ISSN:0192-8562    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

PurposeThis article reviews the complex process of establishing functional long-term hematopoiesis required for successful clinical bone marrow transplantation. The failure to establish sustained hematopoiesis, either primary or secondary graft failure, is defined and multiple etiologic factors involved are discussed.DesignData from published studies of experimental and clinical BMT, as well as in vitro stem cell biology, were used to elucidate the elements required for establishing functional hematopoiesis. These include pleuripotential hematopoietic stem cells; homing of stem cell to the hematopoietic micro-environment; hematopoietic stroma and secreted cytokines acting synergistically to promote expansion and hematopoietic differentiation of the stem cells; and, in the setting of allogeneic transplantation, immunological tolerance between the host and the graft, without which graft rejection or graft-vs.-host disease may occur.ConclusionsThe factors influencing the establishment of functional hematopoiesis and the risks for graft failure vary with the type of transplant performed. In an autologous transplant, damage to the stem cells or to the stromal microenvironment can contribute to prolonged time to engraftment or primary graft failure. In contrast, the hematopoietic stem cells are normal in both syngeneic and allogeneic transplantation. However, in the latter, because of immunological disparity between the host and recipient, there can be either primary or secondary graft failure due to a host-vs.-graft phenomenon, graft rejection. Classic graft rejection is an immunologic phenomenon mediated by residual host immunocompetent cells, either T cells or NK cells, depending on the allogeneic disparity between host and donor. T cell depletion and increased HLA disparity are risk factors for rejection. Numerous strategies have attempted to decrease the risk of rejection; most have focused primarily on increased immunosuppression of the host either with additional radiation, chemotherapy or in vivo anti-T cell serotherapy. Recent attempts have explored preventing rejection by manipulating donor cell composition of the infused graft.

ISSN:0192-8562    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Graft-vs.-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation, which is an important approach for the treatment of various diseases. In experimental animal models, lethal GVHD can be induced in major histocompatibility complex (MHC)-matched strain combinations that differ in their expression of multiple minor histocompatibility antigens. It has been shown that T cell subset populations expressing the CD8+phenotype play an important role in the development of GVHD directed to the minor histocompatibility antigens. Moreover, highly purified preparations of these cells are capable of mediating GVHD without apparent help from mature donor-derived CD4+T cells. CD4+T cells can also mediate GVHD, but only in certain strain combinations. The pathogenesis of GVHD is similar, whether it is mediated by CD4+or CD8+T cells, with the exception that CD4+cells may be responsible for more gastrointestinal injury. The ability of T cells to respond to minor histocompatibility antigens is further complicated by the phenomenon of immunodominance, which causes T cells to focus on a limited number of antigens out of the larger available pool. Immunodominance does occur in GVHD, but it seems to involve a different pattern of responses than those observed for the generation of cytotoxic T lymphocytes in vitro. Under-standing these immunologic interactions is an important step toward the ultimate goal of developing a new approach for bone marrow transplantation, one that will avoid GVHD while retaining enough immunity to counter leukemic relapse and opportunistic infections.

ISSN:0192-8562    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

PurposeAcute graft-vs.-host disease (aGVHD), a relatively common complication of allogeneic bone marrow transplantation, is mediated by graft-derived T-lymphocytes that recognize host antigens not expressed by the donor. Clinical manifestations of aGVHD involve the skin, gut, and liver with varying degrees of severity. Strategies for prevention and treatment of aGVHD are reviewed.Patients and MethodsThe assessment of the degree of disparity in the human leukocyte antigen (HLA) type of donor and recipient pairs using refined serologic and molecular biologic testing is necessary for the prevention of severe aGVHD. T-lymphocyte depletion of the bone mar-row graft removes the effector cells for aGVHD, but is associated with other transplant related morbidity. Immunosuppressive agents, which are used for prevention, are the basis of treatment for aGVHD.ResultsRecently developed techniques for tissue typing may result in the more accurate prediction of aGVHD in donor and recipient pairs. Despite the use of careful do-nor selection, graft T-lymphocyte depletion, and vigorous prophylactic immunosuppression, aGVHD occurs in a large number of bone marrow transplant patients. Treatment of aGVHD with standard immunosuppressive agents is effective in most cases. Newly developed immunosuppressive agents are being studied for the treatment of aGVHD which responds poorly to therapy.ConclusionsAcute graft-vs.-host disease is responsible for significant morbidity in bone marrow transplant patients. Newer approaches to the prevention and treatment of this disease are currently being evaluated.

ISSN:0192-8562    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

PurposeBone marrow transplantation usually entails the ablation of the recipient's immune system. The recovery of immunity post-marrow transplantation is a complex process dependent on a number of pre- and posttransplant factors. This knowledge has led to the development of novel approaches to supportive care of the patient, as well as to methods of augmenting immunity.DesignHematopoietic growth factors are now used to speed neutrophil recovery. Certain lymphokines are being investigated for the enhancement of cell-mediated immunity, and γ globulin preparations are used to support the deficiency in humoral immunity.ConclusionsThis review summarizes the basic concepts of immune reconstitution posttransplant and discusses some of the therapeutic interventions that have been investigated. In addition, some general recommendations are offered regarding supportive care.

ISSN:0192-8562    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

PurposeBone marrow transplantation is an effective treatment for leukemia. Cures are possible in 20–80% of transplant recipients depending on the stage of leukemia at the time of transplant. The antileukemia efficacy of transplants result from high-dose chemotherapy and/or radiation given pretransplant and from immune-mediated effects of the graft.ResultsSuccess of the procedure is limited by transplant-related complications, including graft rejection, graft-vs.-host disease and interstitial pneumonia. Five-year leukemia-free survival ranges from ±25% for children trans-planted with advanced leukemia, to >60% in those transplanted in first remission of acute leukemia or first chronic phase of chronic myeloid leukemia.ConclusionsCandidates for transplant include children failing conventional therapy and, possibly, those with early leukemia characterized by features predicting a poor response to conventional therapy.

ISSN:0192-8562    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

An immunophenotypic pattern characterized by in-creased proportions of CD10, CD19, and HLA-DR+cells is observed in the bone marrow of some children with nonmalignant hematologic diagnoses. The purpose of this study was to ascertain the clinical and pathologic significance of this immunophenotype. The morphologic and immunophenotypic results of bone marrow specimens from 23 children with nonmalignant hematologic conditions are presented. In 11 children, an increased percent-age of immature B-cell precursors was observed, suggesting the presence of B-lineage malignancy. None of the children have developed malignant lymphoproliferative disease in as long as 4 years of follow-up, despite the demonstration of a clonal lymphocyte proliferation in one patient. Although the biologic significance of the bone marrow immunophenotype is not yet understood, it is important to recognize that this lymphocyte pattern occurs commonly in children with nonmalignant hematologic conditions, and may reflect an increase in normally occurring lymphoid precursor cells.

ISSN:0192-8562    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

PurposeRecombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) was administered to two patients with glycogen storage disease, type lb (GSD-lb), with chronic neutropenia, neutrophil dysfunction, and recurrent infections in an effort to increase neutrophil counts and increase resistance to infections.Patients and MethodsThe patients' baseline absolute neutrophil counts (ANC) ranged from 56 to 480 cells/mm3despite increased granulocyte precursors in the bone marrow. GM-CSF was given s.c. at starting doses of 500 μg/m2/day divided into two doses.ResultsAfter 48 h, ANC rose to 2,025 cells/mm3and 3,132 cells/mm3, respectively. Absolute eosinophil counts also rose to 1,048 cells/mm3(24%) and 4,820 cells/mm3(33%) on days 10 and 9 in the two patients. Although an initial 10-day course of GM-CSF was tolerated in one patient without significant reactions, subsequent s.c. injections of GM-CSF were complicated by increasingly painful local reactions that necessitated discontinuation after 7 to 8 days. Intravenous infusion was associated with a febrile systemic reaction. Despite lack of improvement in neutrophil superoxide anion generation measured in one, both patients demonstrated unusually rapid healing of cutaneous infections on GM-CSF.ConclusionOur experience suggests that GM-CSF may be useful for short-term treatment of serious infections in GSD-lb. However, alternate dosage schedules or different preparations of GM-CSF to diminish local reactions would be required for long-term maintenance therapy. Granulocyte colony stimulating factor (G-CSF) has also been shown to increase neutrophils in this disease and has not been associated with allergic reactions.

ISSN:0192-8562    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

An infant boy with severe factor VIII (FVIII) deficiency hemophilia and antibodies against coagulation FVIII is presented. This case is unique from the point of view of the young age of development and recognition of inhibitors to the FVIII and because this patient received recombinant factor Vlla (rFVIIa), prior to a life-saving surgical procedure. Conventional treatment options had been exhausted. The inhibitor was an IgG antibody that had rapidly increased to 100 Bethesda Units (BU). A broviac central line was placed to provide i.v. access for the purpose of treatment. Porcine FVIII had been used but an inhibitor rapidly developed to that product. Using rFVIIa, hemostasis was secured for placement of a second central line and to stop life-threatening mucosal bleeding. rVIIa was an effective treatment alternative for the management of this patient with inhibitors.

ISSN:0192-8562    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

PurposeThe cellular pharmacology of 6-Mercaptopurine (6MP) in acute lymphoblastic leukemia (ALL) is reviewed.DesignRelevant studies on the clinical pharmacology of 6MP were reviewed.Results6MP is one of the major drugs used in maintenance therapy of acute lymphoblastic leukemia (ALL). It is also used to treat steroid unresponsive inflammatory bowel disease. 6MP is an inactive prodrug that requires absorption, cellular uptake, and intracellular anabolism to nucleotides for cytotoxic activity. These nucleotides are ultimately incorporated into DNA and RNA, resulting in cell death. Two analogs of 6MP, azathioprine and 6-thioguanine, are also anabolized to the same intracellular metabolites, suggesting they should be therapeutically equivalent to 6MP. 6MP may be anabolized to nonmethylated nucleotides or may undergo methylation by the enzyme thiopurine methyltransferase to S-methylated nucleotides, which are also cytotoxic.ConclusionRecent studies of 6MP pharmacokinetics in children with ALL have suggested that a higher systemic exposure, as measured by a greater area under the plasma concentration time curve or a higher concentration of 6MP metabolites in red blood cells, is associated with a decreased risk of relapse.

ISSN:0192-8562    

出版商:OVID    

年代:1993

数据来源: OVID