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Biomedical subjects

W Wiktor-Jedrzejczak

Publications and source records attributed to W Wiktor-Jedrzejczak.

At least 19 recordsLinked to original sources
PubMed1992

Distinct in vivo functions of two macrophage subpopulations as evidenced by studies using macrophage-deficient op/op mouse.

The op/op mice totally lack macrophage growth factor colony-stimulating factor (CSF)-1 and thus, by definition are completely depleted of CSF-1-dependent functions of the macrophage cell lineage. Moreover, they possess a severe and generalized macrophage deficiency. However, residual macrophages of these mice should still have normal CSF-1-independent functions. Studies designed to elucidate this issue have revealed that op/op mice are capable of normal in vivo phagocytic function and demonstrate normal humoral and cellular response postimmunization with sheep red blood cells. However, release of monokines such as tumor necrosis factor and granulocyte CSF following administration of endotoxin is severely impaired in op/op mice as compared with littermate controls. These studies suggest that the CSF-1-dependent macrophage population (absent in the op/op mouse) is primarily responsible for regulatory functions of these cells mediated by monokines, while the CSF-1-independent macrophage population (present in the op/op mouse) is primarily responsible for the classical macrophage functions in immunity such as phagocytosis, antigen processing and presentation.

Animals↗
PubMed1992

Administration of colony stimulating factor-1 corrects some macrophage, dental, and skeletal defects in an osteopetrotic mutation (toothless, tl) in the rat.

The toothless (tl/tl) mutation in the rat results in a paucity of osteoclasts and osteopetrosis that cannot be corrected by bone marrow transplantation. In the present study we demonstrate that tl/tl rats also have profound deficiencies of femoral, peritoneal, and pleural cavity macrophages. Furthermore, the macrophage colony stimulating activity of post-endotoxin sera from tl/tl rats is substantially reduced, suggesting that, as in the case of the op mutation in mice, the basis of the tl mutation is a deficiency of the macrophage growth factor, colony stimulating factor-1 (CSF-1). Consistent with this suggestion, treatment of tl/tl rats from birth for up to six weeks with CSF-1 reduced the osteopetrosis, increased body weight, and permitted tooth eruption. In addition, CSF-1 treatment induced large numbers of osteoclasts in tl/tl bones and macrophages in the peritoneal cavity and bone marrow. Persistence of metaphyseal sclerosis, however, indicated that the disease was not totally corrected by this treatment. These studies indicate that the basis of the tl mutation is most likely another CSF-1 deficiency, and further emphasize the role of this growth factor in osteoclast differentiation.

Animals↗
PubMed1992

CSF-1 deficiency in the op/op mouse has differential effects on macrophage populations and differentiation stages.

Osteopetrosis and the absence of colony-stimulating factor 1 (CSF-1) in op/op mice are associated with decreased cellularity of the bone marrow (to one tenth of the normal), a very significant reduction in the number of cells recovered from peritoneal, pleural, and alveolar lavages, moderate leukopenia, and a slight decrease in the number of cells per spleen and thymus. Furthermore, op/op mice possess deficiencies in the number of macrophages in various organs. These cells are apparently absent in the bone marrow, severely reduced (5%-15% of the normal number) in peritoneal and pleural cavities and in the lungs. In addition, a marked decrease in the frequency and total number of circulating monocytes is present (5% of the normal). The deficiency of macrophages is less severe in the liver, spleen, and thymus of op/op mice (approximately 30% of those seen in normal). There is a concomitant redistribution of macrophage progenitor cells (granulocyte-macrophage colony-forming units, CFU-GM) in op/op mice from the marrow to the spleen and liver, associated with an increased sensitivity to interleukin 3 (IL-3). Their total number is decreased at least threefold compared to control mice. Moreover, op/op mice have at least a fivefold reduction in the total number of day-11 spleen colony-forming units (CFU-S) associated with their redistribution to the spleen and liver. These data suggest that the macrophage system in op/op mice is reduced at all levels tested, that is, at the level of mature macrophages, the level of progenitors, and the level of stem cells, whereas the redistribution of progenitor and stem cells could be viewed as a secondary consequence of osteopetrosis. Furthermore, these data suggest that macrophage dependency in vivo on CSF-1 is limited and different in various organs. Particularly in the liver, spleen, and thymus, other growth factors may significantly compensate for CSF-1 deficiency. Based on the relative decrease in the number of CFU-GM in the op/op mice, it appears that the population size of these progenitors is less dependent on CSF-1 than the hematopoietic stem cell population size as evidenced by the day-11 CFU-S assay. The day-11 CFU-S population is severely reduced in op/op mice, suggesting a physiological involvement of CSF-1 in expanding its size. These data provide evidence that CSF-1, besides acting on the final and intermediate stages of macrophage maturation, may also play a role in early stages of hematopoiesis.

Animals↗
PubMed1991

A pregnancy defect in the osteopetrotic (op/op) mouse demonstrates the requirement for CSF-1 in female fertility.

Correlative evidence suggests that maternal production of the mononuclear phagocyte growth factor colony stimulating factor-1 (CSF-1) regulates placental development. In order to study the role of CSF-1 in pregnancy the fertility of CSF-1-less osteopetrotic (op/op) mutant mice was investigated. Homozygous mutant crosses (op/op x op/op) were consistently infertile. As expected, op/op males were almost completely fertile when crossed with heterozygous females. Surprisingly, op/op females when mated to heterozygote males were fertile, although at a rate that was 46% of the rate for +/op females x op/op males. These data suggest that CSF-1 is required for pregnancy. However, a maternal CSF-1 source is not absolutely necessary in that pregnancies involving +/op fathers were partially rescued, suggesting that +/op fetuses and/or +/op seminal fluid provides CSF-1 or CSF-1-induced factors which compensate for the absence of maternally produced CSF-1. Despite the complete absence of CSF-1 in the uterus and placenta of op/op mice placental weights were normal, suggesting that proliferation of decidual cells and trophoblasts, both of which express the CSF-1 receptor, may not be solely regulated by CSF-1. Histochemical staining for F4/80 antigen was used to identify macrophages in the uterus and placenta. Uterine macrophages could not be detected in virgin op/op mice although they were abundant in +/op uteri. Interestingly, macrophages could be detected in op/op uteri as uncharacteristically rounded cells in early gestation, however, they were not maintained and no macrophages were apparent beyond Day 14 of pregnancy in op/op mice. Further studies in the osteopetrotic mouse will be useful in delineating those functions required for pregnancy that are regulated by CSF-1.

Animals↗
PubMed1991

Correction by CSF-1 of defects in the osteopetrotic op/op mouse suggests local, developmental, and humoral requirements for this growth factor.

Mice that are mutant at the op locus have a severe deficiency of mononuclear phagocytes due to an inactivating mutation in the CSF-1 (macrophage colony-stimulating factor, M-CSF) gene. op/op mice are toothless, possessing skeletal abnormalities, a low body weight, and compromised fertility; they are osteopetrotic due to a deficiency of osteoclasts. The congenital osteopetrosis, toothless phenotype, osteoclast deficit, and the defects in splenic and femoral macrophages were corrected by routes of administration of human recombinant CSF-1 that maintained normal circulating CSF-1 concentrations. Early restoration of circulating CSF-1 was required for rescue of the toothless phenotype, but only partially restored body weight. In contrast, the deficiencies of pleural and peritoneal cavity macrophages and the reduced female fertility were not corrected by restoration of circulating CSF-1. These results suggest that although circulating CSF-1 is required for osteoclast and macrophage production, local synthesis and action of the growth factor are important for certain target cell populations.

Animals↗
PubMed1990

Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse.

Osteopetrotic (op/op) mutant mice suffer from congenital osteopetrosis due to a severe deficiency of osteoclasts. Furthermore, the total number of mononuclear phagocytes is extremely low in affected mice. Serum, 11 tissues, and different cell and organ conditioned media from op/op mice were shown to be devoid of biologically active colony-stimulating factor 1 (CSF-1), whereas all of these preparations from littermate control +/+ and +/op mice contained the growth factor. The deficiency was specific for CSF-1 in that serum or conditioned media from op/op mice possessed elevated levels of at least three other macrophage growth factors. Partial correction of the op/op defect was observed following intraperitoneal implantation of diffusion chambers containing L929 cells, which in culture produce CSF-1 as their sole macrophage growth factor. No rearrangement of the CSF-1 gene in op/op mice was detected by Southern analysis. However, in contrast to control lung fibroblasts, which contained 4.6- and 2.3-kilobase CSF-1 mRNAs, only the 4.6-kilobase species was detected in op/op cells. An alteration in the CSF-1 gene is strongly implicated as the primary defect in op/op mice because they do not contain detectable CSF-1, their defect is correctable by administration of CSF-1, the op locus and the CSF-1 gene map within the same region of mouse chromosome 3, their CSF-1 mRNA biosynthesis is altered, and the op/op phenotype is consistent with the phenotype expected in a CSF-1 deficient mouse.

Animals↗
PubMed1990

Serum megakaryocytopoietic activity after allogeneic bone marrow transplantation (BMT).

Platelet recovery after allogeneic bone marrow transplantation for treatment of different haematologic disorders was monitored by ability of sera from BMT recipients to support the clonal growth of normal megakaryocyte progenitors. The resultant megakaryocyte colonies were expressed as a Serum Factor Index-Megakaryocyte (SFI-Mk). In two patients with whole and in one with partial haematological reconstitution SFI-Mk was normal, and in others SFI-Mk value was increased. Our results indicate that sera from BMT recipients contain megakaryocytopoietic activity which inversely correlate with recovery of megakarycytic lineage following bone marrow transplantation.

Adolescent↗
PubMed1989

Interferon-gamma-treated K562 target cells distinguish functional NK cells from lymphokine-activated killer (LAK) cells.

In vitro incubation of the erythroleukemic cell line K562 with interferon-gamma (IFN-gamma) renders these cells relatively resistant to natural killer (NK) cell lysis. However, such treatment does not alter their sensitivity to LAK cell lysis. Thus, the lytic susceptibility of interferon-gamma-treated K562 (I-K562) cells to LAK cells as opposed to its relative resistance to NK cell lysis provides a functional assay to help distinguish these two types of effector cells. The relative resistance of I-K562 for NK cell-mediated lysis was not secondary to the release of soluble factors or the frequency of Leu-19+, CD3+ T cells, residual IFN-gamma, or expression of MHC Class I molecules. Coincubation of I-K562 cells with NK or LAK cells overnight did not appreciably change the pattern of lytic responses against K562 and I-K562 target cells. However, incubation of PBMC in vitro with I-K562 but not native K562 in the presence of r-IL-2 leads to a marked decrease in the generation of LAK cells. The inhibition of LAK cell generation was not secondary to differences in the consumption of bioactive levels of IL-2. Differences in the lytic capability of NK and LAK effector cells suggest heterogeneity among cells that mediate such non-MHC-restricted lysis. Use was made of cells from a patient with a large granular lymphocyte lymphoproliferative disease (greater than 85% Leu-19+) to determine if such cells could be used to distinguish clonal population of cells which would represent NK or LAK cell function. Of interest was the finding that such cells, even after incubation in vitro with IL-2, showed lytic function representative of NK cells but not LAK cells. Data concerning the inhibition of LAK cell generation by I-K562 cells have important implications for future therapeutic trials of IFN-gamma and IL-2 in the treatment of human malignancies.

Antigens, Differentiation↗
PubMed1989

Allogeneic bone marrow transplantation from HLA-identical siblings following conditioning with busulfan and cyclophosphamide. First results.

In the time period from November 1984 to January 1987 eight allogeneic bone marrow transplantation were performed from HLA-identical siblings. The theoretical chance of success in this group was between 21 and 50%, according to the recent data of the International Bone Marrow Transplant Registry, depending on the diagnosis and clinical condition. The average chance was 37.5%. Haemopoietic reconstitution was achieved in 6 recipients, while 2 died of early complications (cytostatic induced hepatocellular damage and fungal sepsis). Another 3 patients died of complications of the intermediate period (pulmonary bleeding, virus hepatitis, graft rejection). The remaining 3 recipients are alive, in excellent clinical condition, including one girl surviving more than 2 years after the transplantation.

Adolescent↗
PubMed1989

Prospects for the future of bone marrow transplantation from the experimental studies on cells and animals.

Despite accumulated extensive clinical experience bone marrow transplantation (BMT) remains a largely experimental procedure with high risk and numerous limitations. Part of the progress has to come from improvements in clinical care, but still as in former years there is a need of implementation of results of experiments on cells and animals. In the area of better engineering of posttransplant haemopoietic and immune cell production, this include variable pretransplant modifications of composition of inoculated cells as well as utilization of new drugs and growth factors. In the area of BM donor selection this includes identification of minor histocompatibility antigens. In the area of applications except for being a replacement therapy of haematologic disorders BMT may be considered as an adjunct therapy for transplantation of various organs. Finally, combination of cellular engineering of BM inoculum with genetic modifications of cells may offer therapy for some patients.

Animals↗
PubMed1989

Elimination of red blood cells from marrow suspension prior to transplantation using polysaccharide-ditrizoate gradient centrifugation. Experimental studies.

In a search of alternative techniques of red cell depletion from the marrow prior AB0 incompatible transplantation we got interested in Böyum technique of polysaccharide-ditrizoate gradient centrifugation for isolation of mononuclear cells. This method might be used for the purpose of red cell depletion only if it preserves haemopoiesis reconstituting stem cells. Whether this is the case was tested using murine model of lethally irradiated donors. Polysaccharide-ditrizoate gradient isolated mononuclear cells contained 100% spleen colony forming stem cells and possessed the same bone marrow and spleen reconstitutive potential as non-manipulated marrow cells. Therefore, this method may be considered for potential clinical application.

Animals↗
PubMed1989

Bone marrow transplantation in Polish conditions. Method for removal of red cells from the transplant in the case of major blood group incompatibility.

A modified polysaccharide-ditrizoate gradient centrifugation method is described. One hundred ml aliquots of marrow mixed 1:1 with medium is layered on 70 ml of polysaccharide-ditrizoate solution of specific density 1.077 in 5 x 19 cm flasks and centrifuged at 400 x g for 20 minutes at 20 degrees C. Interphase cells are collected and used for the transplant. The procedure is closed which reduces the danger of contamination, simple and takes between 2 and 3 hours. Two allogeneic HLA-identical transplants were performed using this technique and both resulted in full hematopoietic reconstitution and long term survival.

Blood Group Incompatibility↗
PubMed1988

Postirradiation recovery of haemopoiesis in Steel mutant mice.

The recovery of haemopoiesis in Steel mutant mice following 1 Gy sublethal irradiation is described. Steel homozygotes (S1/S1) did not display the abortive phase of erythropoietic recovery while the secondary phase of erythropoietic recovery was more pronounced in S1/S1 than in control (+/+) animals. On the contrary, the neutrophilopoietic recovery in S1/S1 mice was defective only during the secondary phase of recovery. Steel heterozygotes (S1/+) manifested similar, albeit less pronounced, defects. In the course of studies of recovery of eosioniphils it was observed that neither wild-type nor mutant animals expressed the abortive rise. Moreover, the kinetics of recovery of eosinophils was essentially different from both erythropoietic and neutrophilopoietic recovery, and the preirradiation level was reached in both normal and mutant animals on day 60 postirradiation as opposed to 24 and 35 days for erythropoiesis and neutrophils respectively.

Animals↗
PubMed1987

Hematological compensation of microphthalmic mice with congenital osteopetrosis.

Microphthalmic mice possess less than 10% of marrow cells. This marrow deficiency is compensated by an increase in the number of spleen cells. Additionally, 2-week-old mi/mi mice have increased frequency of hemopoietic stem cells in the spleen and remaining marrow. In addition they have persistent stem cells in the liver. No other major hematologic abnormalities were found.

Animals↗