Showing papers on "Bone marrow published in 1978"

On the thymus in the differentiation of "H-2 self-recognition" by T cells: evidence for dual recognition?

Abstract: In the thymus, precursor T cells differentiate recognition structures for self that are specific for the H-2K, D, and I markers expressed by the thymic epithelium. Thus recognition of self-H-2 differentiates independently of the T cells H-2 type and independently of recognition of nonself antigen X. This is readily compatible with dual recognition by T cells but does not formally exclude a single recognition model. These conclusions derive from experiments with bone marrow and thymic chimeras. Irradiated mice reconstituted with bone marrow to form chimeras of (A X B)F1 leads to A type generate virus-specific cytotoxic T cells for infected targets A only. Therefore, the H-2 type of the host determines the H-2-restricted activity of killer T cells alone. In contrast, chimeras made by reconstituting irradiated A mice with adult spleen cells of (A X B)F1 origin generate virus-specific cytotoxic activity for infected A and B targets, suggesting that mature T cells do not change their self-specificity readily. (A X B)F1 leads to (A X C)F1 and (KAIA/DC) leads to (KAIA/DB) irradiation bone marrow chimeras responded against infected A but not B or C targets. This suggests that cytotoxicity is not generated against DC because it is abscent from the host's thymus epithelium and not against DB because it is not expressed by the reconstituting lymphoreticular system. (KBIB/DA) leads to (KCIC/DA) K, I incompatible, or completely H-2 incompatible A leads to B chimeras fail to generate any measurable virus specific cytotoxicity, indicating the necessity for I-specific helper T cells for the generation of killer T cells. Finally adult thymectomized, irradiated and bone marrow reconstituted (A X B)F1 mice, transplanted with an irradiated thymus of A origin, generate virus-specific cytotoxic T cells specific for infected A targets but not for B targets; this result formally demonstrates the crucial role of thymic epithelial cells in the differentiation of anti-self-H-2 specificities of T cells.

Lethal graft-versus-host disease after bone marrow transplantation across minor histocompatibility barriers in mice. Prevention by removing mature T cells from marrow.

Abstract: In two situations, transfer of normal unsensitized bone marrow cells into heavily irradiated H-2-identical allogeneic mice caused a high incidence of lethal chronic graft-versus-host disease (GVHD), i.e. mortality occuring between days of 20 and 80 postirradiation. Minor histocompatibility determinants appeared to be the main target for eliciting GVHD. Removing mature T cells from the marrow with anti-Thy 1.2 serum and complement before injection prevented GVHD. On the basis of adding purified T cells to T-cell-depleted marrow cells, it was concluded that contamination of the marrow with as few as 0.3% T cells was sufficient to cause a high incidence of lethal GVHD in certain situations. No GVHD was found with the injection of non-T cells (Thy 1.2-negative cells) or with tolerant T cells. Irradiated recipients of T-cell-depleted marrow cells remained in good health for prolonged periods. These mice showed extensive chimerism with respect to the donor marrow, normal numbers of T and B cells and were immunocompetent. The data provide no support for the view that chronic GVHD developing after bone marrow transplantation in man is the result of an attack by the progeny of the donor stem cells. The results imply that mature T cells contaminating marrow inocula are probably the main cause of GVHD seen in the clinical situation.

The origin, kinetics, and characteristics of the kupffer cells in the normal steady state

Abstract: Enzymatic digestion with pronase and DNAase was used to isolate Kupffer cells from mouse liver. The characteristics of these cells were found to be similar to those of peritoneal macrophages, except that in the initial suspension the percentage of Kupffer cells with Fc receptors was low, C receptors were absent and the ingestion of opsenized bacteria was very poor, because of the effect of pronase on the cell membrane. After 24 h incubation in vitro all these characteristics return. The in vitro and 1 h-pulse [(3)H]thymidine labeling of the Kupffer cells is low (0.8 and 1 percent, respectively) indicating that in essence these cells do not divide. It was also shown that the small percentage of in vitro labeled Kupffer cells was recently derived from the circulation. After an intravenous injection of zymosan the in vitro labeling index of the Kupffer cells increased 16-fold, but it was proven that these dividing cells were immature mononuclear phagocytes very recently recruited from the bone marrow. The labeling of Kupffer cells aider one or four injections of [(3)H]thymidine reached a peak of 10.4 percent at 48 h or 24.1 percent at 60 h, respectively, indicating that these cells are derived from labeled monocytes. Further evidence for this conclusion was obtained by the absence of an increase of labeled Kupffer cells during treatment with hydrocortisone, which causes a monocytopenia during which no circulating monocytes are available to migrate to the tissues. Labeling studies in animals X-irradiated with hind-limb shielding gave a Kupffer cell labeling index of 5-10 percent of the normal values, which confirms their bone marrow origin. A quantitative study on the production of labeled monocytes in the bone marrow and their transit through the circulation showed that in the normal steady state at least 56.4 percent of the monocytes leaving the circulation become Kupffer cells. Considering the Kupffer cells as kinetically homogeneous this gives a mean turnover time of the total population of Kupffer cells of 21 days.

Loss of proliferative capacity in immunohemopoietic stem cells caused by serial transplantation rather than aging.

Abstract: Marrow stem cell lines from old donors and those from young controls gave equally rapid rates of colony growth on spleens of irradiated mice. Old and young stem cell lines competed equally well with chromosomally marked marrow stem cells from a young donor in producing cell types that are stimulated by bleeding; old cells competed 70% as well as young in producing cell types stimulated by phytohemagglutinin (PHA) in vitro. After a single serial transplantation, the rates of colony growth declined 1.5- to 2.5-fold, and the ability to compete declined 2- to 4-fold for bleeding-stimulated and 4- to 10-fold for PHA-stimulated cells. Thus, immediate stem cell proliferative capacities decline much more after one serial transplantation than after a lifetime of normal function.

Bone marrow origin of hepatic macrophages (Kupffer cells) in humans.

Abstract: Hepatic macrophages (Kupffer cells) from two male recipients of bone marrow transplants from females were studied for fluorescent Y body staining and sex chromatin (Barr body). After the transplant, macrophages had the sex karyotype of the donor, indicating that human hepatic macrophages originate in bone marrow.

Cell kinetics and chemotherapy: a critical review.

Abstract: The paper reviews methods of studying cell kinetics in man, cell population kinetics of human tumors and bone marrow, drug interactions and the cell cycle, and possible applications to chemotherapy. The conclusions drawn are: (1) Cell cycle time and S-phase duration for proliferating granulocyte precursors in human bone marrow are poorly defined but are probably shorter than median values for most human tumors, including leukemia. (2) Most drugs have greater toxicity for cycling cells and some variation in toxicity at different phases of the cell cycle. There is a special need for chemotherapy directed at slowly proliferating and hypoxic tumor cells. (3) Pretreatment indices of tumor cell kinetics are of little value in choosing drugs or in predicting response. (4) Experiments in animals have demonstrated that therapeutic index may depend on schedule. Knowledge of cell kinetics in animals rarely allows prediction of the optimal schedule and is unlikely to do so in man. Optimal schedules in mice are not directly relevant to man. (5) Measurement of tumor labeling index or DNA histogram by flow microfluorimetry to detect cell synchrony is of little benefit in scheduling if concurrent changes in bone marrow are ignored; these methods are invalid at short intervals after treatment because surviving clonogenic cells are indistinguishable from a larger number of drug-damaged cells prior to their lysis. (6) The major factor determining the outcome of chemotherapy is the availability of drugs with activity for the tumor and acceptable host toxicity. Claims that complex schedules using several drugs are effective because of synchrony or kinetic differences of tumor and normal tissue are at present unsubstantiated.

B Lymphocyte Precursors in Human Bone Marrow: An Analysis of Normal Individuals and Patients with Antibody-Deficiency States

Abstract: Lymphoid cells containing cytoplasmic IgM but lacking stable surface IgM are believed to be the direct precursors of B lymphocytes. We have characterized these pre-B cells in the bone marrow of normal individuals and patients with a variety of immunoglobulin deficiencies or hematologic disorders by using immunofluorescence and autoradiography. Pre-B cells comprised 5.8 +/- 5.7% of lymphoid cells in normal bone marrow. Eleven patients with infantile X-linked agammaglobulinemia (X-LA) lacked B lymphocytes but had a normal frequency (3.8 +/- 3.6%) of bone marrow pre-B cells. A smaller proportion of marrow pre-B cells from patients with X-LA were engaged in spontaneous DNA synthesis than was found for normal controls. In individuals other than the group with X-LA, the number of circulating B cells was positively correlated with the frequency of marrow pre-B cells. These results indicate that patients with X-LA have a defect in maturation of pre-B cells, and suggest that some patients with acquired B lymphocyte deficiency may have lost the capacity to generate pre-B cells from stem cells.

Hemopoietic stem cell transplantation using mouse bone marrow and spleen cells fractionated by lectins.

Abstract: Mouse bone marrow and spleen cells were fractionated with the aid of soybean agglutinin and peanut agglutinin. A test for spleen colony-forming units in the isolated fractions showed that the hemopoietic stem cells are agglutinated by both of these lectins. The capacity of the agglutinated fractions to reconstitute lethally irradiated allogeneic mice was investigated. A sequential fractionation of splenocytes from SWR donors by soybean agglutinin and peanut agglutinin, or a single fractionation by soybean agglutinin of splenocytes from BALB/c donors, afforded a cell fraction that successfully reconstituted lethally irradiated (BALB/c X C57BL/6)F1 mice, without complications due to graft-versus-host reaction.

Transplantation tolerance in adult rats using total lymphoid irradiation: permanent survival of skin, heart, and marrow allografts.

Abstract: Lewis rats given total lymphoid irradiation (TLI) accepted bone marrow allografts from AgB-incompatible donors. The chimeras showed no clinical signs of graft-versus-host disease. Skin allografts from the marrow donor strain survived for more than 150 days on the chimeras. However, third-party skin grafts were rejected promptly. Although heart allografts survived more than 300 days in Lewis recipients given TLI and bone marrow allografts, detectable levels of chimerism were not required for permanent survival.

Transplantation of allogeneic bone marrow without graft-versus-host disease using total lymphoid irradiation.

Abstract: Bone marrow (BM) and skin allografts from C57BL/Ka (H-2b/b) mice were transplanted to BALB/c (H-2d/d) recipients treated with total lymphoid irradiation (TLI), whole-body irradiation (WBI), or fractionated thymic irradiation TLI prolonged skin allograft survival about five times as long as that in untreated controls, and allowed for permanent engraftment of BM cells in approximately equal to 90% of recipients. None of the BM recipients showed clinical signs of graft-versus-host disease (GVHD) (diarrhea, weight loss, hunched back, etc.). On the other hand, recipients given WBI and allogeneic BM cells developed severe clinical GVHD. The majority of the latter recipients died within 12 days after BM transplantation, and 95% died within 61 days. Although TLI protected BALB/c mice against GVHD induced by BM cells, all recipients given TLI and allogeneic spleen cells developed lethal GVHD. Thymic irradiation alone marginally prolonged skin allograft survival, and did not allow for allogeneic BM engraftment. These results suggest that TLI may be a useful regimen in clinical BM transplantation, since this form of radiotherapy is used extensively in humans and has few severe side effects.

Erythroid Precursors in Congenital Hypoplastic (Diamond-Blackfan) Anemia

Abstract: To explore the etiology of congenital hypoplastic anemia (CHA) or the Diamond-Blackfan anemia, erythropoietin responsive committed erythroid precursors were enumerated by the plasma clot method. These included blood and marrow erythroid burst-forming units (BFU-E) and marrow erythroid colony-forming units (CFU-E). The peripheral blood nucleated cells of 11 patients and the marrow cells of seven of these patients were examined. Studies were repeated in several patients during relapse and after induction of remission. BFU-E were undetectable in the marrow and blood of all but one relapsed patient, and the numbers of marrow CFU-E were depressed in all relapsed patients. Blood BFU-E remained low in all of the patients in remission. No evidence was obtained for suppression of normal CFU-E or BFU-E by CHA lymphocytes. Erythropoietin dose-response curves performed in two patients revealed a 10-fold increase in erythropoietin requirement for marrow CFU-E colony growth. This marked unresponsiveness to erythropoietin was strikingly improved by steroid therapy in one patient. We suggest that CHA is the result of a qualitative and/or quantitative deficiency of BFU-E. If BFU-E are produced, they must be relatively unresponsive to erythropoietin. The abnormal BFU-E give rise to erythropoietin unresponsive CFU-E and, thence, to proerythroblasts that are, in turn, trapped in that early stage of development because of their poor erythropoietic response. Hence, red cell production is deficient. Steroids appear to improve the erythropoietin response of CHA erythroid precursors.

Proliferative capacity of murine hematopoietic stem cells.

Abstract: The present study demonstrates a decrease in self-renewal capacity with serial transfer of murine hematopoietic stem cells. Production of differentiated cell progeny is maintained longer than stem cell self-renewal. In normal animals the capacity for self-renewal is not decreased with increasing donor age. The stem cell compartment in normal animals, both young and old, appears to be proliferative quiescent. After apparent recovery from the alkylating agent busulfan, the probability of stem cell self-renewal is decreased, there is a permanent defect in the capacity of the bone marrow for serial transplantation, and the stem cells are proliferatively active. These findings support a model of the hematopoietic stem cell compartment as a continuum of cells with decreasing capacities for self-renewal, increasing likelihood for differentiation, and increasing proliferative activity. Cell progress in the continuum in one direction and such progression is not reversible.

Suppression of Natural Killer Cell Cytotoxicity by Splenocytes from Corynebacterium Parvum-Injected, Bone Marrow-Tolerant, and Infant Mice

Abstract: Natural killer (NK) cell cytotoxicity to YAC-1 lymphoma was investigated in mice tolerant to bone marrow grafts (BM-tolerant), Corynebacterium parvum- (C parvum) treated mice, and infant mice Also the comparison was made between the NK cells and the hemopoietic-resistance effector (HR-E) cells It was found that the BM-tolerant mice and C parvum -treated mice showed either no or markedly decreased NK cell cytotoxicity These mice were also nonresponders to bone marrow grafts in vivo The lack of or decreased reactivity was apparently caused by the regulatory cell activities of the suppressor cell since the splenocytes from C parvum -treated and BM-tolerant mice suppressed significantly the cytotoxic activities of otherwise fully functional NK cells Similar suppressive effect on NK cells was mounted by splenocytes from infant mice, indicating again the suppressor cell regulation of NK cell cytotoxicity

Mouse Natural Killer Cells: Induction Specificity, and Function

Abstract: Attention has recently focused on the possible significance of natural killer (NK)[2][1] lymphocytes in the surveillance of tumors by the immune system (1). This is because NK cells from several species preferentially lyse transformed target cells in vitro (2–5). NK lymphocytes from mouse and man have both been studied in detail, but the manipulability of the mouse model has allowed for the better resolution of NK cell properties. In this review I will restrict most of my comments to the mouse NK cell system. The properties of human NK cells have recently been reviewed elsewhere (6). Characterization and tissue distribution . It is agreed that mouse NK cells are x-ray-resistant (7) lymphocytes lacking cell surface immunoglobulin (8, 9). They are thought to be derived from bone marrow since their activity is removed by depletion of bone marrow cells with anti-bone marrow antibody or with 89Strontium (7, 10). [1]: #fn-2

Deposition of IgM and Complement at the Dermoepidermal Junction in Acute and Chronic Cutaneous Graft-Vs-Host Disease in Man

Abstract: The presence of cutaneous immunoglobulin and complement was investigated in 88 patients with and without graft- vs -host disease (GVHD) after transplantation of bone marrow from HLA identical siblings for the treatment of acute leukemia or aplastic anemia. For comparison, skin biopsies from the patients obtained before transplantation, from 58 healthy individuals (mostly marrow donors) and from four syngeneic marrow recipients were studied. A direct immunofluorescent staining technique was used. Dermo-epidermal IgM deposits were found in 11% of healthy individuals and patients before grafting but were present in 86% of patients with chronic and 39% of patients with acute GVHD. Patients with allogeneic grafts who never had GVHD or who had recovered from it and patients with syngeneic grafts showed findings not different from those in healthy individuals. Findings similar to those with IgM, although less striking, were made for C3, i.e., patients who had chronic or acute GVHD had a high incidence and intensity of C3 deposits at the dermo-epidermal junction. This observation raises the possibility that humoral immunity is involved in the development of GVHD.

Monocytes and Macrophages: Functions and Diseases

Abstract: The mononuclear phagocyte complex is a widespread system of cells originating in the bone marrow monoblast and promonocyte, passing through the intermediate monocyte stage in the blood, and culminating in the tissue macrophages of the lung, liver, spleen, and pleural and peritoneal spaces The cells are prominently phagocytic and have a well-developed lysosomal system They function in host defense reactions against micro-organisms, in interactions with lymphoid cells in immunity, in disposal of cell debris, and possible in the regulation of granulopoiesis Monocytes and the alveolar macrophage are the most accessible cells of this system for study Several diseases of mononuclear phagocytes have been identified and characterized These include microbicidal defects associated with increased susceptibility to infection, enzyme defects leading to storage diseases, and neoplastic diseases in which both cell proliferation and biologically active cell products contribute to the clinical disorder

Drug-induced agranulocytosis.

Abstract: An unexpected precipitous fall in peripheral leucocyte count may occur during treatment of certain sensitised individuals with drugs usually well tolerated by most people. Three basic mechanisms for drug sensitivity have been found. One is characterised by sudden destruction of large numbers of leucocytes in peripheral blood by antibodies elicited in response to drug sensitivity. A prototype for this type of reaction is aminopyrine. A second mechanism involves the production of a lupus-like syndrome followed by leucopenia in response to sensitisation to drugs such as procainamide. A third type involves development of agranulocytosis following a latent period during which a sensitive patient is treated with large amounts of chlorpromazine. This type of reaction is associated with production of bone marrow insufficiency in a patient who is believed to have a limited proliferative potential of bone marrow cells, which limit compensatory bone marrow response during treatment with a drug (e.g. chlorpromazine) that has limited bone marrow toxicity.

Theophylline modulation of E-rosette formation: an indicator of T-cell maturation.

Abstract: The binding of unsensitized sheep erythrocytes is a characteristic of human thymus dependent T-lymphocytes. We have investigated the effect of theophylline on E-rosette formation using cells from normal individuals, and patients with immunodeficiency or acute lymphoblastic leukaemia, and have attempted to correlate the influence of the drug on distinct T-lymphocyte subpopulations. Three subpopulations of E-rosetting T-lymphocytes can be delineated: theophylline-sensitive T-cells which lose the capacity to form E-rosettes following treatment; theophylline-resistant T-cells which are unaffected by the drug; and theophylline-dependent cells which acquire the ability to form E-rosettes following incubation with theophylline. The action of theophylline was shown to be dose-dependent, temperature-dependent and reversible. Reversibility or re-expression of the receptor for sheep red cells could be blocked by the addition of puromycin. In peripheral blood, E-rosetting T-lymphocytes were roughly divided into two equal populations, one sensitive, the other resistant. Thymocytes were shown to be entirely theophylline-resistant, whereas a small population of cells in peripheral blood and bone marrow were induced to become E-rosetting in the presence of theophylline. Induction by theophylline may be effective at a distinct stage of precursor T-cell differentiation.

Parasinusoidal location of megakaryocytes in marrow: a determinant of platelet release.

Abstract: Megakaryocytopoiesis occurs in the hematopoietic (extravascular) compartment of marrow. Thus, platelets must traverse the wall of the vascular sinuses of marrow to enter the circulation. We have examined mouse and rat marrow, fixed by rapid immersion so as to maintain anatomical relationships as close to the natural state as possible. Quantitative transmission electron microscopy (TEM) of random transections of femurs established that megakaryocytes reside less than 1 mu from a marrow sinus wall with a probability unlikely to be the result of chance (P less than 0.001). An intimate relationship exists between the megakaryocyte periphery and the abluminal surface of the endothelial lining cell. At the time of platelet release megakaryocyte cytoplasm invaginates and penetrates the endothelial lining cell. The penetrating cytoplasm is detached and enters the marrow circulation. From their dimensions in comparison to circulating platelets, the released cytoplasm represents a packet of platelets that undergoes further fragmentation in the circulation. The parasinusoidal location of megakaryocytes and the process of sinus-wall penetration and platelet delivery was observed by TEM and scanning electron microscopy. These studies provided quantitative support for a specific anatomical arrangement of megakaryocytes in marrow. Moreover, the process of platelet release appears to be a physiological form of metastasis with invasion of vascular walls and vascular spread of cells, that are in this case amitotic.