ISSN:1061-6128    

DOI:10.1089/scd.1.1996.5.1

年代:1996

数据来源: MAL

摘要:

ABSTRACTGraft-versus-host disease (GVHD) remains a major complication following allogeneic stem cell transplantation. It is mediated by alloreactive donor T cells recognizing histocompatibility antigens of the host, and ex vivo depletion of these cells from the graft has been used as prophylaxis. This, however, carries increased risk of graft rejection, disease relapse, and impaired immune reconstitution. It now appears that GVHD may be primarily mediated by cytokines. A three-step hypothesis for the involvement of cytokines in the pathophysiology of acute and chronic GVHD is presented, with emphasis on the role of Th1 and Th2 T cell subsets.

ISSN:1061-6128    

DOI:10.1089/scd.1.1996.5.3

年代:1996

数据来源: MAL

摘要:

ABSTRACTThe importance of the stromal tissue of the bone marrow in regulating hemopoiesis is well documented. However, several features of marrow stromal cell biology remain poorly understood, in particular, the ontogeny and phylogeny of the various stromal elements that comprise the microenvironment of the bone marrow. In this article we review recent data concerning the immunophenotype and functional characteristics of precursor cells for marrow stromal tissue. The study of these stromal precursor cells (SPC) represents an exciting new field of research that will amost certainly expand in the future as we gain a greater understanding of the cellular and molecular events, environmental cues, and growth factors that physiologically regulate the commitment and subsequent development of SPC. Although the field of marrow SPC biology is in its infancy, we predict that future studies will result in several novel clinical applications for SPC. We, therefore, conclude this article by speculating on a number of these potential applications and, thus, view SPC and their progeny as likely vehicles for several novel and important cellular therapies, including gene therapy.

ISSN:1061-6128    

DOI:10.1089/scd.1.1996.5.15

年代:1996

数据来源: MAL

摘要:

ABSTRACTThe development of in vitro conditions that promote a numerical expansion of hematopoietic stem cells (HSCs) with long-term reconstituting ability has been a long-standing goal in experimental hematology. In previous studies, we showed that input numbers of such cells, i.e., competitive repopulating units (CRU), could be maintained for 2 weeks when purified Sca-1+Lin−WGA+ adult bone marrow (BM) cells were cultured in serum-free and stromal cell-free cultures containing Steel factor (SF), interleukin 6 (IL-6), and erythropoietin (Epo). In separate studies, we showed that limiting numbers of purified fetal liver (FL) cells that are highly enriched for CRU display a higher proliferative and self-renewal potential in vivo compared with similar cells purified from adult BM. These findings prompted us to explore the possibility of achieving a numerical expansion of purified FL cells in culture. Although we observed an extensive increase in the number of nucleated FL cells in all culture conditions tested, none of the cultures, including cultures in serum-containing medium and cocultures on a preestablished feeder layer of BM stromal cells of S17 cells, sustained the expected expansion or even supported the maintenance of input numbers of FL CRU. Single cell cultures showed that the production of nucleated cells by purified Sca-1++Lin·−AA4.1+ FL cells stayed behind that of purified Sca-1+Lin−WGA+ adult BM cells. Taken together, our results show that a variety of culture conditions tested, including conditions that support maintenance and limited expansion of adult BM CRU do not support the production of repopulating stem cells from FL. Because such expansion can be observed in vivo, this system appears useful to search for novel culture conditions and—perhaps yet unidentified—cytokines or other microenvironment-related factors that may be required for FL CRU to prevent loss of repopulation potential in vitro and allow these cells to exhibit their expected self-renewal

ISSN:1061-6128    

DOI:10.1089/scd.1.1996.5.25

年代:1996

数据来源: MAL

摘要:

ABSTRACTAutologous bone marrow transplantation (ABMT) for acute myeloid leukemia (AML) in first complete remission (CR) results in a prolonged disease-free survival (DFS) of 34%–57%. Relapse of the underlying disease is the major cause for failure of ABMT. Relapse can result fom tumor cells either surviving in the patient or reinfused in the autograft. Genetic marking of autografted cells has demonstrated that transplanted cells contribute to relapse. This finding supports the use of purged autografts. Several purging techniques have been used. Immunologic purging using the monoclonal antibody (mAb) PM-81 (anti-CD15) has been used by our center with a long-term DFS in 50% of AML patients. PM-81 reacts with 90% of AML patients, and we have used it for over 10 years. We have investigated a two-stage purging technique involving initial selection for CD34+ cells followed by mAb purging in bone marrow (BM) and peripheral blood stem cell (PBSC) harvests. This method achieved up to a 7 log diminution in leukemic cells and 1–4 log reduction in CD15+ cells, without a significant loss of hematopoietic progenitor cells. This double-purging technique has the advantages of cytoreduction, elimination of CD34− leukemic cells, and possible improvement in the clinical efficacy of purging by concentrating for CD34+ cells. Cytoreduction by CD34 enrichment followed by purging may facilitate the use of PBSC transplants i

ISSN:1061-6128    

DOI:10.1089/scd.1.1996.5.39

年代:1996

数据来源: MAL

摘要:

ABSTRACTThe ability of lymphokine-activated killer (LAK) cells to discriminate between CD34+ leukemia cells and hematopoietic progenitor cells was investigated. As effector cells, CD4−-LAK generated from a CD4− subset of allogeneic peripheral blood lymphocytes were used. The target cell samples were obtained from peripheral blood stem cell (PBSC) collections. Detection of residual tumor cells was performed using a polymerase chain reaction (PCR) technique for chimeric bcr/abl messenger RNA. When PBSC were obtained from patients with seminoma and lung cancer, treated with the CD4−-LAK for 12 h and the CD34+ cells were isolated, colony formation (CFU-GM) by these cells was preserved. When PBSC were obtained from a patient with PCR-positive acute lymphocytic leukemia and treated with the CD4−-LAK for 3 h, reexamination showed conversion to PCR negativity. Furthermore, when the CD34+ cells isolated from the negative converted PBSC were cultured, they still exhibited colony formation. These results suggest that the CD4−-LAK can kill the CD34+ leukemia cells, discriminating from the normal hematopoietic pr

ISSN:1061-6128    

DOI:10.1089/scd.1.1996.5.49

年代:1996

数据来源: MAL

摘要:

ABSTRACTA significant percentage of women with primary breast cancer have micrometastatic disease in the bone marrow. Bone marrow involvement may be an adverse prognostic factor, and more aggressive therapy may be indicated for these patients. There are a number of different techniques and antibodies used to detect tumor cells in the bone marrow. We used the same panels of four antibreast cancer antibodies and compared three immunodetection techniques: two-color immunofluorescence, immunohistochemical staining, and fluorescence-activated cell sorting with cytologic examination of the sorted cells. The two-color immunofluorescence technique was superior and consistently detected one tumor cell contaminating one million normal bone marrow cells and had no reactivity with normal bone marrow.

ISSN:1061-6128    

DOI:10.1089/scd.1.1996.5.57

年代:1996

数据来源: MAL

摘要:

ABSTRACTWe investigated a dose-escalation effect of G-CSF (5, 10, and 15 μg/kg) on mobilization of committed and primitive hemopoietic progenitor cells, including CFU-GM, BFU-E, and long-term culture-initiating cells (LTC-IC) in addition to CD34+ cells and yields of progenitor cells in PBSC harvests obtained by leukapheresis of healthy adult donors. Results indicate that the mobilization of these progenitor cells is both dose and time dependent. Despite the very small number of healthy donors studied, it is estimated from our data that a sufficient number of CD34+ cells for allogeneic PBSC transplant (PBSCT) could be collected using a 5 day administration of 10 μg/kg of G-CSF to normal adult donors. Adverse effects include general fatigue and bone pain in most of the donors and fever and headache in some. These symptoms were well tolerated in most instances. Laboratory test abnormalities, including transient thrombocytopenia, increased platelet aggregation, and increased serum levels of some liver enzymes, were induced by G-CSF administration, but all were reversible within a short time. These observations suggest that hemopoietic stem cells for allogeneic PBSCT can be mobilized by short-term administration of a relatively high-dose G-CS

ISSN:1061-6128    

DOI:10.1089/scd.1.1996.5.63

年代:1996

数据来源: MAL

摘要:

ABSTRACTThe effects of bone marrow (BM) and peripheral blood progenitor cell (PBPC) concentration during cryopreservation on subsequent hematopoietic engraftment following high-dose chemotherapy were studied in 24 patients. Seventeen BM harvests and 71 PBPC collections were performed between July 1991 and June 1994. The PBPC were frozen at significantly higher cellular concentrations than the BM (medians of 243 × 106/ml versus 73 × 106/ml respectively,p= 0.0003). The recovery of committed progenitor cell colonies (CFU-GM) was significantly lower from PBPC frozen at concentrations above the median, compared with 116% from those frozen at concentrations below the median (p= 0.0467). This phenomenon was not seen in BM, which was generally frozen at a threefold lower concentration. Despite the lower recovery of CFU-GM when PBPC were frozen at a higher concentration, the patients receiving these grafts achieved good hematopoietic recovery. The higher number of PBPC probably compensated for the loss, and the patients still received a substantial number of clonogenic hematopoietic precursor

ISSN:1061-6128    

DOI:10.1089/scd.1.1996.5.73

年代:1996

数据来源: MAL

摘要:

ABSTRACTVenoocclusive disease (VOD) of the liver remains one of the major obstacles for patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT). Many factors have been associated with the development of VOD, including a hypercoagulable state secondary to a drop in protein C and antithrombin III (AT III). We conducted a prospective nonrandomized trial to try to determine whether the development of clinical VOD was associated with a drop in protein C, protein S, and AT III. A total of 42 patients undergoing high-dose chemotherapy and HSCT were enrolled in this study. Eleven patients underwent allogeneic bone marrow transplantation (BMT) following high-dose cyclophosphamide and fractionated total body irradiation (TBI). Thirty-one patients received autologous stem cell rescue following different preparative regimens. Measurements of protein C, protein S, and AT III levels were obtained prior to conditioning therapy and weekly thereafter for 2–3 weeks. A significant difference was noted in the mean levels of protein C on day 7 between those who developed VOD and those who did not (57.5 versus 72.1,p= 0.009). Similarly, there was a significant difference in the mean levels of AT III on days 7 and 14 between the two groups (day 7, 95.5 versus 80.6,p= 0.002; day 14, 99.6 versus 85.2,p= 0.01). The drop in protein S levels on days 7 and 14 was not statistically significant between the two groups. In conclusion, the degree of drop in protein C and AT III levels on day 7 was predictive for the development and severity of VO

ISSN:1061-6128    

DOI:10.1089/scd.1.1996.5.79

年代:1996

数据来源: MAL