Showing papers on "Haematopoiesis published in 1988"

Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells.

Abstract: A common feature of follicular lymphoma, the most prevalent haematological malignancy in humans, is a chromosome translocation (t(14;18] that has coupled the immunoglobulin heavy chain locus to a chromosome 18 gene denoted bcl-2. By analogy with the translocated c-myc oncogene in other B-lymphoid tumours bcl-2 is a candidate oncogene, but no biological effects of bcl-2 have yet been reported. To test whether bcl-2 influences the growth of haematopoietic cells, either alone or together with a deregulated c-myc gene, we have introduced a human bcl-2 complementary DNA using a retroviral vector into bone marrow cells from either normal or E mu-myc transgenic mice, in which B-lineage cells constitutively express the c-myc gene. Bcl-2 cooperated with c-myc to promote proliferation of B-cell precursors, some of which became tumorigenic. To determine how bcl-2 expression impinges on growth factor requirements, the gene was introduced into a lymphoid and a myeloid cell line that require interleukin 3 (IL-3). In the absence of IL-3, bcl-2 promoted the survival of the infected cells but they persisted in a G0 state, rather than proliferating. These results argue that bcl-2 provided a distinct survival signal to the cell and may contribute to neoplasia by allowing a clone to persist until other oncogenes, such as c-myc, become activated.

Purification and Characterization of Mouse Hematopoietic Stem Cells

Abstract: Mouse bone marrow hematopoietic stem cells were isolated with the use of a variety of phenotypic markers. These cells can proliferate and differentiate with approximately unit efficiency into myelomonocytic cells, B cells, or T cells. Thirty of these cells are sufficient to save 50 percent of lethally irradiated mice, and to reconstitute all blood cell types in the survivors.

Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides

Abstract: Murine embryonic stem (ES) cells are pluripotent cell lines established directly from the early embryo which can contribute differentiated progeny to all adult tissues, including the germ-cell lineage, after re-incorporation into the normal embryo. They provide both a cellular vector for the generation of transgenic animals and a useful system for the identification of polypeptide factors controlling differentiation processes in early development. In particular, medium conditioned by Buffalo rat liver cells contains a polypeptide factor, ES cell differentiation inhibitory activity (DIA), which specifically suppresses the spontaneous differentiation of ES cells in vitro, thereby permitting their growth as homogeneous stem cell populations in the absence of heterologous feeder cells. ES cell pluripotentiality, including the ability to give rise to functional gametes, is preserved after prolonged culture in Buffalo rat liver media as a source of DIA. Here, we report that purified DIA is related in structure and function to the recently identified hematopoietic regulatory factors human interleukin for DA cells and leukaemia inhibitory factor. DIA and human interleukin DA/leukaemia inhibitory factor have thus been identified as related multifunctional regulatory factors with distinct biological activities in both early embryonic and hematopoietic stem cell systems.

Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas

Abstract: Human B cell stimulatory factor 2 (BSF-2) was originally characterized and isolated as a T cell-derived factor that caused the terminal maturation of activated B cells to immunoglobulin-producing cells. Molecular cloning of the complementary DNA predicts that BSF-2 is a protein of relative molecular mass (Mr) 26,000 similar or identical to interferon beta 2, hybridoma plasmacytoma growth factor and hepatocyte stimulating factor. IL-6 has been proposed as a name for this molecule. It is now known that BSF-2 has a wide variety of biological functions and that its target cells are not restricted to normal B cells. Responses are also seen in T cells, plasmacytomas, hepatocytes, haematopoietic stem cells, fibroblasts and rat phoeochromocytoma, PC12 (Satoh, T. et al., manuscript in preparation). Of particular interest to this report is that human BSF-2 is a potent growth factor for murine plasmacytomas and hybridomas. This observation suggested to us that constitutive expression of BSF-2 or its receptor could be responsible for the generation of human myelomas. In this study we report that myeloma cells freshly isolated from patients produce BSF-2 and express its receptors. Moreover, anti-BSF-2 antibody inhibits the in vitro growth of myeloma cells. This is direct evidence that an autocrine loop is operating in oncogenesis of human myelomas.

The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function.

Abstract: The study of human hematopoietic cells and the human immune system is hampered by the lack of a suitable experimental model. Experimental data are presented showing that human fetal liver hematopoietic cells, human fetal thymus, and human fetal lymph node support the differentiation of mature human T cells and B cells after engraftment into mice with genetically determined severe combined immunodeficiency. The resultant SCID-hu mice are found to have a transient wave of human CD4+ and CD8+ T cells and human IgG (immunoglobulin G) in the peripheral circulation. The functional status of the human immune system within this mouse model is not yet known.

Heparan sulphate bound growth factors: a mechanism for stromal cell mediated haemopoiesis.

Abstract: The proliferation and development of haemopoietic stem cells takes place in close association with marrow stromal cells1,2. This intimate cell contact presumably enables the stem cells and their progeny to respond to stimuli present on the stromal cell surface. While the nature of these stimuli has not been determined, it is likely that growth factors play some role. Recently, it was demonstrated that the natural and the recombinant haemopoietic growth factor, granulocyte/macrophage colony stimulating factor (GM-CSF), could be adsorbed out of solution by an extract of human marrow stromal extracellular matrix (ECM) with retention of biological activity3. However, the precise ECM molecules involved were not identified. Here, we clearly demonstrate that the major sulphated glycosaminoglycan of mouse marrow stroma, heparan sulphate4, possesses the ability to adsorb both GM-CSF and the multilineage haemopoietic growth factor, Interleukin 3 (IL-3). Furthermore, these growth factors, once bound, can be presented in the biologically active form to haemopoietic cells.

Stimulation of B-cell progenitors by cloned murine interleukin-7.

Abstract: The events involved in the commitment and development of lymphoid lineage cells are poorly understood. We have used a recently described long-term culture system1 to establish a bioassay that can detect a novel growth factor capable of stimulating the proliferation of lymphoid progenitors2. Using direct expression in mammalian cells we have isolated a complementary DNA clone encoding this novel haematopoietic growth factor, designated interleukin-7.

Antigen CD34+ marrow cells engraft lethally irradiated baboons.

Abstract: The CD34 antigen is present on 1-4% of human marrow cells including virtually all hematopoietic progenitors detected by in vitro assays. Since the anti-CD34 monoclonal antibody 12-8 reacts with a similar marrow population in baboons, it was possible to test whether this antigen is expressed by stem cells responsible for hematopoietic reconstitution in vivo. CD34+ cells were enriched from marrows of five baboons using avidin-biotin immunoadsorption. After lethal irradiation, the five animals were given 15-27 X 10(6) autologous marrow cells (3.2-4.4 X 10(6) cells/kg) containing 65-91% CD34+ cells. All animals achieved granulocyte counts greater than 1,000/mm3 and platelet counts greater than 20 X 10(3)/mm3 by 13-24 d posttransplant and subsequently developed normal peripheral blood counts. Two additional animals received 184 and 285 X 10(6) marrow cells/kg depleted of CD34+ cells. One animal died at day 29 without engraftment, while the other had pancytopenia for greater than 100 d posttransplant. The data suggest that stem cells responsible for hematopoietic reconstitution are CD34+.

Purified interleukin 5 supports the terminal differentiation and proliferation of murine eosinophilic precursors.

Abstract: Using a clonal culture system, we investigated the hemopoietic effects of purified recombinant IL-5 obtained from conditioned media of transfected Xenopus oocytes. IL-5 alone acted on untreated bone marrow cells and supported the formation of a small number of colonies, all of which were predominantly eosinophilic. However, it did not support colony formation by spleen cells from 5-FU-treated mice, in which only primitive stem cells had survived, while IL-3 and G-CSF did. Eosinophil-containing colonies were formed from these cells in the presence of IL-5 and G-CSF together. In contrast, G-CSF alone did not support any eosinophil colonies. The eosinophilopoietic effect of IL-5 was dose-dependent, and was neutralized specifically by anti-IL-5 antibody. To exclude the possibility of interactions with accessory cells in the same culture dish, we replated a small number (200 cells/dish) of enriched hemopoietic progenitors, obtained from blast cell colonies, which were formed by cultivation of spleen cells from 5-FU-treated mice in the presence of IL-3 or G-CSF. From these replated blast cells, eosinophil colonies were induced in dishes containing IL-5 but not in those containing G-CSF alone. From these findings, it was concluded that IL-5 did not act on primitive hemopoietic cells, but on blast cells induced by IL-3 or G-CSF. IL-5 specifically facilitated the terminal differentiation and proliferation of eosinophils. In this respect, the role of IL-5 in eosinophilopoiesis seems to be analogous to erythropoietin, which promotes the terminal differentiation and amplification of erythroid cells. Moreover, IL-5 maintained the viability of mature eosinophils obtained from peritoneal exudate cells of the mice infected with parasites, indicating mature functional eosinophils carried IL-5 receptors. The synergistic effects of IL-5 and colony-stimulating factors on the expansion of eosinophils is supposed to contribute to the urgent mobilization of eosinophils at the time of helminthic infections and allergic responses.

Engraftment of immune-deficient mice with human hematopoietic stem cells

Abstract: A system in which immune-deficient mice are repopulated with cells from the human myeloid lineage, and that provides an in vivo stem cell assay for human hematopoietic cells is described. Generation of the chimeric human/immune-deficient (HID) mice was dependent on the use of immune-deficient bg/nu/xid mice. Infusion of these mice with human bone marrow gave rise to increases in human macrophage progenitors during more than 5 weeks of in vivo growth, indicating the seeding, proliferation, and differentiation of human stem cells. The human identity of the progenitors was confirmed by sequence analysis and their dependence on human growth factors. The creation of HID mice lays the foundation for establishing animal models for a wide variety of human hemopathies, from leukemia to infectious disease.

Human IL-3 and GM-CSF Act Synergistically in Stimulating Hematopoiesis in Primates

Abstract: Interleukin-3 (IL-3) is a member of a family of growth factors, each of which supports the proliferation and development of hematopoietic precursors in culture. Although the biologic effects of the different hematopoietic growth factors have been well documented in different culture systems, it has only recently become possible to study the activities of these molecules in vivo. In comparison with the later acting hematopoietic growth factors granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor, IL-3 elicited a delayed and relatively modest leukocytosis when continuously infused intravenously in primates. The IL-3 infusion, however, greatly potentiated the responsiveness of the animal to subsequent administration of a low dose of GM-CSF. These results suggest that IL-3 expands an early cell population in vivo that subsequently requires the action of a later acting factor such as GM-CSF to complete its development. Optimal stimulation of hematopoiesis may be achieved with combinations of hematopoietic growth factors.

Lineage-specific expression of a human β -globin gene in murine bone marrow transplant recipients reconstituted with retrovirus-transduced stem cells

Abstract: Recombinant retroviral genomes encoding a chromosomal human beta-globin gene have been used to transduce murine haematopoietic stem cells in vitro. After permanent engraftment of lethally irradiated recipients with the transduced cells, the human beta-globin gene is expressed at significant levels only within the erythroid lineage. These results indicate that it is possible to obtain stable expression of exogenous chromosomal DNA sequences introduced into mature haematopoietic cells in vivo via stem cell infection, and that human disorders of haemoglobin production may be more feasible candidates for somatic cell gene therapy than previously suspected.

Hemopoietic growth factors: a review.

Abstract: Several hemopoietic growth factors have now been purified, cloned, and produced in bacteria. Granulocyte colony stimulating factor and granulocyte-macrophage colony stimulating factor are already being used in clinical trials. Within 12 months two more hemopoietic growth factors, macrophage colony stimulating factor (also called colony stimulating factor 1) and interleukin 3 (also called multi-colony stimulating factor) will be used for patient treatment. This review discusses the recent advances in our knowledge of the molecular properties and biological specificities of these factors. It is now clear that these molecules are able to modulate selectively the activity of mature blood cells as well as stimulating the production of specific lineages of blood cells. The availability of recombinant hemopoietic growth factors purified from animal or yeast cell conditioned medium or bacteria has facilitated in vivo experiments, as well as the clinical trials. Each of the growth factors has a unique spectrum of biological activities and it appears that the growth factors will enhance the recovery and function of circulating white blood cells after cancer therapy or bone marrow transplantation.

Analysis in serum-free culture of the targets of recombinant human hemopoietic growth factors: interleukin 3 and granulocyte/macrophage-colony-stimulating factor are specific for early developmental stages

Abstract: We have used a serum-free culture system for enriched human hemopoietic progenitors to analyze the developmental stages and lineage specificities of the human hemopoietic colony-stimulating factors. None of the individual factors alone efficiently supported hemopoietic colony formation. Neither interleukin 3 nor granulocyte/macrophage-colony-stimulating factor alone or in combination effectively supported proliferation of progenitor cells. However, when combined with granulocyte-colony-stimulating factor or erythropoietin, these factors yielded neutrophil colonies or erythroid bursts, respectively. Serial observations of interleukin 3-supported cultures revealed sequential emergence and subsequent degeneration of clusters of cells. These observations suggest that the primary targets of interleukin 3 and granulocyte/macrophage-colony-stimulating factor are multipotent progenitors at the early stages of development rather than cells in the terminal process of maturation.

Interleukin 1 stimulates fibroblasts to synthesize granulocyte-macrophage and granulocyte colony-stimulating factors. Mechanism for the hematopoietic response to inflammation.

Abstract: IL-1 is a family of polypeptides which play a critical role in the inflammatory response. Characteristics of this response include an enhanced release of bone marrow neutrophils, activation of circulating and tissue-phase phagocytes, and enhanced production of neutrophils and monocytes. We have sought to understand the hematopoietic response to acute and chronic inflammatory states on a cellular and molecular level. Colony-stimulating factors (CSFs) are glycoproteins involved in the production and activation of neutrophils and monocytes in vitro and in vivo. We have found that quiescent dermal fibroblasts constitutively release granulocyte-macrophage CSF (GM-CSF), granulocyte CSF (G-CSF), and macrophage CSF in culture, and that picomolar concentrations of the inflammatory mediator IL-1 stimulate by at least fivefold the transcription and release of GM-CSF and G-CSF. These findings establish the role of IL-1 in the hematopoietic response to inflammation through the stimulation of the production and release of GM-CSF and G-CSF.

Stimulation of murine hemopoietic colony formation by human IL-6.

Abstract: A novel hemopoietic CSF has been identified in the medium conditioned by lectin-stimulated human T cells. The cDNA clone encoding this factor, isolated by functional expression cloning in monkey cos-1 cells, proved to be identical with the cDNA encoding the cytokine B cell stimulatory factor-2/IFN-beta 2, a factor now known as IL-6. In the murine system, IL-6 indirectly supports the formation of several different types of hemopoietic colonies, including those derived from early blast cells, and directly supports the proliferation of granulocyte/macrophage progenitors. These results expand the range of known target cells of IL-6 to include hemopoietic progenitors in addition to B cells, T cells, and fibroblasts and provide further evidence that this cytokine plays an important role within a network of interacting cytokines that regulates many different biologic responses.

Expression of high affinity receptors for murine interleukin 4 (BSF-1) on hemopoietic and nonhemopoietic cells.

Abstract: In this report a method for the affinity purification and radiolabeling of recombinant mouse interleukin (IL)-4 is described. It is shown on the basis of several criteria that IL-4 retains full biologic activity after radioiodination and can therefore be used as a valid model for measuring the binding characteristics of native IL-4. By using Scatchard plot analysis of equilibrium binding data, it is demonstrated that 125I-IL-4 binds to a high affinity cell surface receptor which is expressed by both hemopoietic and nonhemopoietic cells. The dissociation constant for 125I-IL-4 (Kd = 20 to 60 pM) corresponds to the concentration of IL-4 which gives 50% biologic activity (i.e., 10 to 30 pM). Binding of 125I-IL-4 is rapid (t1/2 of 2 min), whereas dissociation occurs at a slow rate (t1/2 approximately 4 hr). The IL-4 receptor shows a high degree of specificity. Whereas unlabeled mouse IL-4 competed with mouse 125I-IL-4 in an equimolar fashion for binding to IL-4 receptors, several other lymphokines, including mouse IL-2, IL-3, interferon-gamma, granulocyte-macrophage colony-stimulating factor, and human IL-1, IL-2, and IL-4 were unable to inhibit, even at molar excesses of 400 to 800-fold. At 37 degrees C, 125I-IL-4 is rapidly internalized (approximately 200 molecules/cell/min) by HT-2 cells, with at least 85% of cell surface receptors being functional in this respect. Receptors for IL-4 were found to be expressed by subclasses of T and B cells, mast cells, macrophages, and by cells of the myeloid and erythroid lineages. This wide distribution of receptor expression closely matches the known spectrum of biologic activities of IL-4, including proliferation and/or differentiation of T and B cells, mast cells and granulocytes, and induction of macrophage antigen-presenting capacity. IL-4 receptors were also found on a variety of nonhemopoietic cells such as cloned stromal cell lines from the bone marrow, spleen, thymus, and brain, and on muscle, brain, melanoma, fibroblast, and liver cells. Indeed, only 5 of more than 90 cell types tested have undetectable numbers of IL-4 receptors. The biologic effects of IL-4 on nonhemopoietic cells have not yet been reported and await elucidation.

Human granulocyte-macrophage colony-stimulating factor is a growth factor active on a variety of cell types of nonhemopoietic origin

Abstract: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a member of a family of glycoprotein hormones that stimulate the proliferation and differentiation of hemopoietic cells in vitro and in vivo. We now report that human GM-CSF can also stimulate the proliferation of two osteogenic sarcoma cell lines, a breast carcinoma cell line, a simian virus 40-transformed marrow stromal cell line, and normal marrow fibroblast precursors. These findings suggest a more general regulatory function of GM-CSF on nonhemopoietic cell types than previously anticipated. They also raise the possibility of adverse side effects of GM-CSF therapy in patients whose malignant cells may be directly stimulated by this molecule and suggest a previously unanticipated role of GM-CSF gene activation in the evolution of solid tumors and in the pathogenesis of myelofibrosis.

Isolation and preservation of fetal and neonatal hematopoietic stem and progenitor cells of the blood and methods of therapeutic use

Abstract: The present invention relates to hematopoietic stem and progenitor cells of neonatal or fetal blood that are cryopreserved, and the therapeutic uses of such stem and progenitor cells upon thawing. In particular, the present invention relates to the therapeutic use of fetal or neonatal stem cells for hematopoietic (or immune) reconstitution. Hematopoietic reconstitution with the cells of the invention can be valuable in the treatment or prevention of various diseases and disorders such as anemias, malignancies, autoimmune disorders, and various immune dysfunctions and deficiencies. In another embodiment, fetal or neonatal hematopoietic stem and progenitor cells which contain a heterologous gene sequence can be used for hematopoietic reconstitution in gene therapy. In a preferred embodiment of he invention, neonatal or fetal blood cells that have been cryopreserved and thawed can be used for utologous (self) reconstitution.

Characterization of a human hematopoietic progenitor cell capable of forming blast cell containing colonies in vitro.

Abstract: A hematopoietic cell (CFU-B1) capable of producing blast cell containing colonies in vitro was detected using a semisolid culture system. The CFU-B1 has the capacity for self-renewal and commitment to a number of hematopoietic lineages. Monoclonal antibody to the human progenitor cell antigen-1 (HPCA-1) and a monoclonal antibody against the major histocompatibility class II antigen (HLA-DR) were used with fluorescence activated cell sorting to phenotype the CFU-B1. The CFU-B1 was found to express My10 but not HLA-DR antigen; experiments using complement-dependent cytotoxicity to eliminate DR positive cells confirmed this finding. Pretreatment of marrow cells with two chemotherapeutic agents, 5-fluorouracil and 4-hydroperoxycyclophosphamide facilitated detection of CFU-B1 derived colonies, while diminishing or totally inhibiting colony formation by other hematopoietic progenitor cells. CFU-B1-derived colony formation was dependent upon the addition of exogenous hematopoietic growth factors. Media conditioned either by the human bladder carcinoma cell line 5637 or lectin stimulated leukocytes, as well as recombinant granulocyte-macrophage colony stimulating factor, interleukin 3 or interleukin 1 alpha promoted blast cell colony formation. By contrast, neither recombinant erythropoietin, recombinant interleukin 4, purified macrophage colony stimulating factor or recombinant granulocyte colony-stimulating factor alone promoted blast cell colony formation.

Transforming growth factor beta 1 selectively regulates early murine hematopoietic progenitors and inhibits the growth of IL-3-dependent myeloid leukemia cell lines.

Abstract: Transforming growth factor beta 1 (TGF-beta 1) has been shown to be associated with active centers of hematopoiesis and lymphopoiesis in the developing fetus. Therefore, the effects of TGF-beta 1 on mouse hematopoiesis were studied. TGF-beta 1 is a potent inhibitor of IL-3-induced bone marrow proliferation, but it does not inhibit the proliferation induced by granulocyte/macrophage, colony-stimulating factor (CSF), granulocyte CSF, and erythropoietin (Epo). TGF-beta 1 also inhibits IL-3-induced multipotential colony formation of bone marrow cells in soft agar, which includes early erythroid differentiation, while Epo-induced terminal differentiation is unaffected. In addition, IL-3-induced granulocyte/macrophage colonies were inhibited; however, small clusters of differentiated myeloid cells were consistently seen in cultures containing IL-3 and TGF-beta 1. Thus, TGF-beta 1 selectively inhibits early hematopoietic progenitor growth and differentiation but not more mature progenitors. TGF-beta 1 is also a potent inhibitor of IL-3-dependent and -independent myelomonocytic leukemic cell growth, while the more mature erythroid and macrophage leukemias are insensitive. Therefore, TGF-beta 1 functions as a selective regulator of differentiating normal hematopoietic cells, and suppresses myeloid leukemic cell growth.

In vitro and in vivo analysis of the effects of recombinant human granulocyte colony-stimulating factor in patients.

Abstract: Twelve patients with small cell lung cancer were treated with recombinant human granulocyte colony-stimulating factor, rhG-CSF, given by continuous infusion at doses ranging from 1 to 40 micrograms kg-1 day-1. Patients received the rhG-CSF before the start of intensive chemotherapy and after alternate cycles of chemotherapy. Several in vitro assays were performed using peripheral blood neutrophils and marrow progenitor cells collected from patients prior to and after infusion of the growth factor. Peripheral blood neutrophils were tested for mobility and phagocytic activity. In addition, in vitro clonogenic assays of marrow haemopoietic progenitor cells and analysis of bone marrow trephines and aspirates were carried out. We found that rhG-CSF in vivo has at least two main effects: (a) an early fall in peripheral neutrophils, within the first hour, followed by a rapid influx of mature neutrophils into the circulatory pool; (b) stimulation of proliferation and differentiation of neutrophil precursors in the bone marrow. Neutrophils released into the circulation were normal in tests of their mobility and phagocytic activity.

Enhancement of human granulopoiesis in vitro by biosynthetic insulin-like growth factor I/somatomedin C and human growth hormone.

Abstract: The effect of biosynthetic recombinant insulin-like growth factor I/somatomedin C (IGF-I/Sm-C) and human growth hormone (hGH) on the in vitro growth and maturation of human marrow myeloid progenitors was investigated. Myeloid colony formation was maximally enhanced by 60 ng/ml IGF-I/Sm-C and by 250 ng/ml hGH, resulting in an increase in colony numbers of 41 +/- 7 and 38 +/- 4%, respectively (P less than 0.001). Both peptides induced a 1.5-2.5-fold increase in the frequency of colonies composed of granulocytes alone, but did not alter the numbers of monocyte/macrophage or mixed granulocyte/macrophage colonies. IGF-I/Sm-C and hGH were also found to enhance myeloid maturation towards mature granulocytes in suspension cultures of human marrow cells. The effect of both peptides on human marrow granulopoiesis was similarly demonstrable in serum-free cultures stimulated with human recombinant granulocyte/macrophage colony-stimulating factor. Enhancement of human marrow granulopoiesis in vitro by hGH required the presence of marrow adherent cells and was abrogated by specific monoclonal antibodies directed against IGF-I/Sm-C receptors. The effect of hGH on marrow myeloid progenitors thus appears to be mediated by paracrine IGF-I/Sm-C.

T cell depletion with CAMPATH-1 in allogeneic bone marrow transplantation.

Abstract: A total of 282 patients with leukemia have been treated by transplantation from HLA-matched siblings using marrow depleted of T cells with CAMPATH-1 and autologous complement. The incidence of graft-versus-host disease (GVHD) of grades 2-4 was only 12% but the maximum incidence of graft failure was 15%. A significant increase in relapse cannot yet be detected in acute leukemia but relapse in chronic granulocytic leukemia (CGL) was substantially above that reported before T cell depletion. The most important predictive factor for relapse in CGL appeared to be slow engraftment. This finding suggests an alternative explanation for the graft-versus-leukemia effect other than a direct attack on leukemia cells. This is that donor T cells may affect the balance of competition between donor and recipient haemopoesis by preventing a rejection reaction to donor stem cells. Recipient leukemic cells would benefit (i.e. relapse) if recipient hemopoiesis gained an advantage. If this explanation were true we would expect extra immunosuppressive preconditioning of recipients to reduce the incidence of relapse, as well as preventing graft rejection.

Coordinate regulation of immune and inflammatory responses by T cell-derived lymphokines.

Abstract: In response to antigenic stimulation, helper T cells secrete a set of protein mediators called lymphokines that regulate proliferation, differentiation, and maturation of lymphocytes and hemopoietic cells. Because all known lymphokines are composed of a single polypeptide chain, their coding sequences can be isolated by functional expression in appropriate host cells. Based on this expression cloning protocol, a number of T cell lymphokine genes have been isolated, their primary structure has been determined, and biological properties of their recombinant products have been examined. These studies revealed the existence of a regulatory network between lymphoid cells and hemopoietic cells mediated by the actions of multiple pleiotropic lymphokines produced by activated T cells. Because all or a part of this network can be activated in different ways by unique combinations of lymphokines, it is clear that T cells can play a vital role in coordinating the function of different body compartments in the immune...