共查询到20条相似文献,搜索用时 62 毫秒
1.
Zakrzewski JL Kochman AA Lu SX Terwey TH Kim TD Hubbard VM Muriglan SJ Suh D Smith OM Grubin J Patel N Chow A Cabrera-Perez J Radhakrishnan R Diab A Perales MA Rizzuto G Menet E Pamer EG Heller G Zúñiga-Pflücker JC Alpdogan O van den Brink MR 《Nature medicine》2006,12(9):1039-1047
Immunoincompetence after allogeneic hematopoietic stem cell transplantation (HSCT) affects in particular the T-cell lineage and is associated with an increased risk for infections, graft failure and malignant relapse. To generate large numbers of T-cell precursors for adoptive therapy, we cultured mouse hematopoietic stem cells (HSCs) in vitro on OP9 mouse stromal cells expressing the Notch-1 ligand Delta-like-1 (OP9-DL1). We infused these cells, together with T-cell-depleted mouse bone marrow or purified HSCs, into lethally irradiated allogeneic recipients and determined their effect on T-cell reconstitution after transplantation. Recipients of OP9-DL1-derived T-cell precursors showed increased thymic cellularity and substantially improved donor T-cell chimerism (versus recipients of bone marrow or HSCs only). OP9-DL1-derived T-cell precursors gave rise to host-tolerant CD4+ and CD8+ populations with normal T-cell antigen receptor repertoires, cytokine secretion and proliferative responses to antigen. Administration of OP9-DL1-derived T-cell precursors increased resistance to infection with Listeria monocytogenes and mediated significant graft-versus-tumor (GVT) activity but not graft-versus-host disease (GVHD). We conclude that the adoptive transfer of OP9-DL1-derived T-cell precursors markedly enhances T-cell reconstitution after transplantation, resulting in GVT activity without GVHD. 相似文献
2.
Joan M. Redd Anne-Catherine Lagarde Carol A. Kruse Donald Bellgrau 《Cancer immunology, immunotherapy : CII》1992,34(5):349-354
Summary We report the development of cytotoxic T lymphocytes specific for an allogeneic brain tumor in a rat model. DA strain cytotoxic T cell precursors stimulated by an allogeneic tumor (9L gliosarcoma) from the Fischer rat could generate a population of cytotoxic T lymphocytes that lysed the allogeneic 9L tumor but failed to lyse other targets, including Fischer concanavalin-A(ConA)-stimulated lymphoid blast targets. DA T cells depleted of reactivity to the Fischer haplotype (DA-f) retained reactivity to the 9L tumor, demonstrating that T cell precursors with specificity for normal Fischer alloantigens were not required for the generation of a response to the 9L Fischer tumor. The preferential lysis of the tumor target did not simply reflect a higher density of Fischer target antigens on the tumor than that found on normal Fischer ConA blast targets. First, the relative densities of class I antigen on the 9L tumor and normal Fischer ConA blasts were comparable. Second, cytotoxic T cells could not be generated from DA-f precursors when Fischer ConA blasts were used as stimulators. If DA-f T cells were simply responding to the higher density of Fischer antigen found on 9L tumor, it would have been expected that the ConA blasts expressing comparable levels of antigen to that found on the tumor would have generated cytotoxicity for both the 9L and ConA targets. We conclude that the cytotoxic T cells are specific for a determinant expressed only by the tumor. Such tumor-specific cytotoxic T cells could be useful in vivo for adoptive immunotherapy of brain tumors. 相似文献
3.
Turin I Pedrazzoli P Tullio C Montini E La Grotteria MC Schiavo R Perotti C Locatelli F Carretto E Maccario R Siena S Montagna D 《Cytotherapy》2007,9(5):499-507
BACKGROUND: The adoptive transfer of ex vivo-induced tumor-specific T-cell lines provides a promising approach for cancer immunotherapy. We have demonstrated previously the feasibility of inducing in vitro long-term anti-tumor cytotoxic T-cell (CTL) lines directed against different types of solid tumors derived from both autologous and allogeneic PBMC. We have now investigated the possibility of producing large amounts of autologous anti-tumor CTL, in compliance with good manufacturing practices, for in vivo use. METHODS: Four patients with advanced solid tumors (two sarcoma, one renal cell cancer and one ovarian cancer), who had received several lines of anticancer therapy, were enrolled. For anti-tumor CTL induction, patient-derived CD8-enriched PBMC were stimulated with DC pulsed with apoptotic autologous tumor cells (TC) as the source of tumor Ag. CTL were then restimulated in the presence of TC and expanded in an Ag-independent way. RESULTS: Large amounts of anti-tumor CTL (range 14-20 x 10(9)), which displayed high levels of cytotoxic activity against autologous TC, were obtained in all patients by means of two-three rounds of tumor-specific stimulation and two rounds of Ag-independent expansion, even when a very low number of viable TC was available. More than 90% of effector cells were CD3(+) CD8(+) T cells, while CD4(+) T lymphocytes and/or NK cells were less than 10%. DISCUSSION: Our results demonstrate the feasibility of obtaining large quantities of anti-tumor specific CTL suitable for adoptive immunotherapy approaches. 相似文献
4.
Lisa Borkner Andrew Kaiser Willeke van de Kasteele Reinhard Andreesen Andreas Mackensen John B. Haanen Ton N. Schumacher Christian Blank 《Cancer immunology, immunotherapy : CII》2010,59(8):1173-1183
Adoptive cell transfer (ACT), either using rapidly expanded tumor infiltrating lymphocytes or T-cell receptor transduced peripheral
blood lymphocytes, can be considered one of the most promising approaches in cancer immunotherapy. ACT results in the repopulation
of the host with high frequencies of tumor-specific T cells; however, optimal function of these cells within the tumor micro-environment
is required to reach long-term tumor clearance. We and others have shown that ongoing anti-tumor immune responses can be impaired
by the expression of ligands, such as PD-L1 (B7-H1) on tumor cells. Such inhibitory molecules can affect T cells at the effector
phase via their receptor PD-1. PD-L1/PD-1 interaction has indeed been shown crucial in inducing T-cell anergy and maintaining
peripheral tolerance. In order to maximize anti-tumor responses, antibodies that target the PD-1/PD-L1 axis are currently
in phase I/II trials. Alternatively, a more refined approach could be the selective targeting of PD-1 in tumor-specific T
cells to obtain long-term resistance against PD-1-mediated inhibition. We addressed whether this goal could be achieved by
means of retroviral siRNA delivery. Effective siRNA sequences resulting in the reduction of surface PD-1 expression led to
improved murine as well as human T-cell immune functions in response to PD-L1 expressing melanoma cells. These data suggest
that blockade of PD-1-mediated T-cell inhibition through siRNA forms a promising approach to achieve long-lasting enhancement
of tumor-specific T-cell function in adoptive T-cell therapy protocols. 相似文献
5.
The anti-tumor efficacy of lymphokine-activated killer cells and recombinant interleukin 2 in vivo 总被引:15,自引:0,他引:15
We showed previously that adoptive immunotherapy with the combination of LAK cells and recombinant IL 2 (RIL 2) can markedly reduce pulmonary micrometastases from multiple sarcomas established 3 days after the i.v. injection of syngeneic tumor cells in C57BL/6 mice. In this report, we analyzed the factors required for successful therapy. Titration analysis in vivo revealed an inverse relationship between the number of pulmonary metastases remaining after treatment and both the number of LAK cells and the amount of RIL 2 administered. Fresh or unstimulated splenocytes had no anti-tumor effect; a 2- to 3-day incubation of splenocytes in RIL 2 was required. LAK cells generated from allogeneic DBA (H-2d) splenocytes were as effective in vivo as syngeneic, C57BL/6 (H-2b) LAK cells. The anti-metastatic capacity of LAK cells was significantly reduced or eliminated when irradiated with 3000 rad before adoptive transfer. The combined therapy of LAK cells plus RIL 2 was shown to be highly effective in mice immunosuppressed by 500 rad total body irradiation and in treating macrometastases established in the lung 10 days after the i.v. injection of sarcoma cells. Further, reduction of both micrometastases and macrometastases could also be achieved by RIL 2 alone when administered at higher levels than were required with LAK cells. The value of LAK cell transfer and of IL 2 administration for the treatment of tumors established at other sites is currently under investigation. 相似文献
6.
7.
Leen Willems Sabien Fevery Ben Sprangers Omer Rutgeerts Caroline Lenaerts Abdelilah Ibrahimi Rik Gijsbers Stefaan Van Gool Mark Waer An D. Billiau 《Cancer immunology, immunotherapy : CII》2013,62(11):1733-1744
Allogeneic hematopoietic stem cell transplantation and donor leukocyte infusion (DLI) may hold potential as a novel form of immunotherapy for high-risk neuroblastoma. DLI, however, carries the risk of graft-versus-host disease (GvHD). Recipient leukocyte infusion (RLI) induces graft-versus-leukemia responses without GvHD in mice and is currently being explored clinically. Here, we demonstrate that both DLI and RLI, when given to mixed C57BL/6 → A/J radiation chimeras carrying subcutaneous Neuro2A neuroblastoma implants, can slow the local growth of such tumors. DLI provoked full donor chimerism and GvHD; RLI produced graft rejection but left mice healthy. Flow cytometric studies showed that the chimerism of intratumoral leukocytes paralleled the systemic chimerism. This was associated with increased CD8/CD4 ratios, CD8+ T-cell IFN-γ expression and NK-cell Granzyme B expression within the tumor, following both DLI and RLI. The clinically safe anti-tumor effect of RLI was further enhanced by adoptively transferred naïve recipient-type NK cells. In models of intravenous Neuro2A tumor challenge, allogeneic chimeras showed superior overall survival over syngeneic chimeras. Bioluminescence imaging in allogeneic chimeras challenged with luciferase-transduced Neuro2A cells showed both DLI and RLI to prolong metastasis-free survival. This is the first experimental evidence that RLI can safely produce a local and systemic anti-tumor effect against a solid tumor. Our data indicate that RLI may provide combined T-cell and NK-cell reactivity effectively targeting Neuro2A neuroblastoma. 相似文献
8.
Murine bone marrow cells (strain A) have been allowed to differentiate in vivo in syngeneic (A) or semiallogeneic hosts (A × B) to produce mature splenic T lymphocytes. After stimulation of these cells with irradiated allogeneic (C) spleen cells in tissue cultures, the cytotoxic T-cell blasts (CTL) were purified by velocity sedimentation and used to immunize (A × C) F1 hybrid mice, to produce antisera recognizing the receptor structure (for C) on the relevant A cytotoxic cells (and their precursors). Using these sera we have been able to show that the T-cell receptor for alloantigen C on strain A cytotoxic precursor lymphocytes (CTLp) seems to differ according to the host environment in which those T cells differentiate from immature bone marrow precursors. 相似文献
9.
Amitabha Mazumder Elizabeth A. Grimm Steven A. Rosenberg 《Cancer immunology, immunotherapy : CII》1998,15(1):1-10
Summary We have previously demonstrated that cancer patients' peripheral blood lymphocytes (PBL) allosensitized against single or pool normal donor PBL are capable of lysing fresh autologous tumor cells in a 4-h 51Cr-release assay. In this report, we present further investigations into this phenomenon. These alloactivated killer cells (A-AK cells) lysed autologous and allogeneic tumors and allogeneic but not autologous PBL. Furthermore, cold target inhibition studies demonstrated that autologous and allogeneic tumors were lysed by the same effector cells. Multiple metastases from the same patient were equivalently lysed by these A-AK cells. The presence of adherent cells and proliferation of the precursors were necessary to generate A-AK cells, although the effector cell itself was radioresistant and nonadherent. The effects of allosensitization were enhanced by the addition of lectin-free interleukin-2 preparations to the in vitro culture by partial depletion of adherent cells prior to sensitization. The A-AK effector cell was OKT3+, OKT8+, OKT4–, OKM1– and could be generated by just 3 days of allosensitization. The precursors for A-AK cells could be separated from NK cells on percoll gradients and lysis could be generated from thoracic duct lymphocytes, a population devoid of NK cells. The phenotype of the majority of the precursor cells was OKT3+, OKT4–. These allocatived PBL could be expanded in crude or lectin-free interleukin-2 without loss of cytotoxicity for fresh autologous tumor cells. Activated T cells represent a population of non-NK cells with broad lytic specificity for fresh tumor cells. Such cells may be of value in the adoptive immunotherapy of human solid tumors and may play a role in immune surveillance. 相似文献
10.
Lee YJ Min HS Kang EH Park HJ Jeon YK Kim JH Wu HG Lee EB Park CG Yoon SS Park SH Jung KC 《Immunology and cell biology》2012,90(3):358-367
Despite a long-standing hypothesis that chronic graft-versus-host disease (cGVHD) is an autoimmune disorder, most mouse models of cGVHD have been developed on the assumption that donor T cells are essential for its development. Here we show that cGVHD may be caused by autoreactive host T cells in mice that have been lethally irradiated and grafted with T-cell-depleted allogeneic bone marrow cells. In this chimera, host T cells derived from radioresistant intrathymic T-cell precursors caused dermal fibrosis and periportal inflammation, without the requirement for donor T cells. The lack of host DCs within the thymus after high-dose irradiation allowed autoreactive host T cells to escape thymic negative selection. Moreover, the homeostatic expansion of these T cells may augment their autoreactivity. These findings indicate that host T-cell-mediated cGVHD is an autoimmune process that occurs following the grafting of T-cell-depleted BM cells into hosts with functioning thymuses. We propose, based on the present data, that host T-cell-dependent autoimmunity is a potential mechanism by which cGVHD is induced. 相似文献
11.
Simmons AD Li B Gonzalez-Edick M Lin C Moskalenko M Du T Creson J VanRoey MJ Jooss K 《Cancer immunology, immunotherapy : CII》2007,56(10):1653-1665
Granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor cell immunotherapies have demonstrated long-lasting,
and specific anti-tumor immune responses in animal models. The studies reported here specifically evaluate two aspects of
the immune response generated by such immunotherapies: the persistence of irradiated tumor cells at the immunization site,
and the breadth of the immune response elicited to tumor associated antigens (TAA) derived from the immunotherapy. To further
define the mechanism of GM-CSF-secreting cancer immunotherapies, immunohistochemistry studies were performed using the B16F10
melanoma tumor model. In contrast to previous reports, our data revealed that the irradiated tumor cells persisted and secreted
high levels of GM-CSF at the injection site for more than 21 days. Furthermore, dense infiltrates of dendritic cells were
observed only in mice treated with GM-CSF-secreting B16F10 cells, and not in mice treated with unmodified B16F10 cells with
or without concurrent injection of rGM-CSF. In addition, histological studies also revealed enhanced neutrophil and CD4+ T
cell infiltration, as well as the presence of apoptotic cells, at the injection site of mice treated with GM-CSF-secreting
tumor cells. To evaluate the scope of the immune response generated by GM-CSF-secreting cancer immunotherapies, several related
B16 melanoma tumor cell subclones that exist as a result of genetic drift in the original cell line were used to challenge
mice previously immunized with GM-CSF-secreting B16F10 cells. These studies revealed that GM-CSF-secreting cancer immunotherapies
elicit T cell responses that effectively control growth of related but antigenically distinct tumors. Taken together, these
studies provide important new insights into the mechanism of action of this promising novel cancer immunotherapy.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
12.
Dendritic cell maturation and subsequent enhanced T-cell stimulation induced with the novel synthetic immune response modifier R-848. 总被引:7,自引:0,他引:7
C L Ahonen S J Gibson R M Smith L K Pederson J M Lindh M A Tomai J P Vasilakos 《Cellular immunology》1999,197(1):62-72
Agents that enhance dendritic cell maturation can enhance T-cell activation and therefore may improve the efficiency of vaccines or improve cellular immunotherapy. Previously, we demonstrated that a novel low-molecular-weight synthetic immune response modifier, R-848, induces IL-12 and IFN-alpha secretion from monocytes and macrophages. Here we report that R-848 induces the maturation of human monocyte-derived dendritic cells. Characteristic of dendritic cell maturation, R-848 treatment induces cell surface expression of CD83 and increases cell surface expression of CD80, CD86, CD40, and HLA-DR. Additionally, R-848 induces cytokine (IL-6, IL-12, TNF-alpha, IFN-alpha) and chemokine (IL-8, MIP-1alpha, MCP-1) secretion from dendritic cells. Most significantly, R-848 enhances dendritic cell antigen presenting function, as measured by increased T-cell proliferation and T-cell cytokine secretion in both allogeneic and autologous T-cell systems. Consequently, low-molecular-weight synthetic molecules such as R-848 and its derivatives may be useful as vaccine adjuvants or as ex vivo stimulators of dendritic cells for cellular immunotherapy. 相似文献
13.
Matheoud D Baey C Vimeux L Tempez A Valente M Louche P Le Bon A Hosmalin A Feuillet V 《PloS one》2011,6(4):e19104
Dendritic cells (DC) are able to elicit anti-tumoral CD8(+) T cell responses by cross-presenting exogenous antigens in association with major histocompatibility complex (MHC) class I molecules. Therefore they are crucial actors in cell-based cancer immunotherapy. Although apoptotic cells are usually considered to be the best source of antigens, live cells are also able to provide antigens for cross-presentation by DC. We have recently shown that prophylactic immunotherapy by DC after capture of antigens from live B16 melanoma cells induced strong CD8(+) T-cell responses and protection against a lethal tumor challenge in vivo in C57Bl/6 mice. Here, we showed that DC cross-presenting antigens from live B16 cells can also inhibit melanoma lung dissemination in a therapeutic protocol in mice. DC were first incubated with live tumor cells for antigen uptake and processing, then purified and irradiated for safety prior to injection. This treatment induced stronger tumor-specific CD8(+) T-cell responses than treatment by DC cross-presenting antigens from apoptotic cells. Apoptotic B16 cells induced more IL-10 secretion by DC than live B16 cells. They underwent strong native antigen degradation and led to the expression of fewer MHC class I/epitope complexes on the surface of DC than live cells. Therefore, the possibility to use live cells as sources of tumor antigens must be taken into account to improve the efficiency of cancer immunotherapy. 相似文献
14.
Endogenous production of prothymocyte differentiating activity by phytohemagglutinin-stimulated T-cell-depleted human marrow 总被引:1,自引:0,他引:1
M Ahmad J C Lecron J J Descombe J Tanzer P Goube de Laforest 《Cellular immunology》1986,103(2):299-310
The PHA responsiveness of marrow T-cell precursors remains a matter of controversy. We have investigated the capacity of human marrow to proliferate under phytohemagglutinin (PHA) stimulation following extensive removal of mature T cells by complement-dependent cytotoxicity with MBG6 and RFT8 monoclonal antibodies. PHA-induced thymidine uptake by marrow cells occurred with a peak on Days 6-8 of incubation instead of Day 3 for PBL. This peak was observed 48 hr earlier in the presence of PHA-stimulated T-depleted marrow cell supernatants. These supernatants can also promote the growth of mature T-cell colonies from MBG6-, RFT8-, T11-, T3- marrow. However, full colony development requires exogenous interleukin 2 (IL-2). IL-2 could be detected in marrow supernatants but only at very low levels and beyond Days 3 and 4. In contrast Days 1-6 marrow supernatants were equally effective in promoting MBG6-RFT8- marrow cell responsiveness to PHA. We conclude that marrow T-cell precursors are not PHA responsive and that PHA induces the production by marrow non-T cells of a prothymocyte-differentiating activity (PTDA); PTDA can differentiate marrow T-cell progenitors into PHA-responsive T cells; following activation by PHA, these cells undergo limited proliferation induced by IL-2 endogenously released from de novo differentiated T cells. It is suggested that this mechanism may account for extrathymic differentiation of the T-cell lineage in heavily irradiated marrow transplantation recipients. 相似文献
15.
We have isolated a Thy-1+, CD3+, CD4+ T-cell line from the spleen of a 12-week-old nu/nu (nude) BALB/c mouse. The cell line is clonal, and it expresses an alpha beta T-cell antigen receptor. Upon activation, these cells secrete IL-2 but not IL-4, putting them in the Th1 category. The cells can be triggered to proliferate and secrete lymphokines in the presence of irradiated syngeneic or allogeneic splenic feeder cells that express a variety of MHC haplotypes. This response is MHC class II-specific, because it can be blocked by either anti-Ia or anti-CD4 antibodies. From the response pattern of this T-cell line, we conclude that it recognizes a common determinant on class II MHC antigens. This nude mouse T-lymphocyte presumably has not undergone thymic selection. Therefore its unique specificity may reflect both the bias of T-cell antigen receptor genes for encoding receptors that recognize MHC molecules and the requirement for functional thymic epithelial cells for the efficient education of a self-MHC-restricted repertoire. 相似文献
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17.
Anindya Dasgupta 《Biochemical and biophysical research communications》2010,391(1):170-175
Establishment of immunocompetent cell mediated anti-tumor immunity is often mitigated by the myelosuppressive effects during administration of chemotherapy. We hypothesized that protecting these immune cells from drug induced toxicities may allow for the combined administration of immunotherapy and chemotherapy. Using a SIV-based lentiviral gene transfer system we delivered the drug-resistant variant P140KMGMT into the immunocompetent cell lines NK-92 and TALL-104, and the myelogenous leukemia cell line, K562, which is a target for both NK-92 and TALL-104 cells. Genetically engineered immunocompetent cells developed significant resistance to temozolomide compared to non-modified cells, and genetic modification of these cells did not affect their ability to kill K562 cells. We then evaluated the effectiveness of drug-resistant immunocompetent cell mediated killing of tumor cells in the presence and absence of chemotherapy. During a chemotherapy challenge the cytotoxic activity of non-modified immunocompetent cells was dramatically impaired. However, when combined with chemotherapy, genetically-modified immune cells retained their cytotoxic activities and efficiently killed non-modified target cells. These results show that engineering immunocompetent cells to withstand chemotherapy challenges can enhance tumor cell killing when chemotherapy is applied in conjunction with cell-based immunotherapy. 相似文献
18.
Archana Panikkar Katie E. Lineburg Jyothy Raju Keng Yih Chew George R. Ambalathingal Sweera Rehan Srividhya Swaminathan Pauline Crooks Laetitia Le Texier Leone Beagley Shannon Best Matthew Solomon Katherine K. Matthews Sriganesh Srihari Michelle A. Neller Kirsty R. Short Rajiv Khanna Corey Smith 《PLoS pathogens》2022,18(2)
Adoptive T-cell immunotherapy has provided promising results in the treatment of viral complications in humans, particularly in the context of immunocompromised patients who have exhausted all other clinical options. The capacity to expand T cells from healthy immune individuals is providing a new approach to anti-viral immunotherapy, offering rapid off-the-shelf treatment with tailor-made human leukocyte antigen (HLA)-matched T cells. While most of this research has focused on the treatment of latent viral infections, emerging evidence that SARS-CoV-2-specific T cells play an important role in protection against COVID-19 suggests that the transfer of HLA-matched allogeneic off-the-shelf virus-specific T cells could provide a treatment option for patients with active COVID-19 or at risk of developing COVID-19. We initially screened 60 convalescent individuals and based on HLA typing and T-cell response profile, 12 individuals were selected for the development of a SARS-CoV-2-specific T-cell bank. We demonstrate that these T cells are specific for up to four SARS-CoV-2 antigens presented by a broad range of both HLA class I and class II alleles. These T cells show consistent functional and phenotypic properties, display cytotoxic potential against HLA-matched targets and can recognize HLA-matched cells infected with different SARS-CoV-2 variants. These observations demonstrate a robust approach for the production of SARS-CoV-2-specific T cells and provide the impetus for the development of a T-cell repository for clinical assessment. 相似文献
19.
Summary Ninety-six remission patients with acute myelogenous leukemia have been treated with various forms of immunotherapy and chemotherapy in three distinct studies and the clinical outcome of these patients has been reported. In the first study 22 patients were maintained on chemotherapy alone and 28 patients were given the same chemotherapy and additional immunotherapy consisting of BCG and irradiated allogeneic AML cells given at separate sites weekly. It was found that there was a significant increase in survival time of the patients who received immunotherapy (median 510 days) compared with the chemotherapy alone patients (270 days). The p value for this was 0.03. The reason for this prolongation of survival was mainly due to a markedly increased survival time of immunotherapy patients after they relapsed when compared with the chemotherapy patients (165 days compared with 75 days median, p equal to 0.0005). In the second sequential study 24 patients were given immunotherapy alone consisting of irradiated allogeneic AML cells and BCG given at separate sites, and this was compared with unirradiated allogeneic cells and BCG given to 22 patients. There was no difference in the remission length or survival between these two groups. In the third study 13 patients received irradiated cells and BCG as in Study 1 and a further 11 patients received the same immunotherapy but also received a mixture of cells and BCG given during the first three months. There was no difference in the remission and survival of these two groups. The significance of these results is discussed. 相似文献
20.