute myeloid leukemia with myelodysplasia-related changes) and 104 had myelodysplastic syndromes. Morphological and chromosome banding analyses were performed in all cases; subsets of cases were analyzed by polymerase chain reaction and immunophenotyping.Results
Unfavorable karyotypes were more frequent in patients with acute myeloid leukemia than in those with myelodysplastic syndromes (42.6% versus 13.5%; P<0.0001), but their frequency did not differ significantly between patients with acute erythroid leukemia (39.0%), pure erythroid leukemia (57.1%), and acute myeloid leukemia with myelodysplasia-related changes (50.0%). The incidence of molecular mutations did not differ significantly between the different categories. The 2-year overall survival rate was better for patients with myelodysplastic syndromes than for those with acute myeloid leukemia (P<0.0001), without significant differences across the different acute leukemia subtypes. The 2-year overall survival rate was worse in patients with unfavorable karyotypes than in those with intermediate risk karyotypes (P<0.0001). In multivariate analysis, only myelodysplastic syndromes versus acute myeloid leukemia (P=0.021) and cytogenetic risk category (P=0.002) had statistically significant effects on overall survival.Conclusions
The separation of acute myeloid leukemia and myelodysplastic syndromes with 50% or more erythropoietic cells has clinical relevance, but it might be worth discussing whether to replace the subclassifications of different subtypes of acute erythroid leukemia and acute myeloid leukemia with myelodysplasia-related changes by the single entity, acute myeloid leukemia with increased erythropoiesis ≥50%. 相似文献12.
R. S. Weinberg A. Vlachos V. Najfeld Y. Galperin A. Scalise S. Fruchtman & J. M. Lipton 《British journal of haematology》1997,99(1):61-63
A 4-year-old girl with transfusion-dependent β°-thalassaemia received an HLA-identical bone marrow transplant (BMT) from her β°-thalassaemia trait sister. Prior to BMT, chromosomal analysis revealed the recipient to have 46,XX,9qh+, a polymorphic variant of the heterochromatin region of chromosome 9, which her donor did not have. Within 1 month post-BMT, 89% of nucleated bone marrow cells were of donor origin. One year later, donor engraftment had decreased to 44% and 34% in nucleated bone marrow cells and blood lymphocytes, respectively. By 2 years, donor lymphocyte engraftment fell to 5%, raising concern of possible graft rejection. To examine erythroid chimaerism, globin synthesis by individual erythroid progenitor cell derived colonies (BFU-E) was analysed. On days 1000 and 1130 post-BMT, 79% and 77% of colonies, respectively, synthesized β-globin and therefore were of donor origin. 相似文献
13.
Ladan Kobari Frank Yates Noufissa Oudrhiri Alain Francina Laurent Kiger Christelle Mazurier Shaghayegh Rouzbeh Wassim El-Nemer Nicolas Hebert Marie-Catherine Giarratana Sabine Fran?ois Alain Chapel Hélène Lapillonne Dominique Luton Annelise Bennaceur-Griscelli Luc Douay 《Haematologica》2012,97(12):1795-1803
Background
Human induced pluripotent stem cells offer perspectives for cell therapy and research models for diseases. We applied this approach to the normal and pathological erythroid differentiation model by establishing induced pluripotent stem cells from normal and homozygous sickle cell disease donors.Design and Methods
We addressed the question as to whether these cells can reach complete erythroid terminal maturation notably with a complete switch from fetal to adult hemoglobin. Sickle cell disease induced pluripotent stem cells were differentiated in vitro into red blood cells and characterized for their terminal maturation in terms of hemoglobin content, oxygen transport capacity, deformability, sickling and adherence. Nucleated erythroblast populations generated from normal and pathological induced pluripotent stem cells were then injected into non-obese diabetic severe combined immunodeficiency mice to follow the in vivo hemoglobin maturation.Results
We observed that in vitro erythroid differentiation results in predominance of fetal hemoglobin which rescues the functionality of red blood cells in the pathological model of sickle cell disease. We observed, in vivo, the switch from fetal to adult hemoglobin after infusion of nucleated erythroid precursors derived from either normal or pathological induced pluripotent stem cells into mice.Conclusions
These results demonstrate that human induced pluripotent stem cells: i) can achieve complete terminal erythroid maturation, in vitro in terms of nucleus expulsion and in vivo in terms of hemoglobin maturation; and ii) open the way to generation of functionally corrected red blood cells from sickle cell disease induced pluripotent stem cells, without any genetic modification or drug treatment.Key words: human induced pluripotent stem cells, terminal maturation, erythropoietic differentiation 相似文献14.
Rapid establishment of dendritic cell chimerism in allogeneic hematopoietic cell transplant recipients 总被引:12,自引:6,他引:12 下载免费PDF全文
Auffermann-Gretzinger S Lossos IS Vayntrub TA Leong W Grumet FC Blume KG Stockerl-Goldstein KE Levy R Shizuru JA 《Blood》2002,99(4):1442-1448
Regeneration of hematopoiesis after allogeneic hematopoietic cell transplantation (HCT) involves conversion of the recipient's immune system to donor type. It is likely that distinct cell lineages in the recipient reconstitute at different rates. Dendritic cells (DCs) are a subset of hematopoietic cells that function as a critical component of antigen-specific immune responses because they modulate T-cell activation, as well as induction of tolerance. Mature DCs are transferred with hematopoietic grafts and subsequently arise de novo. Little information exists about engraftment kinetics and turnover of this cell population in patients after allogeneic HCT. This study examined the kinetics of DC chimerism in patients who underwent matched sibling allogeneic HCT. T-cell, B-cell, and myelocytic and monocytic chimerism were also studied. Peripheral blood cells were analyzed at defined intervals after transplantation from 19 patients with various hematologic malignancies after treatment with myeloablative or nonmyeloablative preparatory regimens. Cell subsets were isolated before analysis of chimerism. Despite the heterogeneity of the patient population and preparatory regimens, all showed rapid and consistent development of DC chimerism. By day +14 after transplantation approximately 80% of DCs were of donor origin with steady increase to more than 95% by day +56. Earlier time points were examined in a subgroup of patients who had undergone nonmyeloablative conditioning and transplantation. These data suggest that a major proportion of blood DCs early after transplantation is donor-derived and that donor chimerism develops rapidly. This information has potential implications for manipulation of immune responses after allogeneic HCT. 相似文献
15.
Laurent Garderet Ladan Kobari Christelle Mazurier Caroline De Witte Marie-Catherine Giarratana Christine P��rot Norbert Claude Gorin H��l��ne Lapillonne Luc Douay 《Haematologica》2010,95(3):398-405
Background
Anemia is a characteristic of myelodysplastic syndromes, such as the rare 5q- syndrome, but its mechanism remains unclear. In particular, data are lacking on the terminal phase of differentiation of erythroid cells (enucleation) in myelodysplastic syndromes.Design and Methods
We used a previously published culture model to generate mature red blood cells in vitro from human hematopoietic progenitor cells in order to study the pathophysiology of the 5q- syndrome. Our model enables analysis of cell proliferation and differentiation at a single cell level and determination of the enucleation capacity of erythroid precursors.Results
The erythroid commitment of 5q(del) clones was not altered and their terminal differentiation capacity was preserved since they achieved final erythroid maturation (enucleation stage). The drop in red blood cell production was secondary to the decrease in the erythroid progenitor cell pool and to impaired proliferative capacity. RPS14 gene haploinsufficiency was related to defective erythroid proliferation but not to differentiation capacity.Conclusions
The 5q- syndrome should be considered a quantitative rather than qualitative bone marrow defect. This observation might open the way to new therapeutic concepts. 相似文献16.
Sabrina Buoro Mauro Vavassori Silvia Pipitone Anna Benegiamo Eleonora Lochis Sabina Fumagalli Anna Falanga Marina Marchetti Alberto Crippa Cosimo Ottomano Giuseppe Lippi 《Trasfusione del sangue》2015,13(4):588-594
Background
Current haematology analysers have variable sensitivity and accuracy for counting nucleated red blood cells in samples with low values and in all those conditions characterised by altered sensitivity of red blood cells to the lysing process, such as in beta-thalassaemia or sickle-cell diseases and in neonates. The aim of our study was to evaluate the performance of the automated analyser XE-2100 at counting nucleated red blood cells in the above-mentioned three categories of subjects with potentially altered red blood cell lysis sensitivity and yet a need for accurate nucleated red blood cell counts.Materials and methods
We measured nucleated red blood cell count by XE-2100 in peripheral blood samples of 187 subjects comprising 55 patients with beta-thalassaemia (40 major and 15 traits), 26 sickle-cell patients, 56 neonates and 50 normal subject. Results were compared with those obtained by optical microscopy. Agreement between average values of the two methods was estimated by means of Pearson’s correlation and bias analysis, whereas diagnostic accuracy was estimated by analysis of receiver operating characteristic curves.Results
The comparison between the two methods showed a Pearson’s correlation of 0.99 (95% CI; 0.98–0.99; p<0.001) and bias of −0.61 (95% CI, −1.5–0.3). The area under the curve of the nucleated red blood cell count in all samples was 0.98 (95% CI, 0.96–1.00; p<0.001). Sub-analysis revealed an area under curve of 0.99 (95% CI, 0.98–1.00; p<0.001) for patients with thalassaemia, 0.94 (95% CI, 0.85–1.00; p<0.001) for patients with sickle cell anaemia, and 1.00 (95% CI, 1.0–1.0) for neonates.Discussion
XE-2100 has excellent performance for nucleated red blood cell counting, especially in critical populations such as patients with haemoglobinopathies and neonates. 相似文献17.
Mixed chimerism following in utero hematopoietic stem cell transplantation in murine models of hemoglobinopathy 总被引:2,自引:0,他引:2
Hayashi S Abdulmalik O Peranteau WH Ashizuka S Campagnoli C Chen Q Horiuchi K Asakura T Flake AW 《Experimental hematology》2003,31(2):176-184
OBJECTIVE: Mixed hematopoietic chimerism after bone marrow transplantation can provide effective treatment for beta-thalassemia because of the selective advantage that exists for donor erythropoiesis. In utero hematopoietic stem cell transplantation (IUHSCTx) can achieve mixed hematopoietic chimerism, particularly when a selective advantage exists for donor cells. To investigate the biology of IUHSCTx in hemoglobinopathies, we performed fully allogeneic IUHSCTx in murine models of beta-thalassemia (Thal) and sickle cell disease (SCD). MATERIALS AND METHODS: We serially assessed and compared levels of mononuclear cell (MNC) and erythroid chimerism after IUHSCTx of either adult bone marrow (BM)- or fetal liver (FL)-derived allogeneic donor cells in the two hemoglobinopathy models, which differ significantly in their degree of anemia (Thal>SCD) and red cell half-life (Thal相似文献
18.
Anbin Hu Qiang Li Huijuan Shi Qiang Tai Linwei Wu Jun Xiong Bimang Fu Xiaoshun He 《Digestive and liver disease》2012,44(12):988-994
Background and aim
In this study, we investigated immunomodulatory effects of donor-derived bone marrow transfusion in rat heterotopic small bowel transplantation.Methods
Rat heterotopic segmental small bowel transplantation models (male Brown Norway to female Lewis) were established. The recipients were randomly divided into control group (pute small bowel transplantation), tacrolimus group (small bowel transplantation plus oral tacrolimus) and small bowel transplantation plus oral tacrolimus and intraportal infusion of donor-derived bone marrow cells group. We investigated the survival time, graft pathologic injuries and rejection grade by haematoxylin–eosin staining, serum IL-2 and IL-10 detection by enzyme labelled immunosorbent assay after small bowel transplantation. The recipients mixed chimerism were observed by detecting sex-determining region of Y chromosome gene in blood, liver, spleen and intestine by using real-time polymerase chain reaction and fluorescence in situ hybridization.Results
Bone marrow cells group showed a superior survival than the other groups, accompanied by milder pathologic injuries and lower rejection grade, decreasing serum IL-2 and increasing serum IL-10. The recipient chimerism rate in blood, liver, spleen and intestine in bone marrow cells group was significantly higher than the other groups.Conclusion
Transfusion of donor-derived bone marrow cells via portal vein induces mixed chimerism in rats after small bowel transplantation, which may promote a Th2 shift in Th1/Th2 balance and facilitate the induction of immune tolerance. 相似文献19.
Theodosia A. Kalfa Suvarnamala Pushkaran Xiaoling Zhang James F. Johnson Dao Pan Deidre Daria Hartmut Geiger Jose A. Cancelas David A. Williams Yi Zheng 《Haematologica》2010,95(1):27-35
Background
The small Rho GTPases Rac1 and Rac2 have both overlapping and distinct roles in actin organization, cell survival, and proliferation in various hematopoietic cell lineages. The role of these Rac GTPases in erythropoiesis has not yet been fully elucidated.Design and Methods
Cre-recombinase-induced deletion of Rac1 genomic sequence was accomplished on a Rac2-null genetic background, in mouse hematopoietic cells in vivo. The erythroid progenitors and precursors in the bone marrow and spleen of these genetically engineered animals were evaluated by colony assays and flow cytometry. Apoptosis and proliferation of the different stages of erythroid progenitors and precursors were evaluated by flow cytometry.Results
Erythropoiesis in Rac1−/−;Rac2−/− mice is characterized by abnormal burst-forming unit-erythroid colony morphology and decreased numbers of megakaryocyte-erythrocyte progenitors, erythroid colony-forming units, and erythroblasts in the bone marrow. In contrast, splenic erythropoiesis is increased. Combined Rac1 and Rac2 deficiency compromises proliferation of the megakaryocyte-erythrocyte progenitor population in the bone marrow, while it allows increased survival and proliferation of megakaryocyte-erythrocyte progenitors in the spleen.Conclusions
These data suggest that Rac1 and Rac2 GTPases are essential for normal bone marrow erythropoiesis but that they are dispensable for erythropoiesis in the spleen, implying different signaling pathways for homeostatic and stress erythropoiesis. 相似文献20.
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