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1
Zhuk, Ye A. y V. A. Galenok. "T-lymphocyte precursors in diabetics". Problems of Endocrinology 41, n.º 2 (15 de abril de 1995): 4–6. http://dx.doi.org/10.14341/probl11356.
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Patients with types I, II, and pancreatogenic diabetes mellitus were examined for the counts of T precursor cells using autorosette formation test in the presence of t-activin, an activator of T lymphocyte differentiation. The counts of T lymphocyte precursors in patients with type II and pancreatogenic diabetes were virtually the same as in normal subjects. Disorders of cellular immunity in type I diabetes mellitus were found to be associated with depletion of pre-T-lymphocytes. These changes were the most manifest in the decompensation phase (ketoacidosis state). The results may be useful in development of immunomodulating therapy for type I diabetes and in prediction of the disease development in subjects predisposed to it.
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Thiele, D. L. y P. E. Lipsky. "Leu-Leu-OMe sensitivity of human activated killer cells: delineation of a distinct class of cytotoxic T lymphocytes capable of lysing tumor targets." Journal of Immunology 137, n.º 4 (15 de agosto de 1986): 1399–406. http://dx.doi.org/10.4049/jimmunol.137.4.1399.
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Abstract Sensitivity to L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) was used to characterize the phenotype of human activated killer cells. Natural killer cells (NK) and the precursors of both the alloantigen-specific cytotoxic T lymphocytes (CTL) and the NK-like activated killer cells generated after stimulation with allogeneic cells were deleted from human peripheral blood lymphocytes by preincubation with Leu-Leu-OMe. It was noted, however, that cytotoxic lymphocytes could be generated from Leu-Leu-OMe-treated lymphocyte precursors after 2 to 6 days of culture with the nonspecific mitogen, phytohemagglutinin (PHA). The characteristics of these killer cells indicated that they were a unique population that could be distinguished from other cytotoxic cells. Killing by these cells exhibited slow kinetics in that 18 hr cytotoxicity assays were required to detect full cytotoxic potential. When 18 hr assays were used, PHA-stimulated cytotoxic cells generated from Leu-Leu-OMe-treated lymphocytes were able to kill both NK-sensitive K562 cells and the relatively NK-resistant renal cell carcinoma cell line, Cur. These cytotoxic lymphocytes were HNK-1, Leu-11b (CD16), and OKM1 (CR3)-negative at both the precursor and effector stage of activation. Furthermore, these cells were derived from a CD3-positive precursor. Finally, killing by activated effectors was inhibited by OKT3. Unlike activation of Leu-Leu-OMe-sensitive large granular lymphocytes, generation of these cytotoxic T cells was totally prevented by treatment with mitomycin c before stimulation. Thus, a unique class of tumoricidal T cells can be characterized by resistance of lymphocyte precursors to a concentration of Leu-Leu-OMe, which has been shown to ablate NK, mixed lymphocyte culture-activated NK-like cytotoxic precursors, and the precursors of alloantigen-specific CTL.
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Peddie, Clare M. y Valerie J. Smith. "‘Lymphocyte-like’cells in ascidians: Precursors for vertebrate lymphocytes?" Fish & Shellfish Immunology 5, n.º 8 (noviembre de 1995): 613–29. http://dx.doi.org/10.1016/s1050-4648(95)80045-x.
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Sanders, V. M. y F. E. Powell-Oliver. "Beta 2-adrenoceptor stimulation increases the number of antigen-specific precursor B lymphocytes that differentiate into IgM-secreting cells without affecting burst size." Journal of Immunology 148, n.º 6 (15 de marzo de 1992): 1822–28. http://dx.doi.org/10.4049/jimmunol.148.6.1822.
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Abstract Previous studies have shown that early addition of a beta 2-adrenergic agonist to whole splenocyte cultures immunized with SRBC induced an increase in the number of cells secreting Ag-specific antibody. Because of the low frequency of Ag-specific B lymphocytes in these cultures, it has been difficult to determine the cellular mechanism by which this increase is produced. To gain insight into this cellular mechanism, the present study was designed to evaluate the responsiveness of TNP-specific B lymphocytes cultured at both high density and limiting dilution with keyhole limpet hemocyanin (KLH)-specific, IL-4-producing Th lymphocytes, TNP-KLH, and the beta 2-adrenergic agonist, terbutaline. The results showed that a maximal twofold increase in both the number of anti-TNP IgM-secreting cells and the amount of anti-TNP IgM secretion occurred in terbutaline-exposed lymphocytes after 5 days of bulk culture. This response occurred in a concentration-dependent manner and was inhibited by concomitant culture with beta-adrenoceptor antagonists. No appreciable change was measured in the level of either IgG1 secretion in terbutaline plus Ag-exposed bulk cultures or MHC class II expression on terbutaline plus Ag-exposed TNP-specific B lymphocytes as compared with Ag alone. These data raised the possibility that beta 2-adrenoceptor stimulation induced either the differentiation of a larger proportion of TNP-specific B lymphocyte precursors into anti-TNP IgM-secreting cells, or the extensive proliferation of a constant number of TNP-specific B lymphocyte precursors, or both. Limiting dilution results showed that beta 2-adrenoceptor stimulation induced a twofold increase in the number of TNP-specific B lymphocyte precursors that differentiated into anti-TNP IgM-secreting cells, without affecting the number of anti-TNP IgM-secreting cells produced by each precursor clone.
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Griffiths, S. D., D. T. Goodhead, S. J. Marsden, E. G. Wright, S. Krajewski, J. C. Reed, S. J. Korsmeyer y M. Greaves. "Interleukin 7-dependent B lymphocyte precursor cells are ultrasensitive to apoptosis." Journal of Experimental Medicine 179, n.º 6 (1 de junio de 1994): 1789–97. http://dx.doi.org/10.1084/jem.179.6.1789.
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We have compared the sensitivity of clonogenic interleukin 7 (IL-7)-dependent murine B cell precursors with that of clonogenic mature B cells and myeloid precursors to alpha-particles from plutonium-238 and X radiation. All three populations are relatively sensitive, but B cell precursors are ultrasensitive. This differential sensitivity is also observed with corticosteroid, etoposide, and cisplatin, all apoptosis-inducing drugs used in the treatment of leukemia and other cancers. Further, we show that x-rays and drugs induce the bulk of the B cell precursor population to undergo rapid apoptosis, despite the continued presence of IL-7. B cell precursors were found to express very low levels of BCL-2 protein compared with mature splenic B cells and their resistance to x-rays and corticosteroid could be enhanced by expression of a BCL-2 transgene. These data have important implications for normal lymphopoiesis and for the behavior of leukemic lymphoid precursor cells.
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Skinner, M. A., R. W. Finberg y H. C. J. Ertl. "Regulation of cytotoxic lymphocyte precursors". Cellular Immunology 100, n.º 1 (junio de 1986): 239–46. http://dx.doi.org/10.1016/0008-8749(86)90023-7.
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Arvin, A. M., M. Sharp, S. Smith, C. M. Koropchak, P. S. Diaz, P. Kinchington, W. Ruyechan y J. Hay. "Equivalent recognition of a varicella-zoster virus immediate early protein (IE62) and glycoprotein I by cytotoxic T lymphocytes of either CD4+ or CD8+ phenotype." Journal of Immunology 146, n.º 1 (1 de enero de 1991): 257–64. http://dx.doi.org/10.4049/jimmunol.146.1.257.
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Abstract Immunity to varicella-zoster virus (VZV), a member of the alpha-herpes virus family, exemplifies the host response to an ubiquitous human viral pathogen. In this investigation of the cytotoxic T lymphocyte (CTL) response to VZV, the depletion of CD4+ T lymphocytes made it possible to demonstrate CD8(+)-mediated cytotoxic function against autologous VZV-infected lymphoblastoid cells targets. CTL recognition of two major VZV proteins, the immediate early protein (IE62) and gp I, was demonstrated in limiting dilution cultures of T lymphocytes obtained from immune donors, stimulated with inactivated VZV Ag, and tested against lymphoblastoid cells infected with vaccinia recombinants expressing these VZV proteins. Among 11 VZV donors tested at least 20 y after primary infection, the mean precursor frequency for T lymphocytes that recognized the IE62 protein was 1:105,000 +/- 85,000 SD, with a range of 1:13,000 to 1:231,000. The mean frequency of CTL precursors specific for gp I in 11 subjects was equivalent, with a mean of 1:121,000 +/- 86,000 SD (range 1:15,000 to 1:228,000) (p = 0.68). Limiting dilution cultures were also prepared using purified CD4+ or CD8+ T lymphocyte populations recovered from PBMC by sterile fluorescence-activated cell sorting. CTL precursors that recognized the IE62 protein or gp I were derived from each of the major T lymphocyte populations by stimulation with inactivated VZV Ag; CD4+ and CD8+ CTL precursor frequencies for the IE62 protein and gp I were equivalent (p = 0.2). We conclude that antiviral CTL activity against targets expressing VZV proteins was mediated equally well by T lymphocytes of the CD4+ or CD8+ phenotype and that antiviral CTL function could be elicited in each subpopulation by exposure to non-infectious viral Ag.
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Kiziroglu, F. y R. G. Miller. "In vivo functional clonal deletion of recipient CD4+ T helper precursor cells that can recognize class II MHC on injected donor lymphoid cells." Journal of Immunology 146, n.º 4 (15 de febrero de 1991): 1104–12. http://dx.doi.org/10.4049/jimmunol.146.4.1104.
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Abstract Intravenous injection of semiallogeneic (C57BL/6XDBA/2)F1 lymphocytes into adult C57BL/6 recipient mice not only, as previously reported, reduces the recipients' cytotoxic T lymphocyte response in a subsequent in vitro mixed lymphocyte reaction against the injected cell type, but also reduces Th cell function in the same MLR. Thus lymphoid cells derived from the injected mice were greatly reduced in their ability to proliferate and to produce IL-2 in response to (C57BL/6XDBA/2)F1 stimulator cells in vitro, whereas third party responses were unaffected. This appears to be due to a reduction in the precursor frequency of IL-2-producing T lymphocytes specific for the injected cells as measured by limiting dilution analysis. Similar donor-specific reduction in the frequency of precursors of IL-2-producing cells was seen after i.v. injection of A.TL lymphocytes into A.TH recipients (differing at class II determinants I-A and I-E, but identical at K and D). Here there also appeared to be a functional clonal deletion of precursors of IL-2-producing Th cells, shown directly to be class II MHC reactive and CD4+. There is strong evidence that the reduction of class I-specific cytotoxic responses in the injected mice is a manifestation of donor cells that function as veto cells, i.e., that function as deletional APC that inactivate class I-reactive CTL precursors that recognize them. Our data in this study show that class II-specific Th responses are similarly reduced in the injected mice and suggest that CD4+ class II-reactive precursors of Th cells may be functionally inactivated in vivo by donor cells via a veto-like mechanism.
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Janssen, O., C. Nerl y D. Kabelitz. "T cells in B-cell chronic lymphocytic leukemia: quantitative assessment of cytotoxic and interleukin-2-producing lymphocyte precursors by limiting dilution analysis". Blood 73, n.º 6 (1 de mayo de 1989): 1622–26. http://dx.doi.org/10.1182/blood.v73.6.1622.1622.
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Abstract Controversy exists as to the functional capacity of T lymphocytes in patients with B-cell chronic lymphocytic leukemia (CLL). We have used a limiting dilution (LD) culture approach to quantitatively assess frequencies of proliferating lymphocyte precursors (PLP), cytotoxic lymphocyte precursors (CLP), and interleukin-2 (IL-2)-producing helper lymphocyte precursors (HLP). Unseparated mononuclear cells (MNC) or purified T cells (E+) and leukemic B cells (E-) were cocultured under LD conditions with irradiated OKT3 hybridoma cells in the absence (determination of HLP) or presence of recombinant IL-2 (determination of PLP and CLP). Under these conditions, low frequencies of PLP, HLP, and CLP (f = 1/65 to 1/4600) were measured in unseparated MNC of CLL patients. In contrast, purified T cells (50% to 92% CD3+) contained precursors of proliferating, IL-2-producing and cytotoxic T cells in similar frequency as did T cells from healthy control donors (f = 1/4 to 1/24). Leukemic B cells rigorously depleted of T cells did not give rise to measurable frequencies of PLP, HLP, or CLP (f less than 1/50.000) except in one CLL patient where a significant frequency (f = 1/1700) of HLP was consistently present in E- cells, despite the absence of growth-inducible PLP and CLP. Taken together, these results indicate that comparable numbers of IL-2-producing helper T cells and cytotoxic T cells are present in B-CLL patients and healthy controls, respectively. The data are discussed with respect to reported T cell abnormalities in B-CLL.
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Janssen, O., C. Nerl y D. Kabelitz. "T cells in B-cell chronic lymphocytic leukemia: quantitative assessment of cytotoxic and interleukin-2-producing lymphocyte precursors by limiting dilution analysis". Blood 73, n.º 6 (1 de mayo de 1989): 1622–26. http://dx.doi.org/10.1182/blood.v73.6.1622.bloodjournal7361622.
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Controversy exists as to the functional capacity of T lymphocytes in patients with B-cell chronic lymphocytic leukemia (CLL). We have used a limiting dilution (LD) culture approach to quantitatively assess frequencies of proliferating lymphocyte precursors (PLP), cytotoxic lymphocyte precursors (CLP), and interleukin-2 (IL-2)-producing helper lymphocyte precursors (HLP). Unseparated mononuclear cells (MNC) or purified T cells (E+) and leukemic B cells (E-) were cocultured under LD conditions with irradiated OKT3 hybridoma cells in the absence (determination of HLP) or presence of recombinant IL-2 (determination of PLP and CLP). Under these conditions, low frequencies of PLP, HLP, and CLP (f = 1/65 to 1/4600) were measured in unseparated MNC of CLL patients. In contrast, purified T cells (50% to 92% CD3+) contained precursors of proliferating, IL-2-producing and cytotoxic T cells in similar frequency as did T cells from healthy control donors (f = 1/4 to 1/24). Leukemic B cells rigorously depleted of T cells did not give rise to measurable frequencies of PLP, HLP, or CLP (f less than 1/50.000) except in one CLL patient where a significant frequency (f = 1/1700) of HLP was consistently present in E- cells, despite the absence of growth-inducible PLP and CLP. Taken together, these results indicate that comparable numbers of IL-2-producing helper T cells and cytotoxic T cells are present in B-CLL patients and healthy controls, respectively. The data are discussed with respect to reported T cell abnormalities in B-CLL.
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Oliver, Paula M., Michael Wang, Yanan Zhu, Janice White, John Kappler y Philippa Marrack. "Loss of Bim Allows Precursor B Cell Survival But Not Precursor B Cell Differentiation in the Absence of Interleukin 7". Journal of Experimental Medicine 200, n.º 9 (1 de noviembre de 2004): 1179–87. http://dx.doi.org/10.1084/jem.20041129.
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Interleukin (IL)-7 is a stromal cell–derived cytokine required for the survival, proliferation, and differentiation of B cell precursors. Members of the Bcl-2 family of proteins are known to have profound effects on lymphocyte survival, but not lymphocyte differentiation. To distinguish the relative dependence on IL-7 of B cell precursor survival versus B cell differentiation, the combined effects of lack of IL-7 and lack of the proapoptotic Bcl-2 relative, Bim, were studied. Bim is expressed to varying degrees in all B cell precursors and B cells. Lack of Bim compensated for lack of IL-7 in the survival of pro–, pre–, and immature B cells; however, lack of Bim did not substitute for the requirement for IL-7 in B cell precursor differentiation or B cell precursor proliferation. Precursor B cell survival is more dependent on sufficient levels of IL-7 than precursor B cell differentiation because the number of B cells and their precursors were reduced by half in mice heterozygous for IL-7 expression, but were restored to normal numbers in mice also lacking Bim. Hence, Bim and IL-7 work together to control the survival of B cell precursors and the number of B cells that exist in animals.
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Miescher, S., T. L. Whiteside, L. Moretta y V. von Fliedner. "Clonal and frequency analyses of tumor-infiltrating T lymphocytes from human solid tumors." Journal of Immunology 138, n.º 11 (1 de junio de 1987): 4004–11. http://dx.doi.org/10.4049/jimmunol.138.11.4004.
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Abstract A limiting dilution analysis (LDA) was used to assess the functional profiles of tumor-infiltrating lymphocytes (TIL) recovered from 15 human solid tumors. The microculture system applied in this study has been shown to allow virtually all normal peripheral blood T lymphocytes (PBL-T) to undergo clonal proliferation and was applied to obtain estimates of the frequency of both proliferating and cytolytic cells among the TIL population. A total of 624 microcultures proliferating in the presence of irradiated allogeneic spleen cells and interleukin 2 (IL 2) were expanded for clonal analysis. These TIL microcultures were assessed for surface antigen phenotype, IL 2 production (helper function) and for their cytolytic capabilities against the human erythroleukemic line K562 (natural killer (NK)-like activity) and P815, a mouse mastocytoma line, in the presence of phytohemagglutinin (PHA), i.e., lectin-dependent cell cytotoxicity (LDCC) which allows the detection of cytolytic activity irrespective of the antigenic specificity of the effector cells. Whenever feasible, cytolytic activity against autologous and allogeneic tumor cells was tested. LDA first demonstrated that the proliferative potential was decreased in T lymphocytes infiltrating human solid tumors (approximately 1 in 50 to 1 in 2 proliferating T lymphocyte precursors (PTL-P) in this series) as compared to normal PBL-T (1 in 2 to 1 in 1 PTL-P). The growth pattern in the titration cultures showed a remarkable agreement with the single-hit Poisson model implying that third party cells are unlikely to be involved in the reduced proliferative potential. Quantitative estimates of functional precursors showed that, in spite of reduced proliferative potential, cytolytic T lymphocyte precursors (CTL-P) against unknown antigens (LDCC-reactive) accounted for a considerable part of the microcultures in many cases. The precursor frequency of T lymphocytes with NK-like activity was usually low in situ (with the exception of glioma), whereas it was in the normal range in the patient's autologous PBL-T. In four evaluable cases, quantitative assessment showed that 1 in 200 to 1 in 1000 T lymphocytes from TIL was cytolytic against allogeneic tumor cells, which is in the range of alloreactive cytolytic T lymphocytes (CTL) generated in the mixed lymphocyte culture from normal PBL. Cytolytic activity against autologous target cells could not be quantitatively estimated but out of 88 clones from 4 patients, 3 clones originating from 2 glioma patients showed high lytic values against autologous tumor.(ABSTRACT TRUNCATED AT 400 WORDS)
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Medina, K. L., G. Smithson y P. W. Kincade. "Suppression of B lymphopoiesis during normal pregnancy." Journal of Experimental Medicine 178, n.º 5 (1 de noviembre de 1993): 1507–15. http://dx.doi.org/10.1084/jem.178.5.1507.
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We describe a dramatic reduction in numbers and activity of committed B lymphocyte precursors in the bone marrow of normal pregnant mice. Changes in cells responsive to IL-7 were evident as early as 6.5 d of pregnancy and values were < 10% of normal at parturition. B lineage precursors, identified by display of CD45R and absence of surface IgM, were also substantially depressed, and subpopulations representing different stages in the B lineage were assessed by three-color flow cytometry. Early pro-B cells are medium to large in size and have been previously characterized by low expression of the heat-stable antigen (HSA). This category of cells was not reduced, and in fact may have been slightly elevated, during pregnancy. In contrast, all subsequent populations of B lineage precursors, defined by patterns of expression of heat-stable and CD43 antigens, were substantially depressed. The immediate precursors of B cells (small pre-B cells) were identified by small size, expression of CD45R, absence of CD43, and lack of surface IgM. These were the most reduced of any phenotypically defined population in bone marrow. Numbers of newly formed B cells, characterized by the presence of sIgM, but not sIgD, were also diminished. However, B cells with a mature phenotype (sIgM+, sIgD+) were present in normal to somewhat elevated numbers. Mitogen-responsive B cells clonable in a semisolid agar assay were not significantly affected. A bromodeoxyuridine (BrdU) labeling technique was used to evaluate mitotic activity, which revealed an increased proportion of long-lived lymphocytes in the bone marrow of pregnant mice. These observations indicate that B lymphopoiesis is markedly downregulated during pregnancy and that all precursor populations beyond the early pro-B cell stage are affected. The pregnancy-related changes in bone marrow were selective for B lineage precursors, as cells expressing myeloid and erythroid markers were not reduced. In spleen, evidence was obtained for partial depletion of one subset of B cells. These cells, which have been reported to be recent immigrants from marrow, are characterized as having high levels of sIgM and HSA. Changes in other major B lymphocyte subsets in the spleen were less remarkable. When considered with results from the BrdU labeling procedure, the findings indicate that both production and export of lymphocytes from marrow may be substantially decreased. Numbers of B cell precursors were higher in postpartum animals whose litters were removed at birth, suggesting that lactation may prolong regeneration of lymphocyte production.(ABSTRACT TRUNCATED AT 400 WORDS)
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McKearn, J. P., J. McCubrey y B. Fagg. "Enrichment of hematopoietic precursor cells and cloning of multipotential B-lymphocyte precursors." Proceedings of the National Academy of Sciences 82, n.º 21 (1 de noviembre de 1985): 7414–18. http://dx.doi.org/10.1073/pnas.82.21.7414.
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Carmichael, A., X. Jin, P. Sissons y L. Borysiewicz. "Quantitative analysis of the human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocyte (CTL) response at different stages of HIV-1 infection: differential CTL responses to HIV-1 and Epstein-Barr virus in late disease." Journal of Experimental Medicine 177, n.º 2 (1 de febrero de 1993): 249–56. http://dx.doi.org/10.1084/jem.177.2.249.
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Major histocompatibility complex (MHC)-restricted cytotoxic T lymphocytes (CTL) are part of the cellular immune response to human persistent virus infections. Measurements of the frequency and specificity of human immunodeficiency virus type 1 (HIV-1)-specific CTL and their variation with time may indicate their relative importance in modulating the progression of HIV-1 infection. We have used limiting dilution analysis (LDA) to derive quantitative estimates of the frequency of HIV-1-specific CTL precursors in a cross-sectional study of 23 patients at different clinical stages of HIV-1 infection and to compare these with the frequency of CTL precursors specific for another persistent virus (Epstein-Barr virus [EBV]) in the same patients. Peripheral blood mononuclear cells (PBMC) were stimulated in vitro with autologous HIV-1-infected lymphoblasts and assayed for cytotoxicity in 51Cr release assays against autologous and MHC-mismatched lymphoblastoid B cells infected with recombinant vaccinia viruses expressing the three HIV-1 structural gene products. The frequency of MHC-restricted precursors was high in asymptomatic HIV-1-infected patients (env-specific CTL precursors up to 73/10(6) PBMC; gag-specific CTL precursors up to 488/10(6) PBMC), although the relative frequency against the different structural gene products varied from patient to patient. The HIV-1-specific CTL precursor frequency was reduced in patients who had more severe (< 400/microliters) CD4+ lymphocyte depletion, while in the majority of such patients the frequency of CTL precursors against EBV was maintained at levels observed in healthy controls. Direct CTL activity in unstimulated PBMC was observed in three of nine patients but no correlation was found between the presence of an activated CTL response and the magnitude of the CTL response detected after stimulation in LDA. Thus, CTL precursors were detected against all three HIV-1 structural gene products in patients with CD4+ lymphocyte counts > 400/microliters, at frequencies that are high compared with those reported for other persistent viruses. A CTL response directed against multiple protein antigens of HIV-1 may protect the patient against epitope variation. The fact that the EBV-specific CTL precursor frequencies were maintained in advanced HIV-1 infection suggests that there may be selective impairment of the HIV-1-specific CTL response associated with disease progression.
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Carlyle, James R. y Juan Carlos Zúñiga-Pflücker. "Regulation of NK1.1 Expression During Lineage Commitment of Progenitor Thymocytes". Journal of Immunology 161, n.º 12 (15 de diciembre de 1998): 6544–51. http://dx.doi.org/10.4049/jimmunol.161.12.6544.
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Abstract We recently identified a stage in fetal ontogeny (NK1.1+/CD117+) that defines committed progenitors for T and NK lymphocytes. These cells are found in the fetal thymus as early as day 13 of gestation, but are absent in the fetal liver. Nonetheless, multipotent precursors derived from both the fetal thymus and fetal liver are capable of rapidly differentiating to the NK1.1+ stage upon transfer into fetal thymic organ culture (FTOC). This suggests that expression of NK1.1 marks a thymus-induced lineage commitment event. We now report that a subset of the most immature fetal thymocytes (NK1.1−/CD117+) is capable of up-regulating NK1.1 expression spontaneously upon short-term in vitro culture. Interestingly, fetal liver-derived CD117+ precursors remain NK1.1− upon similar culture. Spontaneous up-regulation of NK1.1 surface expression is minimally affected by transcriptional blockade, mitogen-induced activation, or exposure of these cells to exogenous cytokines or stromal cells. These data suggest that induction of NK1.1 expression on cultured thymocytes may be predetermined by exposure to the thymic microenvironment in vivo. Importantly, multipotent CD117+ thymocytes subdivided on the basis of NK1.1 expression after short-term in vitro culture show distinct precursor potential in lymphocyte lineage reconstitution assays. This demonstrates that even the earliest precursor thymocyte population, although phenotypically homogeneous, contains a functionally heterogeneous subset of lineage-committed progenitors. These findings characterize a thymus-induced pathway in the control of lymphocyte lineage commitment to the T and NK cell fates.
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Wu, L., C. L. Li y K. Shortman. "Thymic dendritic cell precursors: relationship to the T lymphocyte lineage and phenotype of the dendritic cell progeny." Journal of Experimental Medicine 184, n.º 3 (1 de septiembre de 1996): 903–11. http://dx.doi.org/10.1084/jem.184.3.903.
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Successive T-precursors isolated from adult mouse thymus were examined for their developmental potential, by transfer to irradiated Ly 5-disparate recipients. The earliest, "low CD4" precursors formed T, B, and dendritic cells (DC), but not myeloid cells, in accordance with earlier studies. Surprisingly, the next downstream CD4-8-3 44+25+ precursor population still formed DC as well as T cells although it no longer formed B or myeloid cells. Further down-stream, the CD4-8 3-44-25+ population formed only T cells. The thymic and splenic DC progeny of the early thymic precursors all expressed high levels of CD8 alpha, in contrast with normal splenic DC and the splenic DC progeny of bone marrow stem cells, which consisted of both CD8 and CD8+ DC. A common precursor of T cells and of a subclass of DC is proposed, with CD8 alpha as a marker of the lymphoid-related DC lineage.
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Park, JR, ID Bernstein y DM Hockenbery. "Primitive human hematopoietic precursors express Bcl-x but not Bcl-2". Blood 86, n.º 3 (1 de agosto de 1995): 868–76. http://dx.doi.org/10.1182/blood.v86.3.868.868.
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Abstract Bcl-2 and its homologue, bcl-xL, encode membrane-associated proteins that suppress programmed cell death of hematopoietic cell lines after growth factor withdrawal, and are expressed in hematopoietic precursor cells. To better understand the maintenance of long-term survival in the hematopoietic stem cell population, we evaluated the expression patterns of Bcl-2 and Bcl-x in primitive hematopoietic precursor populations. Hematopoietic precursor cells expressing CD34 (CD34+) and lacking maturation-linked surface antigens (lin-) were isolated from adult human bone marrow using two-color immunofluorescence cell sorting and fractionated on the basis of forward light scatter characteristics into blast-sized and small to medium lymphocyte-sized cell populations. Bcl-2 expression was shown in 78% to 90% of CD34+ lin- blast-sized cells versus less than 10% of small to medium lymphocyte-sized CD34+ lin- cells by immunohistochemical analysis. Small to medium lymphocyte- sized CD34+ lin- cells were further enriched for primitive precursors by selecting cells that lacked expression of CD38 (CD34+ lin- CD38-). In parallel experiments, only 1% to 4% of CD34+ lin- CD38- cells expressed Bcl-2, whereas 45% to 56% of these cells generated colony- forming cells. In contrast, > or = 94% of cells in all bone marrow subpopulations studied expressed Bcl-x protein. Both alternatively spliced bcl-x transcripts, bcl-xL and bcl-xs, were present. Our data show that the most primitive hematopoietic precursors express Bcl-x but not Bcl-2. Thus, the functional bcl-2 homologue, bcl-xL, may be essential for the long-term survival of the hematopoietic stem cell population.
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Park, JR, ID Bernstein y DM Hockenbery. "Primitive human hematopoietic precursors express Bcl-x but not Bcl-2". Blood 86, n.º 3 (1 de agosto de 1995): 868–76. http://dx.doi.org/10.1182/blood.v86.3.868.bloodjournal863868.
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Bcl-2 and its homologue, bcl-xL, encode membrane-associated proteins that suppress programmed cell death of hematopoietic cell lines after growth factor withdrawal, and are expressed in hematopoietic precursor cells. To better understand the maintenance of long-term survival in the hematopoietic stem cell population, we evaluated the expression patterns of Bcl-2 and Bcl-x in primitive hematopoietic precursor populations. Hematopoietic precursor cells expressing CD34 (CD34+) and lacking maturation-linked surface antigens (lin-) were isolated from adult human bone marrow using two-color immunofluorescence cell sorting and fractionated on the basis of forward light scatter characteristics into blast-sized and small to medium lymphocyte-sized cell populations. Bcl-2 expression was shown in 78% to 90% of CD34+ lin- blast-sized cells versus less than 10% of small to medium lymphocyte-sized CD34+ lin- cells by immunohistochemical analysis. Small to medium lymphocyte- sized CD34+ lin- cells were further enriched for primitive precursors by selecting cells that lacked expression of CD38 (CD34+ lin- CD38-). In parallel experiments, only 1% to 4% of CD34+ lin- CD38- cells expressed Bcl-2, whereas 45% to 56% of these cells generated colony- forming cells. In contrast, > or = 94% of cells in all bone marrow subpopulations studied expressed Bcl-x protein. Both alternatively spliced bcl-x transcripts, bcl-xL and bcl-xs, were present. Our data show that the most primitive hematopoietic precursors express Bcl-x but not Bcl-2. Thus, the functional bcl-2 homologue, bcl-xL, may be essential for the long-term survival of the hematopoietic stem cell population.
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Bonetti, Maria Ida, Laura Pieri, Lola Domenici, Serena Urbani, Giovanni Romano, Alessandra Aldinucci, Clara Ballerini et al. "Dendritic cells with lymphocyte-stimulating activity differentiate from human CD133 positive precursors". Blood 117, n.º 15 (14 de abril de 2011): 3983–95. http://dx.doi.org/10.1182/blood-2010-08-299735.
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Abstract CD133 is a hallmark of primitive myeloid progenitors. We have addressed whether human cord blood cells selected for CD133 can generate dendritic cells, and Langerhans cells in particular, in conditions that promote that generation from CD34+ progenitors. Transforming growth factor-β1 (TGF-β1) and anti–TGF-β1 antibody, respectively, were added in some experiments. With TGF-β, monocytoid cells were recognized after 7 days. Immunophenotypically immature dendritic cells were present at day 14. After 4 more days, the cells expressed CD54, CD80, CD83, and CD86 and were potent stimulators in mixed lymphocyte reaction; part of the cells expressed CD1a and langerin, but not Birbeck granules. Without TGF-β, only a small fraction of cells acquired a dendritic shape and expressed the maturation-related antigens, and lymphocytes were poorly stimulated. With anti–TGF-β, the cell growth was greatly hampered, CD54 and langerin were never expressed, and lymphocytes were stimulated weakly. In conclusion, CD133+ progenitors can give rise in vitro, through definite steps, to mature, immunostimulatory dendritic cells with molecular features of Langerhans cells, although without Birbeck granules. Addition of TGF-β1 helps to stimulate cell growth and promotes the acquisition of mature immunophenotypical and functional features. Neither langerin nor Birbeck granules proved indispensable for lymphocyte stimulation.
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Kouro, Taku, Kay L. Medina, Kenji Oritani y Paul W. Kincade. "Characteristics of early murine B-lymphocyte precursors and their direct sensitivity to negative regulators". Blood 97, n.º 9 (1 de mayo de 2001): 2708–15. http://dx.doi.org/10.1182/blood.v97.9.2708.
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Abstract Recently, a collection of surface markers was exploited to isolate viable Lin− TdT+ cells from murine bone marrow. These early pro-B cells were enriched for B-lineage lymphocyte precursor activity measured by short-term culture and had little responsiveness to myeloid growth factors. Early precursors can be propagated with remarkably high cloning frequencies in stromal cell–free, serum-free cultures, permitting this analysis of direct regulatory factors. Expression of the interleukin-7 receptor (IL-7Rα) chain marks functional precursors and IL-7 is necessary for progression beyond the CD45RA+ CD19− stage. Efficient survival and differentiation were only observed when stem cell factor and Flt-3 ligand were also present. IL-7–responsive CD19+precursors are estrogen resistant. However, B-lineage differentiation was selectively abrogated when highly purified Lin− precursors were treated with hormone in the absence of stromal cells. In addition, early stages of B lymphopoiesis were arrested by limitin, a new interferon (IFN)–like cytokine as well as IFN-α, IFN-γ, or transforming growth factor β (TGF-β), but not by epidermal growth factor (EGF). Lin− TdT+early pro-B cells are shown here to be CD27+AA4.1+/−Ki-67+ Ly-6C−Ly-6A/Sca-1Lo/−Thy-1−CD43+CD4+/−CD16/32Lo/−CD44Hi and similar in some respects to the “common lymphoid progenitors” (CLP) identified by others. Although early pro-B cells have lost myeloid differentiation potential, transplantation experiments described here reveal that at least some can generate T lymphocytes. Of particular importance is the demonstration that a pivotal early stage of lymphopoiesis is directly sensitive to negative regulation by hormones and cytokines.
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Tripp, R. A., D. J. Topham, S. R. Watson y P. C. Doherty. "Bone marrow can function as a lymphoid organ during a primary immune response under conditions of disrupted lymphocyte trafficking." Journal of Immunology 158, n.º 8 (15 de abril de 1997): 3716–20. http://dx.doi.org/10.4049/jimmunol.158.8.3716.
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Abstract In this study we sought to better understand lymphocyte trafficking patterns and the function of secondary lymphoid organs, such as the spleen, during the generation of virus-specific T cell precursors. Treatment of mice with the Mel-14 mAb to CD62L, the lymph node homing receptor, limits trafficking of naive T cells into lymph nodes through high endothelial venules. Administering Mel-14 following respiratory infection with influenza virus forced the generation of primary virus-specific CD4+ and CD8+ T cell precursors from the mediastinal lymph nodes to the spleen. However, splenectomy did not seriously impede virus clearance from the lung and, despite a substantial reduction of the total lymphocyte pool, the acute T cell responses in the regional lymph nodes were largely normal. Mel-14 treatment of splenectomized mice did not affect clonal expansion of the virus-specific T cells in the MLN, while the response in the cervical lymph nodes was still greatly inhibited. More surprisingly, virus-specific T cell precursors were now detected from days 5 to 6 after infection in the bone marrow (BM) of the splenectomized, Mel-14-treated mice. This was not due to contamination with circulating T cells or infection of BM cells because the distribution profiles of precursor T cells for PBL and BM diverged and PCR analysis showed no evidence of virus replication in the BM. It appears that, under these conditions of disrupted lymphocyte trafficking, the BM can supplant the secondary lymphoid tissue either as a site of primary immune response or as a cache for excess T cell precursors.
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Lee, Barclay J. y Emily M. Mace. "From stem cell to immune effector: how adhesion, migration, and polarity shape T-cell and natural killer cell lymphocyte development in vitro and in vivo". Molecular Biology of the Cell 31, n.º 10 (1 de mayo de 2020): 981–91. http://dx.doi.org/10.1091/mbc.e19-08-0424.
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Lymphocyte development is a complex and coordinated pathway originating from pluripotent stem cells during embryogenesis and continuing even as matured lymphocytes are primed and educated in adult tissue. Hematopoietic stem cells develop in a specialized niche that includes extracellular matrix and supporting stromal and endothelial cells that both maintain stem cell pluripotency and enable the generation of differentiated cells. Cues for lymphocyte development include changes in integrin-dependent cell motility and adhesion which ultimately help to determine cell fate. The capacity of lymphocytes to adhere and migrate is important for modulating these developmental signals both by regulating the cues that the cell receives from the local microenvironment as well as facilitating the localization of precursors to tissue niches throughout the body. Here we consider how changing migratory and adhesive phenotypes contribute to human natural killer (NK)- and T-cell development as they undergo development from precursors to mature, circulating cells and how our understanding of this process is informed by in vitro models of T- and NK cell generation.
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Tilden, A. B., K. Itoh y C. M. Balch. "Human lymphokine-activated killer (LAK) cells: identification of two types of effector cells." Journal of Immunology 138, n.º 4 (15 de febrero de 1987): 1068–73. http://dx.doi.org/10.4049/jimmunol.138.4.1068.
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Abstract We analyzed the antigenic phenotype of lymphokine-activated killer (LAK) effector cells. Human blood lymphocytes were cultured for 3 days with 100 U/ml recombinant interleukin 2 (rIL 2), subpopulations isolated with monoclonal antibodies and a fluorescence-activated cell sorter (FACS) and assayed for cytotoxic activity against 51chromium labeled noncultured melanoma tumor cells. Initial experiments compared the LAK effector function of CD5+ T lymphocytes vs CD5- cells (predominantly CD16+ NK cells). The mean percent specific release at a 10:1 effector:target (E:T) ratio was 25% +/- 16 for CD5- cells, 10% +/- 6 for CD5+ cells, and 22% +/- 9 for unsorted cells. In contrast, when lymphocyte subpopulations were isolated before rIL 2 culture (LAK precursors), CD5- cells but not CD5+ cells developed LAK activity (28% +/- 12 vs 1% +/- 1, mean percent specific release, 10:1 E:T ratio), confirming our previous results showing that only CD16+ cells were LAK precursors. The discrepancy between LAK effector and precursor phenotypes suggested that LAK precursors acquired CD5 determinants during rIL 2 culture; however, double label immunofluorescence of rIL 2 cultured CD16+ cells showed that this was not the case. The data suggested that in the presence of other cell types, some T lymphocytes may develop LAK activity, but purified blood T lymphocytes do not develop LAK function when cultured with rIL 2 alone. We also analyzed LAK effector function in lymphocyte subpopulations defined by CD4 and CD8 antigens. The data showed that lymphocytes with a low density expression of CD8 and no expression of CD4 were enriched for LAK effector cells, whereas CD4+ and CD8- had less activity than unsorted cells. Lymphocytes with a high density expression of CD8 had activity similar to unsorted cells. We also assessed the contribution of Leu-7 (HNK-1) granular lymphocytes to LAK effector function. After culture with IL 2, lymphocytes were depleted of Leu-7+ cells by antibody and complement treatment and then were sorted into CD5+ and CD5- fractions. The cytotoxic activity of Leu-7-CD5+ cells was a mean 5% +/- 5 vs a mean 14% +/- 8 for the total CD5+ population (20:1 E:T ratio). The activity of Leu-7- CD5- was slightly less than the total CD5- fraction (21% +/- 9 vs 28% +/- 14, 10:1 E:T ratio). In conclusion, LAK effector function was highest in non-T cell (CD5- CD16+) populations and some activity was also present in T cell populations (CD5+ and predominantly Leu-7+).
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Smithson, G., K. Medina, I. Ponting y P. W. Kincade. "Estrogen suppresses stromal cell-dependent lymphopoiesis in culture." Journal of Immunology 155, n.º 7 (1 de octubre de 1995): 3409–17. http://dx.doi.org/10.4049/jimmunol.155.7.3409.
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Abstract Numbers of pre-B cells change dramatically and reciprocally in response to estrogen levels in mice, suggesting that normal lymphopoiesis may be under hormonal control. However, little is known of the mechanisms involved in this process. We found that estrogen receptor mRNA was detectable by RT-PCR in lymphocyte supporting stromal cells as well as B lymphocyte precursors. Unlike glucocorticoids, estrogen did not induce apoptosis in isolated B lineage lymphocytes or interfere with their responsiveness to IL-7 in semisolid agar. Estrogen did inhibit clonal expansion of B cell precursors in a limiting dilution-type assay when the lymphocytes were cultured on a stromal cell clone. In other experiments, B cell precursors at particular stages of differentiation were isolated by cell sorting and cocultured with stromal cells for 4 days. This revealed that some subsets were more sensitive to an estrogen-containing environment than others. Although numbers of recovered cells were greatly reduced, the remaining lymphocytes had undergone relatively normal differentiation. The surviving population was enriched in cells that had acquired cytoplasmic mu chains, BP-1 Ag, and clonability with IL-7. Hormone-mediated inhibition occurred in serum and phenol-red free medium, and in cultures replete with IL-7. Direct contact between stromal cells and lymphocytes was not required. Furthermore, suppression resulted when stromal cells alone were treated with the hormone. These findings indicate that estrogen may regulate B lymphopoiesis via its influence on the microenvironment and that estrogen-induced stromal cell genes merit further study.
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Kouro, Taku, Vinay Kumar y Paul W. Kincade. "Relationships between early B- and NK-lineage lymphocyte precursors in bone marrow". Blood 100, n.º 10 (15 de noviembre de 2002): 3672–80. http://dx.doi.org/10.1182/blood-2002-02-0653.
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Recent studies have demonstrated that lineage marker–negative (Lin−) c-kitLo Flk-2/Flt3+IL-7R+ Sca-1Lo CD27+Ly-6C− Thy-1−CD43+CD16/32Lo/− terminal deoxynucleotidyl transferase (TdT)+ cells in murine bone marrow are functional lymphocyte precursors. However, it has not been clear if this is an obligate intermediate step for transit of multipotential hematopoietic stem cells to natural killer (NK) cells. We have now used serum-free, stromal cell–free cultures to determine that NK progenitors are enriched among an estrogen-regulated, c-kitLo subset of the Lin− fraction. However, several experimental approaches suggested that this population is heterogeneous and likely represents a stage where B and NK lineages diverge. Although most B-cell precursors were directly sensitive to estrogen in culture, much of the NK-cell precursor activity in that fraction was hormone resistant. B-lineage potential was largely associated with interleukin 7 receptor α (IL-7Rα) expression and was selectively driven in culture by IL-7. In contrast, many NK precursors did not display detectable amounts of this receptor and their maturation was selectively supported by IL-15. Finally, single-cell experiments showed that the Lin−c-kitLo fraction contains a mixture of B/NK, B-restricted, and NK-restricted progenitors. Two-step culture experiments revealed that NK precursors become hormone resistant on or before acquisition of CD122, signaling commitment to the NK lineage. CD45R is preferentially, but not exclusively, expressed on maturing B-lineage cells. Production of these 2 blood cell types is regulated in bone marrow by common and then independent mechanisms that can now be studied with greater precision.
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Thurlow, P. J., L. Kerrigan, R. A. Harris y I. F. McKenzie. "Analysis of human bone marrow with monoclonal antibodies." Journal of Histochemistry & Cytochemistry 33, n.º 12 (diciembre de 1985): 1183–89. http://dx.doi.org/10.1177/33.12.2415573.
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In order to study the antigenic phenotype of different hemopoietic cells, we used a series of monoclonal antibodies to investigate normal bone marrow in a standard immunofluorescence assay. The antibodies detected the following antigens: HLA-ABC, beta 2-microglobulin (beta 2m), HLA-DR (Ia), a lymphocyte subset and specific antigen (T and B) HuLy-m2, m3, T lymphocyte antigen (HuLy-m1), lymphocyte T200 antigen (HuLy-m4), a viral-associated antigen (HuLy-m5), and platelet-specific glycoproteins IIb-IIIa (HuPl-m1). The following results were obtained: (a) normoblasts were weakly HLA-ABC+, beta 2m+ and Ia-; all other lymphocyte and platelet antigens were not detected. (b) Myeloid cells at all stages of differentiation (promyelocytes, myelocytes, metamyelocytes, and neutrophils) were HLA-ABC+; beta 2m+; HuLy-m1-, m2-, m3+/- (20%), m4+, m5+/- (20%); HuPl-m1-; in addition, promyelocytes and myelocytes were Ia+ but neutrophils and metamyelocytes were Ia-. (c) Lymphocytes were HLA-ABC+, beta 2m+, Ia+/- (20-30%), HuLy-m1+/- (40-50%), m2+/- (60-70%), m3+, m4+, m5+; Pl-m1-. (d) Platelets and megakaryocytes were HLA-ABC+; beta 2m+; Ia-; HuLy-m1+-, m2-, m3-, m4-, m5-, HuPl-m1+, and the putative "megakaryocyte precursors" were HuPl-m1+, Ia-, HuLy-m1-. The different cell types in bone marrow could readily be distinguished, particularly cells of the myeloid series (Ia and HuLy-m4, m5), lymphocytes (Ia and HuLy-m1, m2, m3), and platelets and their precursor cells (HuPl-m1). This simple method of defining cellular phenotypes in bone marrow has demonstrated the practicality of using monoclonal antibodies to identify marrow cells and should be of diagnostic value.
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Cochrane, Alexandra, Stuart Imlach, Clifford Leen, Gordon Scott, Dermot Kennedy y Peter Simmonds. "High Levels of Human Immunodeficiency Virus Infection of CD8 Lymphocytes Expressing CD4 In Vivo". Journal of Virology 78, n.º 18 (15 de septiembre de 2004): 9862–71. http://dx.doi.org/10.1128/jvi.78.18.9862-9871.2004.
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ABSTRACT Human immunodeficiency virus (HIV)-infected CD8 lymphocytes have been reported in vivo, but the mechanism of infection remains unclear. Experiments using the thy/hu mouse model support export of intrathymically infected CD8 precursors, while recent in vitro data suggest that mature CD8 lymphocytes upregulate CD4 upon activation (generating a CD8bright CD4dim phenotype) and are susceptible to HIV infection. To determine whether these mechanisms operate in vivo and to assess their relative importance in the generation of circulating HIV-infected CD8 lymphocytes, we quantified HIV long terminal repeat (LTR) DNA in CD8+ CD4− and CD8bright CD4dim lymphocytes isolated from HIV-infected individuals by fluorescence-activated cell sorting. HIV infection of CD8 lymphocytes was demonstrated in 17 of 19 subjects, with a significant inverse relationship between level of infection and CD4 lymphocyte count (R = −0.73; P < 0.001). The level of HIV infection of CD8bright CD4dim lymphocytes was significantly higher (median, 1,730 HIV LTR copies/106 cells; n = 9) than that of CD8+ CD4− lymphocytes (undetectable in seven of nine individuals; P < 0.01) and approached that of CD4 lymphocytes from the same individuals (median, 3,660 HIV LTR copies/106 cells). CD8bright CD4dim lymphocytes represented 0.8 to 3.3% of total CD8 lymphocytes and were most prevalent in the memory subset. Thus, HIV-infected CD8 lymphocytes commonly circulate in HIV-infected individuals and are generated through infection of activated CD8 lymphocytes rather than through export of intrathymically infected precursors. The high level of infection of CD8bright CD4dim lymphocytes could have a direct role in the decline in CD8 lymphocyte function that accompanies HIV disease progression.
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Kimoto, M., V. Kindler, M. Higaki, C. Ody, S. Izui y P. Vassalli. "Recombinant murine IL-3 fails to stimulate T or B lymphopoiesis in vivo, but enhances immune responses to T cell-dependent antigens." Journal of Immunology 140, n.º 6 (15 de marzo de 1988): 1889–94. http://dx.doi.org/10.4049/jimmunol.140.6.1889.
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Abstract We have explored the in vivo effect of IL-3 on the lymphopoiesis and humoral responses of mice bearing osmotic minipumps loaded with murine rIL-3 for 1 to 4 wk. A marked splenomegaly due to the accumulation of hemopoietic precursors was seen, but no increase was found in the lymphoid organs in the total number of cells belonging to the T or B lymphocyte lineage, i.e., of L3T4+ or Lyt-2+, or of allospecific cytotoxic T lymphocyte precursor for the T lineage, or of sIg+ or B220+ cells, or of B colony-forming cells for the B lineage; total activity of natural killer and lymphokine-activated killer cells was decreased. In contrast to the splenomegaly, a marked diminution in the number of thymocytes was observed, suggesting that rIL-3 in large amounts does suppress the T lymphopoiesis, perhaps as the result of the selective stimulation of early progenitor cells toward the hemopoietic pathway. rIL-3 perfusion during immunization increased the IgM and IgG responses to a T cell-dependent antigen, human IgG, and prevented tolerance induction by the deaggregated human IgG, although in the same conditions it did not modify the response to a T cell-independent antigen. Our results suggest that in vivo IL-3 does not act directly on lymphocytes or their precursors, but may potentiate the humoral immune response to T cell-dependent antigens, presumably by acting on accessory cells.
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Borghesi, L. A., G. Smithson y P. W. Kincade. "Stromal cell modulation of negative regulatory signals that influence apoptosis and proliferation of B lineage lymphocytes." Journal of Immunology 159, n.º 9 (1 de noviembre de 1997): 4171–79. http://dx.doi.org/10.4049/jimmunol.159.9.4171.
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Abstract The bone marrow microenvironment influences whether a given B cell proliferates, differentiates, or undergoes apoptosis. In this report, we demonstrate that apoptosis of primary murine B lymphocyte precursors can be regulated either positively or negatively by stroma. Several stromal lines that support lymphocyte outgrowth suppressed the spontaneous apoptosis of pre-B cells by as much as 90%. Direct contact with stromal cells more effectively protected lymphocytes than did stromal cell-CM or a collection of recombinant cytokines. In contrast, one unique stromal cell clone actually induced lymphocyte apoptosis, and a second line appeared inert. A survey of adherent cell lines suggested that expression of life-sparing molecules is widespread but not ubiquitous. Experiments with neutralizing Abs to CD44, vascular cell adhesion molecule-1 (VCAM-1), CD9, intercellular adhesion molecule-1 (ICAM-1), or ICAM-2 suggested that these interaction molecules do not deliver short-term survival signals to B cell precursors. Of particular interest, direct interaction with lymphocyte-supportive stromal cells minimized the negative regulatory effects of IL-1alpha, and a glucocorticoid, but not IFN-beta or PGE2. These results demonstrate that the effect of negative regulators depends upon the context in which these signals are presented. As molecules that influence B lymphopoiesis are better defined, it will be important to consider the role of each in combination with other stimuli.
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Werfel, T., M. Oppermann, M. Schulze, G. Krieger, M. Weber y O. Gotze. "Binding of fluorescein-labeled anaphylatoxin C5a to human peripheral blood, spleen, and bone marrow leukocytes". Blood 79, n.º 1 (1 de enero de 1992): 152–60. http://dx.doi.org/10.1182/blood.v79.1.152.152.
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Abstract The expression of C5a receptors (C5aR) on human leukocytes was evaluated by flow cytometry using fluorescein-labeled human C5a (C5a- F). Granulocytes and CD14+ mononuclear cells (MNL) but not CD3+, CD20+, CD16+, CD56+, or CD11b+ lymphocytes in peripheral blood and spleen bound C5a-F. C5a-F binding was saturable and inhibitable by anti-C5a monoclonal antibody (MoAb) C17/5 or unlabeled C5a. During hemodialysis, which led to the generation of C5a, only granulocytes and monocytes increased their expression of the adhesion molecule CD11b (CR3). In vitro, C5a induced an increase of CR3 and p 150/95 (CD11c/CR4) only on myeloid cells. However, treatment of leukocytes with phorbol 12- myristate 13 acetate increased CR3 and CR4 expression on both myeloid cells and a lymphocyte subpopulation. Stimulation of MNL in mixed lymphocyte cultures or by treatment with conditioned medium or with IFN- gamma did not induce binding sites for C5aR on lymphocytes and reduced the binding of C5a-F to monocytes. The expression of C5aR on low- density bone marrow cells was analyzed by setting appropriate gates during flow cytometry. Cells that bound C5a-F were found in all populations that contained granulocyte and monocyte precursors, but not in lymphocyte precursor populations. All C5aR+ bone marrow cells were CD34 and expressed high levels of CR3, which suggests a late appearance of C5aR during myeloid cell maturation. Our results indicate that C5aR is exclusively expressed on myeloid cells within the hematopoetic cell population.
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Werfel, T., M. Oppermann, M. Schulze, G. Krieger, M. Weber y O. Gotze. "Binding of fluorescein-labeled anaphylatoxin C5a to human peripheral blood, spleen, and bone marrow leukocytes". Blood 79, n.º 1 (1 de enero de 1992): 152–60. http://dx.doi.org/10.1182/blood.v79.1.152.bloodjournal791152.
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The expression of C5a receptors (C5aR) on human leukocytes was evaluated by flow cytometry using fluorescein-labeled human C5a (C5a- F). Granulocytes and CD14+ mononuclear cells (MNL) but not CD3+, CD20+, CD16+, CD56+, or CD11b+ lymphocytes in peripheral blood and spleen bound C5a-F. C5a-F binding was saturable and inhibitable by anti-C5a monoclonal antibody (MoAb) C17/5 or unlabeled C5a. During hemodialysis, which led to the generation of C5a, only granulocytes and monocytes increased their expression of the adhesion molecule CD11b (CR3). In vitro, C5a induced an increase of CR3 and p 150/95 (CD11c/CR4) only on myeloid cells. However, treatment of leukocytes with phorbol 12- myristate 13 acetate increased CR3 and CR4 expression on both myeloid cells and a lymphocyte subpopulation. Stimulation of MNL in mixed lymphocyte cultures or by treatment with conditioned medium or with IFN- gamma did not induce binding sites for C5aR on lymphocytes and reduced the binding of C5a-F to monocytes. The expression of C5aR on low- density bone marrow cells was analyzed by setting appropriate gates during flow cytometry. Cells that bound C5a-F were found in all populations that contained granulocyte and monocyte precursors, but not in lymphocyte precursor populations. All C5aR+ bone marrow cells were CD34 and expressed high levels of CR3, which suggests a late appearance of C5aR during myeloid cell maturation. Our results indicate that C5aR is exclusively expressed on myeloid cells within the hematopoetic cell population.
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Miyake, K., K. Medina, K. Ishihara, M. Kimoto, R. Auerbach y P. W. Kincade. "A VCAM-like adhesion molecule on murine bone marrow stromal cells mediates binding of lymphocyte precursors in culture." Journal of Cell Biology 114, n.º 3 (1 de agosto de 1991): 557–65. http://dx.doi.org/10.1083/jcb.114.3.557.
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Two new mAbs (M/K-1 and M/K-2) define an adhesion molecule expressed on stromal cell clones derived from murine bone marrow. The protein is similar in size to a human endothelial cell adhesion molecule known as VCAM-1 or INCAM110. VCAM-1 is expressed on endothelial cells in inflammatory sites and recognized by the integrin VLA-4 expressed on lymphocytes and monocytes. The new stromal cell molecule is a candidate ligand for the VLA-4 expressed on immature B lineage lymphocytes and a possible homologue of human VCAM-1. We now report additional similarities in the distribution, structure, and function of these proteins. The M/K antibodies detected large cells in normal bone marrow, as well as rare cells in other tissues. The antigen was constitutively expressed and functioned as a cell adhesion molecule on cultured murine endothelial cells. It correlated with the presence of mRNA which hybridized to a human VCAM-1 cDNA probe. Partial NH2 terminal amino acid sequencing of the murine protein revealed similarities to VCAM-1 and attachment of human lymphoma cells to murine endothelial cell lines was inhibited by the M/K antibodies. All of these observations suggest that the murine and human cell adhesion proteins may be related. The antibodies selectively interfered with B lymphocyte formation when included in long term bone marrow cultures. Moreover, they caused rapid detachment of lymphocytes from the adherent layer when added to preestablished cultures. The VCAM-like cell adhesion molecule on stromal cells and VLA-4 on lymphocyte precursors may both be important for B lymphocyte formation.
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Tosato, G., R. M. Blaese y R. Yarchoan. "Relationship between immunoglobulin production and immortalization by Epstein Barr virus." Journal of Immunology 135, n.º 2 (1 de agosto de 1985): 959–64. http://dx.doi.org/10.4049/jimmunol.135.2.959.
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Abstract After infection with Epstein Barr virus (EBV), human B lymphocytes actively secrete immunoglobulin (Ig) and are immortalized to become long-term cell lines. In these studies, we investigated the relationship between these virally induced processes utilizing limiting dilution culture techniques, and asked whether all B cells stimulated by EBV to secrete Ig are also immortalized. The activation of B cells by EBV resulting in Ig production and immortalization involved a single precursor cell, required live viral particles, and was independent of immunity to EBV by the lymphocyte donor. However, the precursor frequency of B cells activated to secrete Ig (mean 4.7%) was higher than the precursor frequency of B cells activated to long-term in vitro growth (mean 2.1%). When examined at a single cell level, it appeared that although the vast majority of the immortalized B cells also secrete Ig, only approximately 50% of the B cell precursors induced by EBV to secrete Ig go on to form long-term cell lines. In addition, although immortalized B cell clones producing all major classes of Ig were detected, IgM-committed precursors were more likely to become immortal than were precursors committed to IgG or IgA production. In contrast to these findings in B cells freshly infected with EBV, Ig production was almost always associated with evidence of long-term growth when B cells from previously established EBV-induced B cell lines were tested in identical limiting dilution cultures. Thus, after infection with EBV, human B cells can either become transiently activated to proliferate and to secrete Ig, or become transformed into long-term cell lines most of which produce Ig.
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Kasid, A., G. I. Bell y E. P. Director. "Effects of transforming growth factor-beta on human lymphokine-activated killer cell precursors. Autocrine inhibition of cellular proliferation and differentiation to immune killer cells." Journal of Immunology 141, n.º 2 (15 de julio de 1988): 690–98. http://dx.doi.org/10.4049/jimmunol.141.2.690.
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Abstract With subpopulations of human lymphoid cells that were enriched for lymphokine-activated killer (LAK) cell precursors, studies were performed to examine the effects of transforming growth factor-beta (TGF-beta) on their IL-2-dependent growth and differentiation to killer cells. The majority of the LAK precursor cells appeared to reside in nonadherent, non-T, and non-B lymphocyte populations that expressed CD11 and CD16 Ag. These cells were induced to proliferate and become LAK cells by high concentrations of rIL-2 alone in the apparent absence of any prior activation with mitogen or Ag. The partially purified lymphocyte subpopulations generated varying but several-fold greater levels of LAK killing on a per cell basis than did unfractionated lymphocytes. The exogenous addition of TGF-beta to the LAK precursor cultures, markedly inhibited IL-2-stimulated growth as well as the development of LAK activity in a dose-dependent manner. The antimitotic effect of TGF-beta was reversible; inhibition of proliferation could be largely restored by increasing the concentration of IL-2 in culture. In contrast, TGF-beta inhibition of cytotoxicity was relatively independent of the concentration of IL-2. Further, LAK precursors constitutively expressed TGF-beta mRNA and high affinity receptor for TGF-beta. Activation of LAK precursors with IL-2 alone, resulted in a three- to fivefold up-regulation of intracellular TGF-beta mRNA and TGF-beta biologic activity secreted in the culture media. Furthermore, Northern blotting revealed that the resting LAK precursors did not express the Tac-mRNA. Receptor binding studies with 125I-IL-2 suggested the presence of a single class of IL-2R with an apparent Kd of intermediate range (beta-chain of IL-2R) on the unstimulated cells. Stimulation with high concentrations of Il-2 induced Tac-mRNA (both the 3.5- and 1.5-kb transcripts) and resulted in the expression of high affinity IL-2R (Kd approximately 10(-11) M) on these cells. Suppression of IL-2-dependent responses by TGF-beta was accompanied by a selective down-regulation of the 1.5-kb Tac-mRNA as well as by reduction in high affinity IL-2R. The results suggest a negative autocrine control of TGF-beta on IL-2-dependent growth and differentiation of human LAK cells, possibly related to regulate the killer activation function.
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Gisler, R. H., A. Söderberg y M. Kamber. "Functional maturation of murine B lymphocyte precursors. II. Analysis of cells required from the bone marrow microenvironment." Journal of Immunology 138, n.º 8 (15 de abril de 1987): 2433–38. http://dx.doi.org/10.4049/jimmunol.138.8.2433.
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Abstract The development of mature B cells in cultures of early B cell precursors depends on the presence of a confluent adherent bone marrow (aBM) cell layer. Adherent and sIgM+ cell-depleted bone marrow (BM) from untreated or 5-fluorouracil-pretreated donors or day 12 fetal liver cells were used as precursor cell populations. When adherent cells from thymus or highly enriched BM-derived macrophages were co-cultured with precursor cells, mature B cells were not developed. Similarly, aBM cell layers generated in the presence of hydrocortisone and horse serum were unable to support aBM cell-dependent precursor differentiation, even though cortisone was removed before the addition of precursor cells. In contrast, this type of microenvironment promoted the differentiation of precursor of myeloid cell lineages. Repeated treatment of established aBM cell populations with a monoclonal anti-macrophage antibody (31.3, known to recognize a surface marker on a subset of BM macrophages) and complement abolished the capacity of otherwise functional aBM cells to sustain the development of B cell precursors. Macrophage-depleted aBM cells regained their function after supplementation with highly enriched BM-derived macrophages grown in vitro. Limiting dilution analysis of aBM cells in microcultures containing saturating numbers of early B cell progenitors also suggests the participation of more than one cell type in the BM cell population. In conclusion, differentiation of early B cell progenitors requires macrophages in addition to at least one additional cell type contained in the aBM cell population.
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Houssaint, E., A. Mansikka y O. Vainio. "Early separation of B and T lymphocyte precursors in chick embryo." Journal of Experimental Medicine 174, n.º 2 (1 de agosto de 1991): 397–406. http://dx.doi.org/10.1084/jem.174.2.397.
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Embryonic chimeras were used to demonstrate an early separation of chicken T and B cell precursors. Genetically polymorphic cell surface antigens, Bu-1 and Ov, which are expressed on cells of the B and T lineage, respectively, are useful markers in adoptive cell transfer studies. Allelic products Bu-1a and Bu-1b can be detected with monoclonal antibodies (mAbs) L22 and 11G2, respectively, and the Ov antigen with mAb 11A9. Chimeric chickens were constructed by reconstituting irradiated 14-d Ov- H.B19 embryos with the sorted Bu-1+ or Bu-1- fractions of spleen cells from age-matched H.B19 Ov+ embryos. Chimeras were analyzed, 3-4 wk after hatching, for the presence of Ov+ cells in the bursa, thymus, spleen, and peripheral blood lymphocytes. T cell precursors giving rise to thymocytes and peripheral T cells were present only in the Bu-1-, but not in the Bu-1+, fraction. We previously demonstrated that, in contrast, all B cell precursors in spleen from 14-d embryos are exclusively present in the Bu-1+ fraction. We also analyzed the immunoglobulin light chain gene rearrangement in these populations by polymerase chain reaction. We show here that VJ recombination occurs in the Bu-1+, but not in the Bu-1-, fraction of spleen. These data demonstrate an early commitment to the B cell lineage, which occurs before the colonization of the bursa of Fabricius. Segregation of B cell precursors from the other hemopoietic precursors, and consequently separation of T and B cell precursors, occurs before the colonization of the primary lymphoid organs.
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Sanderson, R. D., P. Lalor y M. Bernfield. "B lymphocytes express and lose syndecan at specific stages of differentiation." Cell Regulation 1, n.º 1 (noviembre de 1989): 27–35. http://dx.doi.org/10.1091/mbc.1.1.27.
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Lymphopoietic cells require interactions with bone marrow stroma for normal maturation and show changes in adhesion to matrix during their differentiation. Syndecan, a heparan sulfate-rich integral membrane proteoglycan, functions as a matrix receptor by binding cells to interstitial collagens, fibronectin, and thrombospondin. Therefore, we asked whether syndecan was present on the surface of lymphopoietic cells. In bone marrow, we find syndecan only on precursor B cells. Expression changes with pre-B cell maturation in the marrow and with B-lymphocyte differentiation to plasma cells in interstitial matrices. Syndecan on B cell precursors is more heterogeneous and slightly larger than on plasma cells. Syndecan 1) is lost immediately before maturation and release of B lymphocytes into the circulation, 2) is absent on circulating and peripheral B lymphocytes, and 3) is reexpressed upon their differentiation into immobilized plasma cells. Thus, syndecan is expressed only when and where B lymphocytes associate with extracellular matrix. These results indicate that B cells differentiating in vivo alter their matrix receptor expression and suggest a role for syndecan in B cell stage-specific adhesion.
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Davignon, J. L., R. C. Budd, R. Ceredig, P. F. Piguet, H. R. MacDonald, J. C. Cerottini, P. Vassalli y S. Izui. "Functional analysis of T cell subsets from mice bearing the lpr gene." Journal of Immunology 135, n.º 4 (1 de octubre de 1985): 2423–28. http://dx.doi.org/10.4049/jimmunol.135.4.2423.
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Abstract The autosomal recessive lpr (lymphoproliferation) gene is responsible for a thymus-dependent massive lymphoproliferation associated with the development of lupus-like autoimmune disease. Phenotypic analysis of adult lpr/lpr lymph nodes has demonstrated accumulation of a dull Lyt-1+, Thy-1+ population that expresses neither Lyt-2 nor L3T4 antigens. With the use of a depletion method based on complement-mediated lysis with an anti-Lyt-2 monoclonal antibody (31 M) and a new anti-L3T4 monoclonal antibody (RL 172.4), we have purified the Lyt-2- L3T4- subset from lymph nodes or spleens of C57BL/6-lpr/lpr mice and determined whether they are immunologically functional in vitro. Production of neither interleukin 2 nor interferon-gamma was detected by the double-negative subset after stimulation with concanavalin A and/or phorbol myristate acetate. The frequencies of allospecific cytotoxic T lymphocyte (CTL) precursors and lectin-induced antigen-nonspecific CTL precursors were diminished to almost undetectable levels, whereas the Lyt-2+ population from lpr/lpr mice had CTL-precursor frequencies comparable with that of +/+ mice. These results show that the major cell subset of adult lpr/lpr lymph nodes or spleens is composed of lymphocytes with markedly limited potential for lymphokine production or antigenic stimulation.
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Berdova, F. K., I. K. Vorotnikov y N. N. Tupitsyn. "Bone marrow B-lymphocyte subpopulations of breast cancer patients in the prognosis of the disease". Russian Journal of Biotherapy 21, n.º 1 (14 de abril de 2022): 50–56. http://dx.doi.org/10.17650/1726-9784-2022-21-1-50-56.
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Introduction. Among the immunological prognostic factors in breast cancer, intratumoral lymphocytes play an important role. Pronounced infiltration of the tumor by CD8 lymphocytes is associated with a favorable prognosis. The expression of transferrin receptor (CD71) on tumor cells, on the contrary, is associated with an unfavorable prognosis. The bone marrow of breast cancer patients has been studied very little in terms of the prognostic role of hematopoietic cells and lymphocyte subpopulations.The study objective was to investigate the bone marrow B-lymphocyte subpopulations of breast cancer patients and evaluate their prognostic value.Materials and methods. Detailed bone marrow studies were carried out in 107 patients who were treated in the department of mammary gland tumors mainly in the period 2013–2016. Thus, the duration of the follow-up period after surgical treatment was mainly from 5 to 8 years. W hen diagnosing patients, a standard study of the receptor status, Her2 / neu, Ki-67 expression, etc. was performed. Morphological examination of the bone marrow (myelogram) was performed in all patients. Clarification of the life expectancy of patients was carried out by personal surveys or through the Registry Office. If possible, the life expectancy of patients, the duration of the period without progression etc. were clarified.Results. In cases with B-lymphocytes of more than 10 %, survival rates were more favorable (p = 0.019). Bone marrow B cells and, in particular, CD10‑positive B-linear precursors may have prognostic value in breast cancer. Thus, CD10 expression on 12 percent or more of bone marrow B cells of breast cancer patients was associated with a more favorable prognosis (p = 0.042). The prognostic role of the CD10 antigen was realized with a follow-up period of more than 5 years. The expression of CD38 on bone marrow B cells is a prognostically favorable factor (overall survival, p = 0.026), the role of which is realized within 5–10 days of follow-up after surgery. Bone marrow B1 lymphocytes had no association with breast cancer prognosis (overall survival), however, they were correlated (p = 0.07) with progression-free survival.Conclusion. Total relative number of (more than 10 %) of bone marrow B-lymphocytes (CD19+) of breast cancer patients were significantly related to the more favorable prognosis (overall survival) primarily because of B-cell precursors (CD10+) CD38+ bone marrow cells were also associated with more favorable prognosis. Levels of B1‑lymphocytes (CD5+) in bone marrow lymphocytes were not related to the prognosis of breast cancer. Prognositic role of B-lineage precursors and CD38‑positive cells was noted in the periods of 5–10 years after operation.
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Krowka, J. F., C. Guidos, A. Sinha, K. C. Lee, E. Diener y L. M. Pilarski. "Comparative functional analysis of helper T lymphocyte responses to soluble and particulate antigens." Journal of Immunology 138, n.º 10 (15 de mayo de 1987): 3114–19. http://dx.doi.org/10.4049/jimmunol.138.10.3114.
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Abstract An adaptable and sensitive assay to analyze the roles of helper T lymphocytes (TH) which recognize soluble or cell-surface bound antigens in the induction of cytotoxic T lymphocyte precursors (CTLp) is described. Long-term T cell lines that recognize purified protein derivative, keyhole limpet hemocyanin, or Corynebacterium parvum were used in these studies. The ability of T cells from these lines to induce cytotoxic T lymphocyte or antibody responses were compared with their ability to proliferate or release interleukin 2 (IL 2). The results demonstrate that these T cell lines are able to react to soluble antigen by proliferation and IL 2 release. Moreover, the same cell lines are able to interact with CTLp or with the precursors of antibody-secreting B cells to induce a response. In the induction of CTLp we observed an inverse correlation between the number of TH cells required and the concentration of antigen used to pulse the antigen presenting cells. However the correlation between the ability of TH lines to proliferate specifically in response to antigen and to act as helpers for CTLp and B cells was not absolute as cells with compromised proliferative capacity were able to efficiently deliver inductive signals.
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Müller-Sieburg, C. E. "Separation of pluripotent stem cells and early B lymphocyte precursors with antibody Fall-3." Journal of Experimental Medicine 174, n.º 1 (1 de julio de 1991): 161–68. http://dx.doi.org/10.1084/jem.174.1.161.
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A major goal in the study of hematopoiesis is to obtain populations of primitive stem cells, free of restricted and mature cells. We previously showed that a small population of normal bone marrow, the Thy-1loLin- cells, was highly enriched for pluripotent stem cells that repopulate lethally irradiated mice. These cells also differentiated along the B lymphocyte lineage in response to the stromal elements in Whitlock-Witte cultures. These two hematopoietic activities were entirely contained in and were enriched to similar extents in the Thy-1loLin- population. Here we show for the first time that these two activities can be resolved functionally and phenotypically. The cells that respond to the stroma in lymphoid culture are more sensitive to the cytotoxic drug 5-Fluorouracil than are stem cells. Furthermore, we have derived a new monoclonal antibody, Fall-3, that detects primitive stem cells but does not label the B cell precursor. This indicates that the small Thy-1loLin- population is heterogeneous, containing precursors restricted to the B cell lineage as well as pluripotent stem cells. Antibody Fall-3 defines a novel stem cell antigen, expressed on all primitive stem cells and thus, will be useful in the further characterization and isolation of both stem cells and B cell precursors.
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Ishii, Tatsuaki, Heiichiro Udono, Taketoshi Yamano, Hiroyuki Ohta, Akiko Uenaka, Toshiro Ono, Akio Hizuta, Noriaki Tanaka, Pramod K. Srivastava y Eiichi Nakayama. "Isolation of MHC Class I-Restricted Tumor Antigen Peptide and Its Precursors Associated with Heat Shock Proteins hsp70, hsp90, and gp96". Journal of Immunology 162, n.º 3 (1 de febrero de 1999): 1303–9. http://dx.doi.org/10.4049/jimmunol.162.3.1303.
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Abstract We have previously demonstrated that vaccination with heat shock proteins hsp70, hsp90, and gp96 elicits specific immunity against the tumor from which the hsps were purified. Although the association of tumor Ag peptides with these hsps have been suggested, the identification of the peptides or their precursors stripped from the hsps remained to be resolved. We show in this report that an Ld-restricted cytotoxic T lymphocyte epitope of a mouse leukemia RL♂1 and its precursors are associated with the chaperones hsp90 and hsp70 in the cytosol and gp96 in the lumen of the endoplasmic reticulum. Hsp70 was associated with only final sized octamer, while hsp90 was found to associate with the octamer and two distinct precursor peptides. The gp96 was associated with the octamer and one of the two precursors. Thus, each of the hsps bound a distinct set of peptides. Our results have demonstrated for the first time that the hsps associate not only with final sized tumor Ag peptide but also with its precursors. The implication of this evidence is also discussed in terms of the roles of hsps in MHC class I Ag processing/presentation.
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HUSMANN, L. A. y M. J. BEVAN. "Cooperation between Helper T Cells and Cytotoxic T Lymphocyte Precursors". Annals of the New York Academy of Sciences 532, n.º 1 Cytotoxic T C (agosto de 1988): 158–69. http://dx.doi.org/10.1111/j.1749-6632.1988.tb36335.x.
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Kincade, Paul W., Kay L. Medina, Kimberly J. Payne, Maria Isabel D. Rossi, Kim-Sue R. S. Tudor, Yoshio Yamashita y Taku xx. "Early B-lymphocyte precursors and their regulation by sex steroids". Immunological Reviews 175, n.º 1 (junio de 2000): 128–37. http://dx.doi.org/10.1111/j.1600-065x.2000.imr017502.x.
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Asai, Tadao, Walter J. Storkus y Theresa L. Whiteside. "Evaluation of the Modified ELISPOT Assay for Gamma Interferon Production in Cancer Patients Receiving Antitumor Vaccines". Clinical Diagnostic Laboratory Immunology 7, n.º 2 (1 de marzo de 2000): 145–54. http://dx.doi.org/10.1128/cdli.7.2.145-154.2000.
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ABSTRACT Frequencies of vaccine-responsive T-lymphocyte precursors in peripheral blood mononuclear cells (PBMC) prior to and after administration of peptide-based vaccines in patients with cancer can be measured by limiting-dilution assays (LDA) or by ELISPOT assays. We have used a modified version of the ELISPOT assay to monitor changes in the frequency of gamma interferon (IFN-γ)-producing T cells in a population of lymphocytes responding to a relevant peptide or a nonspecific stimulator, such as phorbol myristate acetate-ionomycin. Prior to its use for monitoring of patient samples, the assay was validated and found to be comparable to the LDA performed in parallel, using tumor-reactive cytolytic T-lymphocyte (CTL) lines. The sensitivity of the ELISPOT assay was found to be 1/100,000 cells, with an interassay coefficient of variation of 15%, indicating that it could be reliably used for monitoring of changes in the frequency of IFN-γ-secreting responder cells in noncultured or cultured lymphocyte populations. To establish that the assay is able to detect the T-cell precursor cells responsive to the vaccine, we used CD8+T-cell populations positively selected from PBMC of HLA-A2+patients with metastatic melanoma, who were treated with dendritic cell-based vaccines containing gp100, MELAN-A/MART-1, tyrosinase, and influenza virus matrix peptides. The frequency of peptide-specific responder T cells ranged from 0 to 1/2,600 before vaccination and increased by at least 1 log unit after vaccination in two patients, one of whom had a clinical response to the vaccine. However, no increases in the frequency of peptide-responsive T cells were observed in noncultured PBMC or PBMC cultured in the presence of the relevant peptides after the melanoma patients enrolled in another trial were treated with the intramuscular peptide vaccine plus MF59 adjuvant. Thus, while the ELISPOT assay was found to be readily applicable to assessments of frequencies of CTL precursors of established CTL lines and ex vivo-amplified PBMC, its usefulness for monitoring of fresh PBMC in patients with cancer was limited. In many of these patients antitumor effector T cells are present at frequencies of lower than 1/100,000 in the peripheral circulation. Serial monitoring of such patients may require prior ex vivo amplification of specific precursor cells.
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Martin, D. R. y R. G. Miller. "In vivo administration of histoincompatible lymphocytes leads to rapid functional deletion of cytotoxic T lymphocyte precursors." Journal of Experimental Medicine 170, n.º 3 (1 de septiembre de 1989): 679–90. http://dx.doi.org/10.1084/jem.170.3.679.
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It is well established that a single intravenous injection of F1 lymphocytes can rapidly and specifically reduce the ability of a parental recipient to generate CTL against donor alloantigens in a subsequent MLR. By fluorescently labeling the injected cells, we have been able to identify, and if desired, remove them in cell suspensions prepared from recipient spleen and lymph node. The injected cells, whether F1 or syngeneic, appeared to form part of the normal recirculating pool. Removal of injected F1 cells from responder lymph node or spleen cell suspensions had no effect on the response reduction observed in the 5-d in vitro MLR (typically 80% reduction for responder cells taken 2 d after injection of F1 cells). When the frequency of CTL precursors (CTLp) was measured by limiting dilution, it was reduced to the same degree as the MLR response, implying that response reduction is due to a reduction in the number of activatable CTL in the responder cell suspension. An equal mixture of responder cells from treated (i.e., F1 injected) and control mice gave a measured CTLp frequency equivalent to the average of the separate frequencies, implying the absence of suppressor cells active in vitro. Labeled F1 cells recovered from a first recipient could be used to induce response reduction in a second recipient. The results are discussed in terms of APCs that functionally delete rather than stimulate CTLp that recognize them (i.e., a "veto mechanism"). These experiments appear to rule out a role for in vivo-induced suppressor cells up to 8 d after injection of semiallogeneic cells but do not address the question of whether they are induced at later times.
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Sun, Lei, Patricia A. Goodman, Carla M. Wood, Mya-Lisa Crotty, Martha Sensel, Harland Sather, Christopher Navara et al. "Expression of Aberrantly Spliced Oncogenic Ikaros Isoforms in Childhood Acute Lymphoblastic Leukemia". Journal of Clinical Oncology 17, n.º 12 (diciembre de 1999): 3753–66. http://dx.doi.org/10.1200/jco.1999.17.12.3753.
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PURPOSE: We sought to determine if molecular abnormalities involving the Ikaros gene could contribute to the development of acute lymphoblastic leukemia (ALL) in children. PATIENTS AND METHODS: We studied Ikaros gene expression in normal human bone marrow, normal thymocytes, normal fetal liver–derived immature lymphocyte precursor cell lines, eight different ALL cell lines, and leukemic cells from 69 children with ALL (T-lineage ALL, n = 18; B-lineage ALL, n = 51). Expression of Ikaros protein and its subcellular localization were examined by immunoblotting and confocal laser-scanning microscopy, respectively. Polymerase chain reaction (PCR) and nucleotide sequencing were used to identify the specific Ikaros isoforms expressed in these cells. Genomic sequencing of splice junction regions of the Ikaros gene was performed in search for mutations. RESULTS: In each of the ALL cases, we found high-level expression of a non–DNA-binding or aberrant DNA-binding isoform of Ikaros with abnormal subcellular compartmentalization patterns. In contrast, only wild-type Ik-1 and Ik-2 isoforms with normal subcellular localization were found in normal bone marrow cells and thymus-derived or fetal liver–derived normal lymphocyte precursors. In leukemic cells expressing the aberrant Ikaros coding sequences with the 30-base-pair deletion, genomic sequence analysis of the intron-exon junctions between exons 6 and 7 yielded the wild-type sequence. We identified a single nucleotide polymorphism (SNP) affecting the third base of the triplet codon for a proline (CCC or CCA) in the highly conserved bipartite activation region (viz, A or C at position 1002 numbering from the translation start site of Ik-1) within our Ikaros clones. Bi-allelic expression of truncated and/or non–DNA-binding isoforms along with wild-type isoforms was observed in leukemic cells, which implicates trans-acting factor(s) affecting splice site recognition. CONCLUSION: Our findings link specific molecular defects involving the Ikaros gene to childhood ALL. Posttranscriptional regulation of alternative splicing of Ikaros RNA seems to be defective in leukemic lymphocyte precursors from most children with ALL. Consequently, leukemic cells from ALL patients, in contrast to normal lymphocyte precursors, express high levels of non–DNA-binding Ikaros isoforms that are reminiscent of the non–DNA-binding Ikaros isoforms that lead to lymphoblastic leukemia in mice.
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Uckun, FM, S. Haissig, JA Ledbetter, P. Fidler, DE Myers, V. Kuebelbeck, D. Weisdorf, K. Gajl-Peczalska, JH Kersey y NK Ramsay. "Developmental hierarchy during early human B-cell ontogeny after autologous bone marrow transplantation using autografts depleted of CD19+ B-cell precursors by an anti-CD19 pan-B-cell immunotoxin containing pokeweed antiviral protein". Blood 79, n.º 12 (15 de junio de 1992): 3369–79. http://dx.doi.org/10.1182/blood.v79.12.3369.3369.
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Abstract Sequential immunophenotypes of bone marrow (BM) and peripheral blood (PBL) lymphoid cells from 15 B-lineage acute lymphoblastic leukemia (ALL) patients who underwent autologous bone marrow transplantation (BMT) during complete remission were determined by dual-color immunofluorescence and multiparameter flow cytometry. Autografts were depleted of CD19+ B-cell precursors by an immunochemopurging protocol that combines B43-PAP, a potent anti-CD19 immunotoxin, and the cyclophosphamide congener 4-hydroperoxycyclophosphamide (4-HC). A marked interpatient variation was observed in the appearance and expansion of B-cell precursors repopulating the posttransplant marrow. The expression of CD10 and CD19 antigens during early B-cell ontogeny post-BMT preceded the expression of CD20, CD21, CD22, CD40, and sIgM. The surface antigen profiles of the emerging B-cell precursors were similar to those of fetal liver or fetal bone marrow B-cell precursors. Our comparisons of BM and PBL samples from patients in the early post- BMT period demonstrated that (1) PBL initially contains fewer B-lineage cells than does BM, and (2) circulating B-lineage lymphoid cells have a more mature immunophenotype than do BM B-lineage lymphoid cells. Comparison of the surface antigen profiles of day 30 versus day 100 or year 1 BM or PBL lymphoid cells showed an increase in the percentages of CD10+CD22- undifferentiated lymphocyte precursors, as well as CD19+sIgM- B-cell precursors (pre-pre-B), consistent with a time- dependent expansion of these B-cell precursor populations post-BMT. Importantly, the percentages of CD10+CD22+ and CD19+sIgM+ B-cell precursor (pre-B) populations also increased between 30 days and 1 year post-BMT, confirming the ability of emerging immature B-cell precursors to differentiate along the B-precursor pathway. The acquisition and expression of B-lineage differentiation antigens at different stages of the post-BMT B-cell ontogeny support the notion that the expression of these antigens is developmentally programmed. Similar to patients in previous autologous BMT studies, recipients of B-cell precursor- depleted autografts had normal or nearly normal serum immunoglobulin levels, suggesting that the maturing B-cell/plasma cell populations can produce and secrete immunoglobulins. The development of a functional CD19+ B-lineage lymphoid compartment in recipients of autografts which were depleted of CD19+ B-cell precursors corroborates the previously postulated existence of CD19- B-lineage lymphoid progenitor cells.
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Uckun, FM, S. Haissig, JA Ledbetter, P. Fidler, DE Myers, V. Kuebelbeck, D. Weisdorf, K. Gajl-Peczalska, JH Kersey y NK Ramsay. "Developmental hierarchy during early human B-cell ontogeny after autologous bone marrow transplantation using autografts depleted of CD19+ B-cell precursors by an anti-CD19 pan-B-cell immunotoxin containing pokeweed antiviral protein". Blood 79, n.º 12 (15 de junio de 1992): 3369–79. http://dx.doi.org/10.1182/blood.v79.12.3369.bloodjournal79123369.
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Sequential immunophenotypes of bone marrow (BM) and peripheral blood (PBL) lymphoid cells from 15 B-lineage acute lymphoblastic leukemia (ALL) patients who underwent autologous bone marrow transplantation (BMT) during complete remission were determined by dual-color immunofluorescence and multiparameter flow cytometry. Autografts were depleted of CD19+ B-cell precursors by an immunochemopurging protocol that combines B43-PAP, a potent anti-CD19 immunotoxin, and the cyclophosphamide congener 4-hydroperoxycyclophosphamide (4-HC). A marked interpatient variation was observed in the appearance and expansion of B-cell precursors repopulating the posttransplant marrow. The expression of CD10 and CD19 antigens during early B-cell ontogeny post-BMT preceded the expression of CD20, CD21, CD22, CD40, and sIgM. The surface antigen profiles of the emerging B-cell precursors were similar to those of fetal liver or fetal bone marrow B-cell precursors. Our comparisons of BM and PBL samples from patients in the early post- BMT period demonstrated that (1) PBL initially contains fewer B-lineage cells than does BM, and (2) circulating B-lineage lymphoid cells have a more mature immunophenotype than do BM B-lineage lymphoid cells. Comparison of the surface antigen profiles of day 30 versus day 100 or year 1 BM or PBL lymphoid cells showed an increase in the percentages of CD10+CD22- undifferentiated lymphocyte precursors, as well as CD19+sIgM- B-cell precursors (pre-pre-B), consistent with a time- dependent expansion of these B-cell precursor populations post-BMT. Importantly, the percentages of CD10+CD22+ and CD19+sIgM+ B-cell precursor (pre-B) populations also increased between 30 days and 1 year post-BMT, confirming the ability of emerging immature B-cell precursors to differentiate along the B-precursor pathway. The acquisition and expression of B-lineage differentiation antigens at different stages of the post-BMT B-cell ontogeny support the notion that the expression of these antigens is developmentally programmed. Similar to patients in previous autologous BMT studies, recipients of B-cell precursor- depleted autografts had normal or nearly normal serum immunoglobulin levels, suggesting that the maturing B-cell/plasma cell populations can produce and secrete immunoglobulins. The development of a functional CD19+ B-lineage lymphoid compartment in recipients of autografts which were depleted of CD19+ B-cell precursors corroborates the previously postulated existence of CD19- B-lineage lymphoid progenitor cells.