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PubMed1992

Reconstitution of B cell immunity following bone marrow transplantation.

Bone marrow transplant recipients are known to be immunodeficient in cellular and humoral immune responses for months to years. Mechanisms underlying the post-transplant immunodeficiency are mostly unknown and therefore it has been difficult to design therapeutic strategies to address this problem. Here, we review studies of post-transplant B cell (humoral) immunity including B cell blood counts, phenotype, function and origin, and the morphology of lymphoid organs. We postulate that the aetiology of post-transplant humoral immunodeficiency is multifactorial, involving: B cell immaturity due to recapitulation of their ontogenesis, and, in some patients, insufficient T cell help and/or exaggerated CD8+ T cell/NK cell suppression. Implications for clinical practice are outlined, e.g. hypersensitivity reactions and autoimmune diseases as part of the differential diagnosis of post-transplant disorders, questionable diagnostic benefit of serologic studies, and usefulness of prophylactic intravenous immunoglobulin.

Antibody Formation↗
PubMedDate not supplied

[Molecular study of bone marrow chimerism and expression of EVI-1 gene as manifestations of minimal residual disease after bone marrow transplantation (BMT)].

Leukaemias are the most frequent tumour diseases in children. Bone marrow transplantation (BMT) is the most effective therapy for many patients with leukaemia. Highly polymorphic microsatellite markers provide useful genetic markers for detection of complete or mixed chimerism in patients after (BMT). Chimerism can be monitored successfully using several polymerase chain reaction (PCR) techniques and cytogenetic analysis, especially fluorescent in situ hybridization (FISH). It is still unclear whether individuals with mixed chimerism after bone marrow transplantation have an increased risk of developing leukaemic relapse or graft rejection. EVI-1 gene was mapped in human chromosome 3q26. It encodes zinc finger, DNA binding protein detected only in the nucleus. The EVI-1 function is unknown. It is not expressed in normal human haematopoietic cells, but is expressed in leukaemias especially with 3q26 abnormalities. Expression of the EVI-1 may play a significant role in pathogenesis of human leukaemias. Molecular study of chimerism and expression of EVI-1 gene may be useful for monitoring residual disease after bone marrow transplantation.

Bone Marrow↗
PubMed1995

Natural killer cell regeneration after transplantation with mafosfamide purged autologous bone marrow.

Autologous bone marrow transplantation (ABMT) is used increasingly for the treatment of acute leukemias, lymphomas and solid tumors. Since ABMT is burdened by high risk of relapse, mafosfamide or 4-hydroperoxycyclophosphamide chemical marrow purging is employed. Mafosfamide acts by exerting a potent cytotoxic effect and by promoting apoptosis of leukemic cells. A third proposed mechanism of action involves an effect on immune regeneration in vivo. It was the aim of this study to investigate natural killer (NK) cell regeneration in a group of patients undergoing mafosfamide-purged ABMT. Fifteen patients (8 acute myelogenous leukemia, AML; 4 acute lymphoblastic leukemia, ALL; 3 non-Hodgkin's lymphoma, NHL) were treated with high-dose chemotherapy followed by transplantation with marrow purged with mafosfamide. Prior to ABMT and at different intervals thereafter, NK cell number and function were studied by evaluating the percentage of circulating CD16 positive cells and cytotoxic activity against the leukemic cell line, K562. In comparison to pre-ABMT values, AML patients showed a significant increase in cytotoxic activity, expressed as percentage of chromium release (42.5 +/- 3 vs 32.5 +/- 6, P < or = 0.025 at 4 months) which still persisted at 12 months post-ABMT (54 +/- 6, P < or = 0.05). The behavior of NK functional activity was paralleled by an increase of the percentage of CD16-positive cells (8.4 +/- 2.2 vs 5 +/- 1.3, P < or = 0.05 at 4 months; 12.8 +/- 2.4, P < or = 0.005 at 12 months post-ABMT). Similar significant and long-lasting increments in NK cells were also found in NHL patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Hodgkin's disease with bone marrow involvement.

Bone marrow involvement was seen in 11 percent of patients with Hodgkin's Disease which was determined from pre-treatment biopsy specimens using established histopathologic criteria. Analysis of 32 evaluable patients with marrow involvement showed male preponderance with a peak in fourth decade of life. Twenty four cases (75%) had B-symptoms and 15 (46%) presented within six months of onset of symptoms. On categorizing for clinical staging, 21 (65%) belonged to stage III and IV. Hepatomegaly (greater than or equal to 2 cms) was present in seven cases (21%) and splenomegaly in 13 cases (40%). Mixed cellularity and lymphocytic depletion histopathologic subtypes showed the highest frequency of involvement (21 cases; 65%). Out of 28 cases ESR was raised in 27 cases (96%). Eighteen cases (56%) showed elevated serum alkaline phosphatase levels. Serum copper levels were determined in 14 cases, out of which 12 (85%) showed elevated levels. These parameters along with anemia (hemoglobin of 12 g/dl or less) in 26 cases (81%), correlated well with the disease activity. Only four cases had leukopenia at presentation pointing to no hindrance for aggressive chemotherapy. All cases received minimum of six courses of standard combination chemotherapy with or without local radiotherapy. Sixteen cases (50%) relapsed subsequently and were managed accordingly. A five year follow-up revealed a minimal 31 percent overall survival, and 18 percent of patients were disease free and well since the time of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Actuarial Analysis↗
PubMed1998

Magnetic resonance imaging of the normal bone marrow.

The bone marrow is a complex organ that contains fat and nonfat cells, the proportions of which vary greatly with age and in the different bones of the skeleton. Magnetic resonance (MR) imaging provides information on the composition of the medullary cavity of any given bone and on the distribution of red and yellow marrow in the skeleton. This article deals with the wide spectrum of appearances of the normal bone marrow at MR imaging.

Adipocytes↗
PubMed1997

Allogeneic bone marrow transplantation for agnogenic myeloid metaplasia. French Society of Bone Marrow Transplantation.

Agnogenic myeloid metaplasia is a rare indication for allogeneic bone marrow transplantation (BMT). We have retrospectively studied 12 patients allografted for this disease within the French BMT group. Prior to BMT, the mean age was 40 years (range 14-49). Diagnosis was based on the Polycythaemia Vera Study Group criteria. Before BMT, 10 patients had been splenectomized, eight required transfusions, and four had received at least two lines of chemotherapy. Cyclophosphamide and total body irradiation was the main conditioning regimen used (n=8). The donor was an HLA-identical sibling except in one case where there was one HLA-DR mismatch. Acute graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate and cyclosporine A. 11 patients engrafted with median times to achieve absolute neutrophil count > 0.5 x 10(9)/l and platelet count > 50 x 10(9)/l of 17 (range 12-44) and 29 (range 12-196) days respectively. One primary graft failure occurred. 10 patients developed grade II-IV acute GVHD, four developed extensive chronic GVHD. One patient relapsed 16 months post-BMT and was untreated and well 14 months later. Three patients died from the BMT procedure. In May 1996 the median follow-up was 25 months and the 4-year overall and event-free survivals were 71% and 59%, respectively. Thus, we conclude that extensive myelofibrosis is not associated with delayed engraftment, and that HLA-identical sibling allogeneic BMT can be considered in a small proportion of patients with agnogenic myeloid metaplasia.

Adolescent↗
PubMed1987

Defective lymphopoiesis in the bone marrow of motheaten (me/me) and viable motheaten (mev/mev) mutant mice. II. Description of a microenvironmental defect for the generation of terminal deoxynucleotidyltransferase-positive bone marrow cells in vitro.

We have presented evidence in a previous paper that the development of prothymocytes, pre-B cells, and TdT+ lymphoid precursor cells in the bone marrow of motheaten (me/me) and viable motheaten (mev/mev) mice is defective. In the present study, we have used a selective culture system that supports the generation of rat- and mouse-origin TdT+ bone marrow lymphoid cells in vitro to further investigate the early stages of lymphopoiesis in me/me and mev/mev mice. The results demonstrate that bone marrow stromal cell feeder layers derived from me/me and mev/mev mice do not support the growth of rat TdT+ cells in vitro, whereas stromal cell feeder layers from heterozygous (+/-) littermates and wild type (+/+) control mice do. Moreover, composite feeder layers formed by mixing as few as one part me/me and mev/mev bone marrow cells with 7 to 9 parts +/- littermate bone marrow cells also fail to effectively support the generation of TdT+ cells in vitro. In contrast to me/me and mev/mev mice, other mutant mouse models of autoimmune (NZB, NZB/W), immunodeficient (nu/nu), and hemopoietic (W/Wv, Sl/Sld) disorders form feeder layers that support normal to elevated levels of TdT+ cell growth in vitro. Thus, to date, only the me/me and mev/mev mutant mice have been found to lack the appropriate microenvironment for the generation of TdT+ bone marrow cells. Histologic analysis of the stromal cell feeder layers that are formed in our culture system shows that multilayered cellular patches, which normally are the most active sites of TdT+ cell development in vitro, are absent in feeder layers of me/me and mev/mev cells. Moreover, feeder layers from mev/mev mice contain a population of MAC 1+, basophilic, nonvacuolated, macrophage-like cells; whereas feeder layers from control mice contain MAC 1+, eosinophilic, vacuolated macrophage-like cells. Stromal cell feeder layers formed by mixtures of me/me or mev/mev and control mouse bone marrow cells contain numerous multilayered cellular patches and vacuolated mononuclear cells, but also contain large numbers of basophilic mononuclear cells. These composite feeder layers have a disproportionately reduced capacity to support the generation of TdT+ cells in vitro. Although the stromal microenvironment of me/me and mev/mev bone marrow does not support the growth of TdT+ cells in vivo or in vitro, the bone marrow from these mutant mice contains detectable numbers of pre-TdT+ cells. Thus, when cultured on normal mouse feeder layers, mutant mouse bone marrow rapidly generates TdT+ cells in vitro, albeit at significantly reduced levels as compared to +/- littermate controls.(ABSTRACT TRUNCATED AT 400 WORDS)

Acid Phosphatase↗
PubMed1987

Effect of bone marrow mononuclear phagocytes on the bone matrix-induced bone formation in rats.

Experimental ulnar bone defects in rats were grafted with freshly isolated whole bone marrow cells; bone marrow mononuclear phagocytes (macrophages); or both types of marrow cell preparations in combination with demineralized bone matrix gelatin (BMG). In the absence of BMG, the osteogenic performance of the marrow cell preparations was superior to that of the macrophages. In the presence of BMG (composite grafts), their osteogenic potential was nearly identical and significantly improved the level of bone formation stimulated by implants of BMG alone. The results encourage speculation and further research on sequential activities of bone marrow monocyte-macrophage (osteoclast) lineages and marrow stromal (osteoprogenitor) cell in bone morphogenetic protein (BMP)-induced regeneration.

Animals↗
PubMed1991

[Regeneration of bone marrow tissue. Growth and differentiation of hematopoietic stem cells and the role of bone marrow microenvironment on hematopoiesis].

Hematopoietic stem cell proliferation and differentiation is regulated by a multistep process involving stem cell self-renewal, commitment, differentiation and maturation. Each process is controlled by a variety of humoral factors and cell-cell interactions, i.e., (i) growth factor and growth inhibitor acting toward the cascade of stem cell proliferation and differentiation, (ii) cytokine network involving cytokine-producing hematopoietic cells and stromal cells, (iii) interaction between hematopoietic cells and bone marrow microenvironment that is consisted of stromal cells and extracellular matrix. Recent advances in cell biology and cell physiology enabled us to understand the roles of these marrow microenvironments on hematopoiesis in molecular basis. We here discuss the complexities of hematopoietic system and the mechanism of the regeneration of hematopoietic tissues in special reference to bone marrow transplantation.

Animals↗
PubMed1996

Clinical significance of bone marrow metastases as detected using the polymerase chain reaction in patients with breast cancer undergoing high-dose chemotherapy and autologous bone marrow transplantation.

PURPOSE: The present study evaluates the clinical significance of detection of cytokeratin 19 (K19) in the bone marrow of patients with breast cancer undergoing high-dose chemotherapy (HDCT) and autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: We studied retrospectively cryopreserved bone marrow aspirates from 83 patients with high-risk stage II, III, and IV breast cancer obtained before bone marrow harvest but after induction chemotherapy. All samples were histologically negative for metastases. Polymerase chain reaction (PCR) for K19 was performed according to methods described previously and results were correlated with the probability of relapse following HDCT and ABMT. RESULTS: The incidence of occult metastases as defined by PCR for K19 message was 52% for 19 stage II, 57% for 14 stage III, and 82% for 50 stage IV patients (two-tailed P = .0075, chi 2 test). The probability of relapse at 3 years after ABMT was 32% and 94% for K19-positive stage II/III and stage IV patients, respectively, versus 10% and 14% for K19-negative stage II/III and stage IV patients, respectively. The difference was significant for stage IV patients (two-tailed P = .0002). CONCLUSION: It has been shown that PCR is a highly sensitive method to detect K19 message in the bone marrow. The incidence of K19 positivity in bone marrow increases significantly with advancing stage. In patients with breast cancer, especially metastatic breast cancer, undergoing HDCT and ABMT, the presence of K19 is associated with a poor prognosis.

Adult↗
PubMed1994

Impact of liver disease and hepatitis infections on allogeneic bone marrow transplantation in Europe: a survey from the European Bone Marrow Transplantation (EBMT) Group--Infectious Diseases Working Party.

This survey investigated allogeneic bone marrow transplantation (BMT) policy in European BMT units by questionnaire, in relation to pre-transplant liver disease. It also assessed diagnostic standards for viral hepatitis infections and their prevalence in BMT candidates. Sixty-three EBMT centers from 22 countries participated in the survey. Median pre-transplant prevalences of HBsAg and anti-HCV positivity were 3.5% (range 0-15%) and 5% (range 0-45%), respectively. Forty-six (73%) centers adopt the policy of cancelling or postponing BMT in patients with ALT abnormalities but in four of these centers, BMT is not delayed when progressive disease or acute leukemia is present. In 17 institutions (27%) BMT was reported to be carried out irrespective of transaminase values. Data on fatal post-BMT liver disease were provided by 45 centers. The overall mortality rate for liver failure was 4.5% (258 of 5788) with no differences between centers performing or not performing BMT in cases of ALT elevation. These results indicate that there is strong concern in most European BMT units about performing BMT in the presence of ALT elevation and prospective studies on its real impact on fatal post-BMT liver disease should be conducted.

Alanine Transaminase↗
PubMed2006

MRI of bone marrow oedema associated with focal bone lesions.

AIM: To quantify the volume of bone marrow oedema surrounding focal bone lesions and to identify its relevance relative to diagnosis. METHODS: Three hundred and eighty-eight of 1456 patients included in the orthopaedic oncology database who underwent magnetic resonance imaging (MRI) demonstrated bone marrow oedema and were included in the study. There were 225 males and 163 females, age range 1-87 years (mean 29 years). MRI images were retrospectively reviewed and assessed for the extent of bone marrow oedema. The amount of oedema was graded: grade 1: oedema present but smaller than the lesion size; grade 2: oedema equivalent to the lesion size; grade 3: oedema greater than the lesion size. RESULTS: There were 190 grade 1 lesions: 56% malignant, 33% benign, 11% non-neoplastic; 74 grade 2 lesions: 19% malignant, 50% benign, 31% non-neoplastic; and 124 grade 3 lesions: 10% malignant, 46% benign, 44% non-neoplastic. There was a significant relationship between oedema grade (i.e., volume of oedema) and final diagnosis (p<0.0005). CONCLUSION: Bone marrow oedema may be associated with a wide range of focal bony lesions, including malignant, benign and non-neoplastic causes. As the volume of bone marrow oedema increases relative to the size of the underlying lesion, the probability that the underlying lesion is benign is increased.

Adolescent↗
PubMed1992

Proliferation of abnormal bone marrow histiocytes, an undesired effect of granulocyte macrophage-colony-stimulating factor therapy in a patient with Hurler's syndrome undergoing bone marrow transplantation.

Granulocyte macrophage-colony-stimulating factor (GM-CSF) has shown promise as a means of alleviating leukopenia associated with a wide variety of disorders. It is currently undergoing evaluation as an adjunct to bone marrow transplantation but its use in patients with metabolic disorders, such as Hurler's syndrome (HS), has not been explored. We followed bone marrow morphology in a 2-year-old male with HS who received up to 8 micrograms/kg GM-CSF per day because of failure of allogeneic bone marrow engraftment. Both premortem and postmortem bone marrow sampling revealed almost complete replacement of the marrow space by sheets of histiocytes demonstrating metachromatic cytoplasmic granules. Such cells were present in far greater numbers than are usually seen in untreated patients with HS or patients with HS undergoing successful bone marrow transplantation without GM-CSF. Moreover, the in vitro culture of bone marrow from a second HS patient showed a GM-CSF dose-related increase in colony formation up to a dose of 250 units/ml. Microscopic examination of these colonies showed a high percentage of histiocytes identical to those seen in the patient's bone marrow. These observations suggest that caution should be exercised when considering administration of CSFs to patients with HS and similar metabolic storage diseases.

Bone Marrow↗
PubMed1993

Bone marrow transplantation in Europe: major geographical differences. The European Group for Bone Marrow Transplantation [EBMT].

In 1991 171 teams in 21 European countries performed 4976 bone marrow transplants. There were 1829 transplants from an HLA-identical sibling donor, 101 from a nonidentical family member, 30 from a twin, 217 from an unrelated volunteer donor and 2799 autologous transplants. Indications for transplants were leukaemias in 2569 (52%), lymphoproliferative disorders in 1472 (30%), solid tumours in 549 (11%), aplastic anaemia and thalassaemia in 261 (5%), inborn errors in 97 and miscellaneous disorders in 28 patients. There are marked differences between the participating European countries. They relate to absolute numbers, indications and techniques. Less than 10 transplants per 10-million inhabitants are performed in Eastern European countries. Ten to fifty transplants per 10-million inhabitants are done in two, 50-100 transplants per 10-million inhabitants in five, 100-200 transplants per 10-million inhabitants in eight countries and more than 200 per 10-million inhabitants in one country (P < 0.01). The number of transplant teams ranges from less than one to twelve per 10-million inhabitants (P < 0.01). For the continent it becomes 3.3 per 10-million inhabitants. The reasons for these differences are not explained by this survey. The most likely explanation for the differences in transplant activity is availability of transplant beds, trained staff and resources. Bone marrow transplants are expensive. However, the demand is increasing and will increase further with the routine availability of unrelated volunteer donors. Clearly, criteria are required in Europe to define the indications and solutions to meet the legitimate requirements for transplantation in the various regions of Europe.

Bone Marrow Transplantation↗
PubMed1984

Pre-B cells in mouse bone marrow: in vitro maturation of peanut agglutinin binding B lymphocyte precursors separated from bone marrow by fluorescence-activated cell sorting.

Peanut agglutinin (PNA) binding by mouse bone marrow cells and fractionation by the fluorescence-activated cell sorter have previously been shown to separate high concentrations of pre-B cells, as identified by cytoplasmic mu-chains (c mu). PNA+ and PNA- marrow cell fractions have now been assayed for the presence of functional pre-B cells able to generate mature B cells in culture, as defined by three criteria, the appearance of cell surface mu-chains (s mu), immunoglobulin secretion in response to bacterial lipopolysaccharides, and B cell colony formation. Small PNA+ cell fractions contained pre-B cells that developed into mature B lymphocytes in 1/2 to 1 day but did not sustain B cell production. Large PNA+ cells included pre-B cells that gave rise to mature B lymphocytes after an interval of 1 1/2 to 3 days and were able to sustain B cell genesis in vitro for at least 3 to 5 days thereafter. PNA- cell fractions contained mature B cells but lacked pre-B cell activity. The results demonstrate that PNA binding allows the separation of functional subsets of pre-B cells from bone marrow and that the three in vitro assays used in this study are closely comparable with one another as functional pre-B cell criteria. The findings suggest correlations between functional assays, c mu expression, PNA receptors, and cell size in characterizing stages of pre-B cell development.

Animals↗
PubMed2003

Construction of ectopic xenogeneic bone marrow structure associated with persistent multi-lineage mixed chimerism by engraftment of rat bone marrow plugs into mouse kidney capsules.

Poor bone marrow (BM) engraftment in a xenogeneic combination results at least in part from the limited engraftment capacity of BM-derived stromal cells, which support hematopoietic repopulation in a species-specific fashion. We attempted to construct a BM stromal microenvironment by engraftment of BM plug fragments into kidney capsules in a rat-to-mouse combination. BM plugs from F344/N Jcl-rnu/rnu (F344 nu) rats were transplanted into the kidney capsules of C.B-17 scid/scid (C.B-17 scid) mice treated with rabbit anti-asialo-GM1 serum to deplete natural killer (NK) cells and then with 3 Gy of whole body irradiation. As a conventional control, an equivalent amount of F344 nu bone marrow cells (BMCs) was intravenously injected into C.B-17 scid mice treated with a similar conditioning regimen. In both mouse recipients of rat BM plug engraftment in the kidney capsules and recipients of intravenous injection of rat BMC suspension, comparable extents of donor rat class I+ cells were persistently detected in the peripheral blood. However, the differentiation of rat-derived B cells in the mouse recipients of rat BM plugs was more rapid than that in the recipients of rat BMC suspension. In the late phase (10 weeks after BM transplantation), the percentage of rat-derived T cells (CD4+ cells) in the mouse recipients of rat BM plugs was significantly higher than that in the recipients of rat BMC suspension. At this time point, ectopic BM structure consisting of bone, mesenchymal cells, and hematopoietic progenitors was constructed in the kidney capsules of mice that received rat BM plugs. Most of the cells in the ectopic BM were derived from the donor rat. Thus, engraftment of BM plugs into the kidney capsules results in the construction of a donor-derived BM microenvironment, facilitating multilineage mixed xenogeneic chimerism.

Animals↗
PubMed1999

Establishment of nurse-like stromal cells from bone marrow of patients with rheumatoid arthritis: indication of characteristic bone marrow microenvironment in patients with rheumatoid arthritis.

OBJECTIVE: To investigate the microenvironment of bone marrow (BM) of patients with rheumatoid arthritis (RA). METHODS: Nurse cell-like BM stromal cell lines were established from BM mononuclear cells of patients with RA. We examined the various characteristics of these cell lines, including morphology, pseudoemperipolesis activity, cell surface markers, cytokine production and hyaluronan (HA) production. RESULTS: These RA BM nurse cell-like lines (RA-BMNC) were of mesenchymal origin and positive for CD44, CD54 and HLA-DR. They were defined as nurse cells because of pseudoemperipolesis activity that allowed lymphocytes to migrate underneath. RA-BMNC lines produced HA and multiple cytokines including interleukin (IL)-6, IL-7, IL-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF). HA production by BM stromal cells was correlated with pseudoemperipolesis activity. RA-BMNC produced significantly higher levels of IL-6, IL-8 and GM-CSF by co-culture with lymphocytes. The cells also produced IL-1beta, G-CSF and tumour necrosis factor only when co-cultured with lymphocytes. The RA-BMNC maintained the growth of CD14+ myeloid cells unique to severe RA. CONCLUSION: The present results both indicate that RA-BMNC are nurse cells and suggest that they may play an important role in the pathogenesis of RA.

Antigens, CD↗