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J L Abkowitz

Publications and source records attributed to J L Abkowitz.

At least 55 records · Page 3Linked to original sources
PubMed1990

Evidence for the maintenance of hematopoiesis in a large animal by the sequential activation of stem-cell clones.

To test if hematopoiesis can be maintained by the sequential activation of stem-cell clones, we performed autologous marrow transplantations with limited numbers of cells in cats heterozygous for the X chromosome-linked enzyme glucose-6-phosphate dehydrogenase (G6PD) and observed the G6PD phenotypes of erythroid and granulocyte/macrophage progenitors over time. The animals were the female offspring of Geoffroy male and domestic female cats. In repeated studies of marrow from control animals (n = 5) or experimental animals prior to transplantation (n = 3), the percent of progenitors with domestic-type G6PD did not vary. After transplantation, the peripheral blood counts, marrow morphologies, frequencies of progenitors, and progenitor cell cycle kinetics returned to normal. However, abrupt and significant fluctuations were seen in the G6PD type of progenitors from each cat during the 1-1.5 years of observation. These data cannot be explained if there were either a large or constant population of active stem cells and thus imply, in a large-animal system, that hematopoiesis was maintained through clonal succession. A stochastic model was developed to estimate the numbers of active clones and their mean lifetimes.

Animals↗
PubMed1990

A stochastic model for haematopoiesis in cats.

Haematopoiesis is the process by which progenitor cells differentiate into competent mature blood cells. Only those cells in the latter stages of haematopoiesis can be observed in vitro, so theories about the early stages of the process cannot be tested directly. Experimental data of bone marrow samples from Safari cats provides evidence for the clonal succession hypothesis of early haematopoiesis. In this paper, a hidden Markov model is constructed to quantify this support. Recursive updating techniques are derived and are used to calculate the likelihood and to construct fitted values for the model. Inference is based on multimodal likelihood surfaces.

Animals↗
PubMed1989

Feline lymphomas: immunological and cytochemical characterization.

The immunological and cytochemical phenotypes of five primary feline lymphomas and six feline lymphoma lines are reported. Thymic lymphomas induced by the Rickard strain of FeLV (FeLV-R) are of prothymocyte or (immature) cortical thymocyte origin, as these express terminal deoxynucleotidyl transferase, the guinea pig erythrocyte rosette receptor, Ia antigens, partial cortisone sensitivity, and nonspecific esterase. Lymphomas associated with other strains of FeLV form rosettes with guinea pig erythrocytes, frequently have Ia antigens and cytoplasmic nonspecific esterase, and probably originate from helper T-cells, monocyte/macrophages, or null cells. These data belie previous conclusions that FeLV leukemogenesis is restricted to mature T-cells; rather, the considerable heterogeneity in the surface and cytochemical phenotype of feline lymphomas probably reflects transformation of multipotent lymphoid or monocytoid precursors in the bone marrow by FeLV.

Animals↗
PubMed1989

Chronic leukopenia associated with feline immunodeficiency virus infection in a cat.

Leukopenia attributable to lymphopenia and neutropenia was detected over a 28-week period in a 12-year-old domestic cat infected with feline immunodeficiency virus (FIV). Mild normocytic, normochronic anemia also was evident. Platelet counts were normal, and serum biochemical values were unremarkable. Antibodies to FIV were detected in serum by use of immunofluorescence and immunoblot electrophoresis assays. Cytologic evaluation of bone marrow aspirates revealed normal cellular morphologic features, maturation, and myeloid-to-erythroid ratio. Normal marrow cellularity was determined histologically. There was, however, a significant (P less than 0.01) inhibition of colony-forming unit granulocyte/macrophage-derived progenitors when marrow cells were cultured in the presence of autologous serum, compared with that when marrow cells were cultured in the presence of serum obtained from clinically normal cats, thus suggesting the presence of a humoral inhibitory substance directed specifically at the granulocyte/macrophage lineage. These cell culture results were consistent with those reported for human beings with acquired immunodeficiency syndrome and neutropenia. Thus, FIV infection may be an excellent animal model in which to study human immunodeficiency virus and should be considered in the differential diagnosis of cats with chronic leukopenia.

Animals↗
PubMed1988

Cyclic hematopoiesis in dogs: studies of erythroid burst-forming cells confirm an early stem cell defect.

Studies of early erythropoiesis in dogs have been hampered by the lack of an efficient assay for canine erythroid burst-forming cells (BFU-E). We have developed a methyl-cellulose culture system for hematopoietic progenitors in dog marrow with a plating efficiency for BFU-E of 98 +/- 26 (SD) per 10(5) marrow mononuclear cells. We then applied this assay to the study of cyclic hematopoiesis in grey collie dogs, and regular fluctuations of colonies derived from erythroid colony-forming cells (CFU-E), BFU-E, and granulocyte-macrophage colony-forming cells (CFU-GM) were seen at 12- to 13-day intervals. Defining Cycle Day 1 as the first day that the granulocyte count falls below 1000/mm3, we found that the peak frequency of BFU-E (Cycle Day 10) always preceded the peak frequency of CFU-E (Cycle Day 12), which preceded that of the reticulocyte count (Cycle Day 3). The peak frequency of CFU-GM (Cycle Days 9-2) and neutrophil-containing colonies in agar culture (Cycle Days 1-2) preceded the peak of granulocytes (Cycle Day 6). The percentage of the various progenitors in the DNA synthetic phase of the cell cycle was similar in grey collies and normal dogs and showed no cyclic fluctuations. These data indicate that cyclic hematopoiesis results from a defect in a hematopoietic stem cell more primitive than BFU-E and CFU-GM. Cycling appears to be due to the commitment of this primitive cell to differentiation only at discrete intervals. The cell cycle kinetics and differentiation of subsequent cells appear normal.

Animals↗
PubMed1988

Clonal evolution following chemotherapy-induced stem cell depletion in cats heterozygous for glucose-6-phosphate dehydrogenase.

The number of hematopoietic stem cells necessary to support normal hematopoiesis is not known but may be small. If so, the depletion or damage of such cells could result in apparent clonal dominance. To test this hypothesis, dimethylbusulfan [2 to 4 mg/kg intravenously (IV) x 3] was given to cats heterozygous for the X-linked enzyme glucose-6-phosphate dehydrogenase (G-6-PD). These cats were the daughters of domestic X Geoffroy parents. After the initial drug-induced cytopenias (2 to 4 weeks), peripheral blood counts and the numbers of marrow progenitors detected in culture remained normal, although the percentages of erythroid burst-forming cells (BFU-E) and granulocyte/macrophage colony-forming cells (CFU-GM) in DNA synthesis increased, as determined by the tritiated thymidine suicide technique. In three of six cats treated, a dominance of Geoffroy-type G-6-PD emerged among the progenitor cells, granulocytes, and RBCs. These skewed ratios of domestic to Geoffroy-type G-6-PD have persisted greater than 3 years. No changes in cell cycle kinetics or G-6-PD phenotypes were noted in similar studies in six control cats. These data suggest that clonal evolution may reflect the depletion or damage of normal stem cells and not only the preferential growth and dominance of neoplastic cells.

Animals↗
PubMed1987

Retrovirus-induced feline pure red cell aplasia: the kinetics of erythroid marrow failure.

Cats viremic with feline leukemia virus subgroup C (FeLV-C) develop pure red cell aplasia (PRCA) characterized by the loss of detectable late erythroid progenitors (CFU-E) in marrow culture. Normal numbers of early erythroid progenitors (BFU-E) and granulocyte-macrophage progenitors (CFU-GM) remain, suggesting that the maturation of BFU-E to CFU-E is impaired in vivo. We have examined the cell cycle kinetics of BFU-E and their response to hematopoietic growth factor(s) to better characterize erythropoiesis as anemia develops. Within 3 weeks of FeLV-C infection, yet 6-42 weeks before anemia, the traction of BFU-E in DNA synthesis as determined by tritiated thymidine suicide increased to 43 +/- 4% (normal 23 +/- 2%) while there was no change in the cell cycle kinetics of CFU-GM. In additional studies, we evaluated the response of marrow to the hematopoietic growth factor(s) present in medium conditioned by FeLV-infected feline embryonic fibroblasts (FEA/FeLV CM). With cells from normal cats or cats viremic with FeLV-C but not anemic, a 4-fold increase in erythroid bursts was seen in cultures with 5% FEA/FeLV CM when compared to cultures without CM. However, just prior to the onset of anemia, when the numbers of detectable CFU-E decreased, BFU-E no longer responded to FEA/FeLV CM in vitro. BFU-E from anemic cats also required 10% cat or human serum for optimal in vitro growth. These altered kinetics and in vitro growth characteristics may relate to the in vivo block of BFU-E differentiation and PRCA. Finally, when marrow from cats with PRCA was placed in suspension culture for 2 to 4 days in the presence of cat serum and CM, the numbers of BFU-E increased 2- to 4-fold although no CFU-E were generated. By 4 to 7 days, CFU-E were detected, suggesting that conditions contributing to the block of erythroid maturation did not persist. The suspension culture technique provides an approach to study further the defect in erythroid differentiation characteristic of feline PRCA.

Animals↗
PubMed1987

Lymphocytes and antibody in retrovirus-induced feline pure red cell aplasia.

The possible role of antibody and T-lymphocytes was investigated in the pure red cell aplasia (PRCA) associated with feline leukemia virus, subgroup C (FeLV-C), infection. In previous studies, erythroid colony-forming cells were undetectable in marrow culture of cats with PRCA. Yet erythroid burst-forming cells (BFU-E) remained, suggesting that BFU-E were able to differentiate in vitro but not in vivo. It was inferred that immunologic suppression may contribute to the pathogenesis of feline PRCA, and the interactions of antibody and T-lymphocytes with erythroid and granulocyte-macrophage progenitors were studied. Incubation of normal or PRCA marrow cells with PRCA serum or IgG concentrated from this serum and then complement (C') failed to decrease hematopoietic colony growth when compared to the results obtained with cultures of marrow cells incubated with C' alone. In crossover coculture studies, T-cells from Safari cats with PRCA had no inhibitory effect on colony growth from normal or autologous PRCA marrow cells. For the determination of whether feline PRCAs were associated with a clonal T-cell process, lymphocytes were obtained periodically from glucose-6-phosphate dehydrogenase (Glc-6-PD) heterozygous cats following FeLV-C infection and were expanded with a crude preparation of interleukin-2. The ratios of Glc-6-PD enzyme types in these samples did not change as cats developed anemia, suggesting that the inhibition of erythropoiesis was not associated with the clonal expansion of T-cells. These studies, therefore, do not support the premise that feline PRCA results from the interaction of antibody or T-cells with erythroid progenitors.

Animals↗
PubMed1987

Retrovirus-induced feline pure red cell aplasia. Hematopoietic progenitors are infected with feline leukemia virus and erythroid burst-forming cells are uniquely sensitive to heterologous complement.

Feline leukemia virus subgroup C/Sarma (FeLV-C) induces pure red cell aplasia (PRCA) in cats. Just before the onset of anemia, erythroid colony-forming cells (CFU-E) become undetectable in marrow culture, yet normal frequencies of erythroid burst-forming cells (BFU-E)- and granulocyte-macrophage colony-forming cells (CFU-GM) persist. To determine if erythroid progenitors were uniquely infected with retrovirus, marrow mononuclear cells from cats viremic with FeLV-C were labeled with monoclonal antibodies to gp70 and then analyzed with a fluorescence-activated cell sorter. Both erythroid and granulocyte-macrophage progenitors were among cells sorting positively, suggesting that infection of BFU-E alone did not result in PRCA. The results were confirmed by complement (C') lysis studies using baby rabbit or guinea pig sera as sources of C'. These studies also suggested that BFU-E from cats with PRCA were unusually sensitive to C' alone, without the addition of antibody. In further studies, we demonstrated that C' activation was via the classical pathway and that C' sensitivity was unique to BFU-E and not a property of CFU-E, CFU-GM, or progenitors that were capable of giving rise to BFU-E in suspension culture. As BFU-E from cats viremic with FeLV-A/Glasgow-1 or the Rickard strain of feline leukemia virus were not sensitive to C', this finding may relate to the pathogenesis of feline PRCA. We hypothesize that, in cats viremic with FeLV-C, the abnormal C' sensitivity of BFU-E leads to the absence of CFU-E and anemia.

Animals↗
PubMed1986

Pure red cell aplasia: response to therapy with anti-thymocyte globulin.

Pure red cell aplasia (PRCA) results from the failure of erythrocyte differentiation and may respond to immunosuppressive therapies. We have treated nine patients with PRCA refractory to steroids and/or cyclophosphamide with anti-thymocyte globulin (ATG). Six patients had normal numbers of erythroid bursts (from erythroid burst-forming units) or erythroid colonies (from erythroid colony-forming units) detectable in vitro, and all responded to therapy with ATG. In vitro studies suggested T-cell inhibition of erythropoiesis in four of these six patients and humorally mediated erythroid suppression in one. In three individuals, virtually no erythroid progenitors were detected in marrow culture. None of these patients responded to ATG. Myelofibrosis, 5q- chromosomal abnormality, or the subsequent development of thrombocytopenia in these individuals suggested that PRCA resulted from an intrinsic stem cell disorder. Our studies demonstrate that ATG is effective therapy for PRCA, and it may be especially useful in children or other patients in whom alkylating agents are not appropriate. We also confirm that erythroid growth in marrow culture predicts those patients who will respond to ATG or other immunosuppressive therapies.

Adolescent↗
PubMed1986

Multilineage, non-species specific hematopoietic growth factor(s) elaborated by a feline fibroblast cell line: enhancement by virus infection.

In studies designed to determine the role of feline leukemia virus (FeLV) in the pathogenesis of marrow failure in the cat, we tested medium conditioned by uninfected and FeLV-infected feline embryonic fibroblasts (FEA) for its effect on hematopoietic colony growth in culture. As opposed to an inhibitory effect, we found that the conditioned medium (CM) from FEA or FEA/FeLV increased the in vitro growth of multiple hematopoietic progenitor cell types including erythroid burst-forming cells (BFU-E), granulocyte/macrophage colony-forming cells, megakaryocytic colony-forming cells, and mixed-cell colony-forming cells. Furthermore, CM enhanced the growth of progenitors in cultures of mouse or human marrow cells, as well as cat marrow cells. Stimulation of feline BFU-E was most marked with an increment in growth of 400% over control. The human burst promoting activity (BPA) of the CM was equivalent or better than other CM available in our laboratory. The evidence suggest that the growth-promoting activity is a constitutive product(s) released by FEA which was enhanced eightfold with virus infection. Studies with non-adherent and T-lymphocyte-depleted human marrow cells and human peripheral blood cells suggest that the growth factor(s) acts directly on progenitor cells and not through readily identified accessory cells. These findings are consistent with the concept that mesenchymal cells such as fibroblasts have the capacity to release hematopoietic growth factor(s) capable of acting on primitive hematopoietic progenitors. The results provide an example of how injury of such cells, through virus infection, may enhance growth factor(s) release and influence the hematopoietic microenvironment.

Animals↗
PubMed1986

Agreement between laboratory tests and self-reports of alcohol, tobacco, caffeine, marijuana and other drug use in post-partum women.

The agreement between self-reported consumption of several drugs and laboratory tests used to detect their use is examined. Post-partum women (N = 108) enrolled in a research study participated in a detailed interview covering alcohol and caffeine ingestion, tobacco smoking and use of marijuana and other psychoactive drugs. They also kept a 4-day record of their use of these substances. Blood and urine samples were taken and a physical exam done at the close of the record period. Laboratory tests to detect use of alcohol, tobacco, caffeine, marijuana and other drugs were carried out and the results compared to self-reported drug use in the interview and the record. The degree of agreement depended on the drug taken, the test used and the pattern of drug use in the sample. Sporadic or infrequent consumption related poorly to laboratory tests, especially those that were designed as screening tools. Regular consumption could be identified with greater accuracy. However, the group associations evident between self-reports of drug use and laboratory results were not sufficient to guarantee that subjects were correctly classified. Error in both self-report and the decision made from laboratory values must be taken into account in determining the confidence that should be placed in the data and the conclusions drawn from it.

Adult↗
PubMed1986

Pure red cell aplasia: lymphocyte inhibition of erythropoiesis.

The pathogenesis of pure red cell aplasia (PRCA) was studied in a patient who had no evidence of malignancy. In marrow culture, no erythroid colonies (from late erythroid progenitors [CFU-E]) but normal numbers of well-haemoglobinized erythroid bursts (from early erythroid progenitors [BFU-E]) were found, indicating that BFU-E existed in the patient but that their subsequent in vivo differentiation was inhibited. Autologous coculture studies suggested that inhibition was mediated by the patient's ER + lymphocytes. After remission was induced with cyclophosphamide, autologous ER + cells no longer suppressed in vitro erythropoiesis. However, cryopreserved ER + cells, obtained with anaemia, suppressed BFU-E growth from remission marrow. An expanded population of large granular lymphocytes (LGL) with ER +, Fc gamma +, T3+, T8+, HNK-1+, Ia-, M1 -- phenotype and no functional natural killer (NK) cell activity was noted during PRCA that reverted to normal with remission. For this patient, both in vivo and in vitro evidence demonstrates a cellular inhibition of erythropoiesis at the level of differentiation between BFU-E and CFU-E.

Bone Marrow↗
PubMed1986

Quantitative studies of erythropoiesis in the clinically normal, phlebotomized, and feline leukemia virus-infected cat.

Erythropoiesis was evaluated in 5 cats at base line with normal PCV and then in the same cats with anemia induced by phlebotomy and in 5 other cats with nonregenerative anemia from community-acquired feline leukemia virus (FeLV) infection. The hematologic evaluation included complete blood cell and reticulocyte counts, marrow morphologic features, determination of serum erythropoietin concentrations by radioimmunoassay, ferrokinetic studies, and in vitro marrow culture of early erythroid progenitors (erythroid burst-forming units; BFU-E) and late erythroid progenitors (erythroid colony-forming units; CFU-E). Phlebotomized cats developed marrow erythroid hyperplasia and an increased reticulocyte count. Ferrokinetic studies revealed an increase in plasma iron turnover from 1.4 to 3.8 mg of Fe/dl of blood/day and RBC use from 50.4% to 78.5%. The mean CFU-E number and CFU-E/BFU-E ratio increased after phlebotomy, but the increase was not significant (P greater than 0.05). Serum erythropoietin values did increase significantly. In FeLV-infected cats, a nonregenerative anemia was demonstrated by marrow erythroid hypoplasia and a low total reticulocyte count. An increased percentage of rubriblasts and prorubricytes was observed in 4 of the 5 cats. Although serum erythropoietin values were high (321 +/- 123 mU/ml vs normal 14 +/- 1 mU/ml), ferrokinetic data revealed decreased erythropoiesis. Marrow culture studies in the FeLV-infected cats also revealed low numbers of BFU-E and CFU-E, but normal numbers of granulocyte-macrophage progenitors remained. Seemingly, the FeLV infection impaired the ability of feline marrow to respond physiologically to anemia.

Anemia↗
PubMed1985

Feline glucose-6-phosphate dehydrogenase cellular mosaicism. Application to the study of retrovirus-induced pure red cell aplasia.

Neoplasms result from the uncontrolled proliferation of abnormal or transformed cells. The early stages of this process are difficult to study because of the lack of sensitive and specific markers of clonal evolution in an experimental system. We have developed a cat model using cellular mosaicism for glucose-6-phosphate dehydrogenase (G-6-PD). Our findings confirm that the structural locus for feline G-6-PD is on the X-chromosome and demonstrate that it is randomly inactivated in somatic cells. Heterozygous cats have balanced ratios of G-6-PD enzyme types in peripheral blood cells and hematopoietic progenitors that remain stable over time. In our initial studies, we used the model to analyze the events surrounding marrow failure experimentally induced by selected strains of feline leukemia virus (FeLV). Two G-6-PD heterozygous cats, one F1 male hybrid and one domestic cat were infected with FeLV (C or KT) and developed pure red cell aplasia (PRCA). Colonies arising from the more mature erythroid colony-forming cell were not detected in marrow culture of anemic animals although erythroid bursts persisted, suggesting that the differentiation of early erythroid progenitors (BFU-E) was inhibited in vivo. The ratio of G-6-PD types in hematopoietic progenitors and peripheral blood cells from the heterozygous cats did not change when the animals developed PRCA. Thus, the anemia did not result from the clonal expansion of a transformed myeloid stem cell. With this experimental approach, one may prospectively assess clonal evolution and cellular interactions in other FeLV-induced diseases.

Animals↗
PubMed1985

Leukemia of large granular lymphocytes: association with clonal chromosomal abnormalities and autoimmune neutropenia, thrombocytopenia, and hemolytic anemia.

Three patients had leukocytosis of large granular lymphocytes and chronic neutropenia. Clonal chromosomal abnormalities (trisomy 8 and trisomy 14) and lymphocytic infiltration of splenic red pulp, hepatic sinusoids, and bone marrow indicated the neoplastic nature of the large granular lymphocytes. Demonstration of a T3+, T8+, HNK-1 + phenotype and low natural killer cell activity that was augmented by interferon treatment showed the leukemic cells to be immature natural killer cells. Multiple autoantibodies were present and included rheumatoid factor and antinuclear, antineutrophil, antiplatelet, and antierythrocyte antibodies, suggesting a defect of B-cell immunoregulation. In addition, in-vitro studies showed impaired suppression of immunoglobulin biosynthesis by abnormal cells from one patient. Antineutrophil antibodies and absence of direct cell-mediated inhibition of granulocyte-macrophage colony formation supported a humoral immune mechanism for the neutropenia. In these patients the syndrome of splenomegaly, multiple autoantibodies with neutropenia, and lymphocytosis of large granular lymphocytes is due to a neoplastic proliferation of immature natural killer cells.

Adult↗
PubMed1984

Pancytopenia as a clonal disorder of a multipotent hematopoietic stem cell.

Hematopoiesis was investigated in a 14-yr-old girl who had a 2-yr history of stable asymptomatic pancytopenia and who was also heterozygous at the structural locus for glucose-6-phosphate dehydrogenase (G-6-PD). There was no morphologic or cytogenetic evidence for preleukemia and no suggestion of Fanconi anemia. In the skin and sheep erythrocytes-rosetted T lymphocytes, the ratio of G-6-PD A/B activities was 1:1. However, only type B activity was found in peripheral blood erythrocytes, granulocytes, and platelets. Most erythroid bursts and all granulocyte/macrophage colonies formed in methylcellulose culture were derived from the abnormal clone. These findings demonstrate that (a) some cases of pancytopenia are stem cell diseases that apparently develop clonally; (b) circulating differentiated cells originate from this clone; (c) despite a hypoproliferative anemia, the in vivo expression of presumably normal (nonclonal) progenitors is suppressed. In this patient, the relationship between clonal dominance and possible malignancy may be assessed prospectively.

Bone Marrow↗