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J L Abkowitz

Publications and source records attributed to J L Abkowitz.

At least 37 records · Page 2Linked to original sources
PubMed1995

Plasma/serum levels of flt3 ligand are low in normal individuals and highly elevated in patients with Fanconi anemia and acquired aplastic anemia.

The flt3 ligand is a growth factor that stimulates the proliferation of hematopoietic progenitor and stem cells. We established a sensitive enzyme-linked immunosorbent assay (ELISA) to measure the concentration of flt3 ligand in plasma or serum from normal individuals, as well as in patients with hematopoietic disorders. Concentrations of flt3 ligand in plasma or serum from normal individuals were quite low: only 12% (7 of 60) of normal individuals had flt3 ligand levels above 100 pg/mL (the limit of detection). In contrast, 86% (19 of 22) of samples from patients with Fanconi anemia and 100% (eight of eight) of samples from patients with acquired aplastic anemia had plasma or serum levels above 100 pg/mL. Mean plasma or serum concentrations (calculated by assigning a value of 0 pg/mL to any sample reading below the level of detection) were as follows: normal volunteers, 14 pg/mL; patients with Fanconi anemia, 1,331 pg/mL; and patients with acquired aplastic anemia, 460 pg/mL. Concentrations of flt3 ligand in blood are, therefore, specifically elevated to a level that may be physiologically relevant in hematopoietic disorders with a suspected stem cell component. The elevated flt3 ligand concentrations in these individuals may be part of a compensatory hematopoietic response to boost the level of progenitor cells.

Anemia, Aplastic↗
PubMed1995

Behavior of hematopoietic stem cells in a large animal.

To study the behavior of hematopoietic stem cells in vivo, we transplanted glucose-6-phosphate dehydrogenase (G6PD) heterozygous (female Safari) cats with small amounts of autologous marrow. The G6PD phenotypes of erythroid burst-forming units and granulocyte/macrophage colony-forming units were repeatedly assayed for 3.5-6 years after transplantation to track contributions of stem cell clones to the progenitor cell compartment. Two phases of stem cell kinetics were observed, which were similar to the pattern reported in comparable murine studies. Initially there were significant fluctuations in contributions of stem cell clones. Later clonal contributions to hematopoiesis stabilized. The initial phase of clonal disequilibrium, however, extended for 1-4.5 years (and not 2-6 months as seen in murine experiments). After this subsided, all progenitor cells from some animals expressed a single parental G6PD phenotype, suggesting that blood cell production could be stably maintained by the progeny of one (or a few) cells. As the hematopoietic demand of a cat (i.e., number of blood cells produced per lifetime) is over 600 times that of a mouse, this provides evidence that an individual hematopoietic stem cell has a vast self-renewal and/or proliferative capacity. The long phase of clonal instability may reflect the time required for stem cells to replicate sufficiently to reconstitute a large stem cell reserve.

Animals↗
PubMed1995

Marrow accessory cell infection and alterations in hematopoiesis accompany severe neutropenia during experimental acute infection with feline immunodeficiency virus.

Severe neutropenia and bone marrow (BM) morphologic abnormalities occur during experimentally induced primary infection with feline immunodeficiency virus (FIV), a lentivirus biologically similar to human immunodeficiency virus (HIV). To further characterize the mechanisms involved in this acute infection model of lentivirus-induced BM suppression, peripheral blood counts, histologic BM studies, and BM culture assays were performed on 12 cats that underwent necropsy at regular intervals postinoculation (PI) with FIV Petaluma. Plasma viremia developed at week 3 PI and neutropenia was initially detected at week 6 PI. Low neutrophil counts, but normal hematocrits and platelet counts, persisted through week 12 PI. Infected BM mononuclear cells and megakaryocytes were identified by in situ hybridization assays for FIV nucleic acids in BM sections of cats that underwent necropsy at weeks 4 to 12 PI, correlating with detection of soluble FIV p24 antigen and identification of infected mononuclear and macrophage cells in BM buffy-coat cell cultures from these cats. At weeks 1.5 to 4 PI, the mean frequencies (number per 10(5) BM mononuclear cells) of erythroid progenitors (erythroid colony-forming units [CFU-E] and erythroid burst-forming units [BFU-E] and granulocyte/macrophage progenitors (CFU-granulocyte/macrophage [CFU-GM]) were increased to 508 +/- 74, 143 +/- 24, and 110 +/- 17, respectively (n = 5 cats) as compared with controls (172 +/- 24, 86 +/- 26, and 44 +/- 10; n = 3 cats; P < .02), and the percentages of progenitors in the DNA-synthetic phase of the cell cycle were equivalent to controls. In contrast, the progenitor frequencies at weeks 6 to 12 PI were significantly decreased (72 +/- 16, 43 +/- 6, and 19 +/- 4, respectively; n = 7 cats; P < .01), and these progenitors were more frequently in S-phase. Autologous serum significantly inhibited (P < .05) the growth of CFU-GM in 6 of 9 cats and failed to support the maximal growth of BFU-E in 4 of 9 cats studied at weeks 4 to 12 PI, whereas no such abnormalities were observed in colony assays containing autologous sera from control cats (n = 3) or cats studied at weeks 1.5 or 3 PI (n = 3). In comparison, sera from FIV-infected cats did not inhibit the growth of normal, allogeneic progenitors. However, FIV serum frequently failed to support maximal in vitro growth of normal CFU-GM as compared with uninfected allogeneic sera, further suggesting a lack of progenitor growth-promoting substances in infected cat sera.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Haematological disorders associated with feline retrovirus infections.

Feline oncornavirus and lentivirus infections have provided useful models to characterize the virus and host cell factors involved in a variety of marrow suppressive disorders and haematological malignancies. Exciting recent progress has been made in the characterization of the viral genotypic features involved in FeLV-associated diseases. Molecular studies have clearly defined the causal role of variant FeLV env gene determinants in two disorders: the T-lymphocyte cytopathicity and the clinical acute immunosuppression induced by the FeLV-FAIDS variant and the pure red cell aplasia induced by FeLV-C/Sarma. Variant or enFeLV env sequences also appear to play a role in FeLV-associated lymphomas. Additional studies are required to determine the host cell processes that are perturbed by these variant env gene products. In the case of the FeLV-FAIDS variant, the aberrant env gene products appear to impair superinfection interference, resulting in accumulation of unintegrated viral DNA and cell death. In other cases it is likely that the viral env proteins interact with host products that are important in cell viability and/or proliferation. Understanding of these mechanisms will therefore provide insights to factors involved in normal lymphohaematopoiesis. Similarly, studies of FeLV-induced haematological neoplasms should reveal recombination or rearrangement events involving as yet unidentified host gene sequences that encode products involved in normal cell growth regulation. These sequences may include novel protoncogenes or sequences homologous to genes implicated in human haematological malignancies. The haematological consequences of FIV are quite similar to those associated with HIV. As with HIV, FIV does not appear to directly infect myeloid or erythroid precursors, and the mechanisms of marrow suppression likely involve virus, viral antigen, and/or infected accessory cells in the marrow microenvironment. Studies using in vitro experimental models are required to define the effects of each of these microenvironmental elements on haematopoietic progenitors. As little is known about the molecular mechanisms of FIV pathogenesis, additional studies of disease-inducing FIV strains are needed to identify the genotypic features that correlate with virulent phenotypic features. Finally, experimental FIV infection in cats provides the opportunity to correlate in vivo virological and haematological changes with in vitro observations in a large animal model that closely mimics HIV infection in man.

Animals↗
PubMed1995

Stem cell factor production by human marrow stromal fibroblasts.

To characterize the production of stem cell factor (SCF, the ligand for the c-kit receptor protein) and its regulation by inflammatory cytokines and glucocorticoids, primary marrow stromal fibroblasts were isolated from normal individuals and two patients with Diamond-Blackfan anemia. Unstimulated normal marrow stromal fibroblasts constitutively expressed a low level of SCF mRNA (9 +/- 2 copies/cell [mean +/- SEM]), continually secreted soluble SCF into the supernatant of 1- to 5-day-old cultures (0.16 +/- 0.02 to 0.73 +/- 0.04 ng/mL per 10(6) cells, respectively), and expressed membrane-bound SCF. Stimulation with interleukin-1 beta (IL-1 beta) only modestly increased SCF mRNA levels, soluble SCF production at 24 hours, and membrane-bound SCF. In comparison, hydrocortisone or tumor necrosis factor alpha (TNF-alpha) exposure increased SCF mRNA levels 3.5- to four-fold above controls, but with different kinetics. The peak TNF-alpha effect was at 6 hours, with return to near control levels at 24 hours, whereas hydrocortisone induced maximal mRNA increases at 12 to 18 hours, and the levels remained high at 24 hours. Similarly, a sustained increase in soluble SCF production was detected during 1 to 5 days of hydrocortisone exposure (0.27 +/- 0.03 to 1.10 +/- 0.08 ng/mL per 10(6) cells), while TNF-alpha stimulation modestly increased the production of soluble SCF in 24-hour cultures only. Unstimulated normal marrow fibroblasts expressed predominantly the long species of alternatively spliced SCF mRNA, and the relative amounts of long and short mRNAs did not change after stimulation with IL-1 beta, hydrocortisone, or TNF-alpha. SCF production by marrow stromal fibroblasts from a symptomatic patient with Diamond-Blackfan anemia was equivalent to simultaneously studied normal marrow fibroblasts. In contrast, marrow fibroblasts from a Diamond-Blackfan anemia patient in untreated hematologic remission constitutively expressed high levels of SCF mRNA (21 +/- 4 copies/cell) and soluble protein (0.40 ng/mL per 10(6) cells at 24 hours). Together, these observations suggest that SCF is constitutively produced by fibroblasts in the human marrow microenvironment and that hydrocortisone induces a modest but sustained increase in SCF gene expression and protein production, compared to only a transient increase induced by TNF-alpha. In addition, these findings support the hypothesis that endogenous or corticosteroid-induced increases in the production of SCF could play a physiologic role in the clinical improvement of congenital anemia.

Adult↗
PubMed1995

Feline leukemia virus infection downmodulates the production of growth-inhibitory activity by marrow stromal cells.

To determine the role of infected marrow accessory cells in the pathogenesis of viral-associated hematologic disorders, we evaluated whether feline leukemia virus (FeLV) infection alters the cytoadhesive properties of long-term marrow culture (LTMC) stromal cells, the support of stromal-associated progenitors in LTMCs, and the production of progenitor growth-promoting and -inhibiting activities by marrow stromal cells. Our previous studies demonstrated that LTMCs containing FeLV-infected stromal cells generated two- to three-fold higher numbers of total nonadherent cells and nonadherent granulocyte-macrophage progenitors (CFU-GM) compared with uninfected LTMCs. In the present studies, CFU-GM and primitive erythroid progenitors (BFU-E) bound equivalently to FeLV-infected or uninfected LTMC stromal cells in a 2-hour adherence assay. In recharge LTMC studies, the numbers of adherent CFU-GM maintained in cultures containing stromal cells infected with FeLV-A/61E were not significantly different from controls (range 84-191% of uninfected control cultures, p > 0.1); however, the percentages of adherent CFU-GM in S phase of the cell cycle were consistently increased (range 42-62% compared with controls, range 5-23%). FeLV infection had no significant effect on the cell-cycle status of the nonadherent CFU-GM in LTMCs. Agar co-culture assays revealed that multilineage colony-stimulating activity was constitutively and equivalently produced by feeder cell layers consisting of either uninfected or FeLV-infected irradiated heterogeneous LTMC stromal cells, homogeneous marrow stromal fibroblasts, or a fibroendothelial marrow stromal cell line. However, FeLV infection significantly attenuated the soluble progenitor growth-inhibitory activity associated with higher densities of these stromal cells. Assays of conditioned medium from cultures of irradiated stromal cells demonstrated that FeLV infection or hydrocortisone exposure decreased the utilization of glucose, the production of acidic metabolic products, and the constitutive production of active and latent transforming growth factor beta (TGF-beta) bioactivity and TGF-beta 2 immunoreactivity. Levels of macrophage inflammatory protein 1 alpha (MIP-1 alpha) and tumor necrosis factor alpha (TNF-alpha) were undetectable and unchanged in CM samples. Together, these observations suggest that downmodulation of TGF-alpha and/or the basal metabolic status of stromal cells may be responsible for the high basal proliferative activity of adherent CFU-GM in FeLV-infected LTMCs, and by extension, that retroviral infection in vivo could alter hematopoiesis by perturbing the progenitor growth-regulatory and -supportive function of marrow stromal cells.

Animals↗
PubMed1994

Parvovirus B19 as a cause of acquired chronic pure red cell aplasia.

Parvovirus B19 infection causes chronic anaemia in immunodeficient individuals by selective suppression of erythropoiesis. The bone marrow morphology is characteristic of pure red cell aplasia (PRCA). To determine the frequency of B19-induced PRCA we retrospectively analysed a series of 57 PRCA patients. B19 DNA was present in serum of eight patients (14%) and could be extracted from bone marrow aspirate slides from five of these patients. Recent exposure to the virus was confirmed by the presence of anti-B19 IgM in sera from four and by the finding of giant pronormoblasts in marrow aspirates from five of the B19 DNA-positive patients. The sensitivities of anti-B19 IgM and of giant pronormoblasts were only 50% and 63%, respectively; specificities were 90% and 92%. Unexpectedly, PRCA in two B19 DNA-positive patients remitted after antilymphocyte globulin or cyclosporin A therapy, suggesting that the clinical course of B19-induced PRCA may be indistinguishable from other forms of PRCA. As therapy with immunoglobulin is uniformly effective for treatment of B19-associated anaemia, our data suggest that all patients with acquired PRCA should be evaluated for evidence of B19 infection. B19 DNA analysis is the most reliable method to demonstrate infection.

Adolescent↗
PubMed1993

Behavior of feline hematopoietic stem cells years after busulfan exposure.

The kinetics of hematopoietic stem cells were investigated in glucose-6-phosphate dehydrogenase (G-6-PD) heterozygous cats treated with dimethylbusulfan. Because of X-chromosome inactivation during embryogenesis, each somatic cell from these animals contains either maternal- or paternal-type G-6-PD. Therefore, all hematopoietic progenitor cells carry the G-6-PD phenotype of the most primitive cell (stem cell) from which they originate. For up to 6.5 years after dimethylbusulfan therapy, we determined the percentages of erythroid and granulocyte/macrophage progenitor cells with each G-6-PD phenotype. Significant variations were seen in studies from five of six cats, showing that the population of stem cells contributing to hematopoiesis was neither large nor constant. With mathematical analyses, we estimated that the proliferative potential of residual stem cells was much less than that of normal stem cells reduced in number by autologous transplantation (Abkowitz et al, Proc Natl Acad Sci USA 87:9062, 1990). There was no evidence for the regeneration of a normal stem cell reserve over time; rather, damage was most pronounced years after dimethylbusulfan exposure. These data may help explain the high clinical incidence of aplastic anemia and myelodysplasia after alkylating agent therapies.

Animals↗
PubMed1993

Coincident involvement of flvi-2, c-myc, and novel env genes in natural and experimental lymphosarcomas induced by feline leukemia virus.

The flvi-2 locus is a target of insertional mutagenesis in thymic lymphosarcomas induced by feline leukemia virus (FeLV). flvi-2 encodes the gene bmi-1, whose product is implicated as a myc-collaborator in the induction of B- and T-cell lymphoma. We have examined the involvement of flvi-2 and myc in natural and experimentally induced FeLV-positive feline lymphosarcomas which are heterogeneous in anatomical origin, geographic origin, and strain of FeLV involved. We further compared these findings with previous reports of novel FeLV env genes in the same tumors. The results show that proviral insertion at flvi-2 occurs commonly in natural and experimental feline thymic lymphosarcomas of diverse origins [52% overall], and that alterations in c-myc commonly accompany insertional mutagenesis of flvi-2 [54% overall]. However, 46% of tumors with flvi-2 insertions apparently lack involvement of c-myc. These observations support the hypothesis that interruption of flvi-2 may be an early event in a multistep cascade, one possibility for completion of which is activation of c-myc. Interruption of flvi-2 was not observed in nonthymic lymphosarcomas of alimentary or multicentric origin, although c-myc may be involved. A proportion of both thymic and nonthymic tumors have been shown previously to contain FeLV proviruses with recombinant or mutant env genes. Our findings strongly implicate the insertional mutagenesis of flvi-2, the activation of c-myc, and the emergence of novel env genes in FeLV-mediated lymphomagenesis, particularly in the induction of thymic lymphosarcoma. The data show that these events may overlap, but do not necessarily occur concurrently.

Animals↗
PubMed1992

Studies in feline long-term marrow culture: hematopoiesis on normal and feline leukemia virus infected stromal cells.

To study the effects of feline leukemia virus (FeLV) on the hematopoietic microenvironment, a two-step feline long-term marrow culture (LTMC) system was developed and characterized. The adherent, stromal layer of these cultures is composed of fibroblastoid cells (50% to 80%), macrophages (10% to 30%), fat cells (10% to 20%), and large, polygonal cells that express muscle actin (1% to 2%). When fresh, enriched marrow mononuclear cells (MMNC) were added to 3-week-old irradiated stromal cultures, nonadherent erythroid progenitors (BFU-E) and granulocyte/macrophage progenitors (CFU-GM) could be detected for up to 5 and 12 weeks, respectively. LTMC stromal layers established from marrow cells from cats viremic with either a nonpathogenic strain of FeLV (FeLV-A/61E) or the anemogenic strain FeLV-C/Sarma were morphologically equivalent to uninfected LTMC stromal layers, although more than 80% of the stromal cells expressed FeLV gag protein. When FeLV-infected stromal cultures were recharged with uninfected MMNC, altered patterns of hematopoiesis were observed, compared with recharged, uninfected stromal cultures. In cultures with infected stroma, fewer nonadherent cells (NAC), nonadherent BFU-E, and nonadherent CFU-GM were detected during the first 4 to 5 weeks after recharge. In contrast, greater numbers of NAC and nonadherent CFU-GM were found from weeks 5 to 12 after recharge. When FeLV-infected stromal cultures were recharged with MMNC from a cat heterozygous for the X-chromosome-linked enzyme glucose-6-phosphate dehydrogenase (G-6-PD), the percentage of nonadherent CFU-GM expressing the domestic type G-6-PD isoenzyme remained stable over time (mean % domestic [%d], 53% +/- 3%), and was equivalent to that of nonadherent CFU-GM maintained in uninfected cultures (mean %d, 56% +/- 3%), indicating that clonal drift or clonal selection was not responsible for the enhanced maintenance of CFU-GM. Furthermore, as only 10% to 20% of recharged hematopoietic cells became infected with FeLV in vitro, it is unlikely that the altered pattern was due to progenitor infection. We hypothesize that the increase in NAC and nonadherent CFU-GM in FeLV-infected cultures resulted from enhanced growth factor production by stromal cells. The two-step LTMC system may facilitate the characterization of stromal-derived factors that affect progenitor cell engraftment and proliferation.

Acid Phosphatase↗
PubMed1992

Absence of abnormalities of c-kit or its ligand in two patients with Diamond-Blackfan anemia.

As Diamond-Blackfan anemia shares clinical features with W and Steel defects in mice, we investigated the possibility that this human disorder might result from an abnormality of the c-kit receptor or its ligand, stem cell factor (SCF). For these studies, full nucleotide sequences for coding regions of c-kit and SCF were generated for two Diamond-Blackfan anemia patients and were normal. Similarly, the kds of SCF receptors on their marrow cells (31 pmol/L, 43 pmol/L) were comparable with those found in three normal controls (50 pmol/L, 55 pmol/L, 27 pmol/L). Serum SCF concentrations were 6.9 ng/mL in patient A, 14.6 ng/mL in patient B, who has been in hematologic remission since adolescence, and 2.7 ng/mL in the 3-year-old daughter of patient B, who also has Diamond-Blackfan anemia but is transfusion-dependent. It is possible that the SCF level in patient B increased with puberty, leading to her remission. These data provide evidence that Diamond-Blackfan anemia does not result from structural abnormalities of c-kit or SCF.

Adult↗
PubMed1992

In vivo infection of marrow stromal fibroblasts by feline leukemia virus.

Marrow stromal fibroblasts (FBs) likely play an important role in the regulation of hematopoiesis within the marrow microenvironment. Infection of these cells by feline leukemia virus (FeLV) might not only contribute to the pathogenesis of FeLV-induced hematologic diseases, but could provide a reservoir for virus in the infected cat. To determine the frequency of FeLV infection among marrow FB precursor cells (fibroblast colony-forming units, CFU-F) of cats viremic with FeLV-C/Sarma and FeLV-A/61E, marrow FBs and FB cell clones were isolated and assayed for expression of FeLV gag protein. From 30% to 86% and 64% to 88% of marrow FB precursors were infected with FeLV-C/Sarma and FeLV-A/61E, respectively. CFU-F from a cat viremic with FeLV-A/61E were not affected by exposure to antibody against FeLV envelope glycoprotein gp70 and heterologous complement, whereas similarly treated hematopoietic progenitors (erythroid colony-forming units, CFU-E; erythroid burst-forming units, BFU-E; and granulocyte-macrophage colony-forming units, CFU-GM) and culture-propagated, FeLV-infected marrow FBs were effectively lysed, suggesting that infected CFU-F within the marrow microenvironment do not express a significant amount of gp70 on their cell membranes. Thus, marrow FB precursor cells appear to be a major target for FeLV in vivo. Furthermore, the low level of gp70 antigen expression on the surface of these cells in vivo may allow them to escape immune surveillance and provide a reservoir of virus during active or latent infection.

Animals↗
PubMed1991

Diamond-blackfan anemia: in vitro response of erythroid progenitors to the ligand for c-kit.

To provide insights into the pathogenesis of Diamond-Blackfan anemia, we examined the in vitro response of erythroid progenitors to the recently isolated ligand for c-kit (stem cell factor, SCF). For these studies, marrow or blood mononuclear cells from 10 Diamond-Blackfan patients were cultured with erythropoietin (Ep), Ep and interleukin-3, Ep and granulocyte-macrophage colony-stimulating factor, or Ep and lymphocyte conditioned media (LCM). These combinations were tested in the presence or absence of SCF. The mean number of cells per erythroid burst increased 5 to 50-fold in cultures containing SCF. Furthermore, many additional erythroid bursts were seen (mean increment 3.2 x baseline values). Although burst-forming unit-erythroid (BFU-E) from all patients responded, there were differences among individuals in the sensitivity of their BFU-E to SCF. In six patients and all control studies, plateau frequencies of erythroid bursts were achieved with less than or equal to 10 ng/mL SCF, whereas in studies from the other four patients, over 50 ng/mL SCF was required. These data invite speculation that the c-kit receptor/ligand axis is involved in the pathogenesis of Diamond-Blackfan anemia. More importantly and regardless of whether the observed patterns of response reflect the primary defect or an epiphenomenon, our data strongly support a therapeutic trial of SCF in patients with Diamond-Blackfan anemia.

Adolescent↗
PubMed1991

Hematopoiesis in asymptomatic cats infected with feline immunodeficiency virus.

Anemia and neutropenia often develop in cats that are infected with the feline immunodeficiency virus (FIV), a lentivirus biologically similar to the human immunodeficiency virus (HIV). To assess the role of FIV in the pathogenesis of these abnormalities, marrow culture studies were performed on nine asymptomatic, hematologically normal cats that were chronically infected with FIV. In these experiments, the frequencies of granulocyte/macrophage progenitors (CFU-GM) and early and late erythroid progenitors (CFU-E and BFU-E, respectively) were equivalent to progenitor frequencies in simultaneously studied uninfected control cats. Asymptomatic FIV infection was not associated with a change in the cell-cycle kinetics of CFU-E, BFU-E, or CFU-GM, nor was there an alteration in the dose-response of BFU-E or CFU-GM to hematopoietic growth factors present in fibroblast-derived conditioned medium. Sera from FIV-infected cats supported progenitor growth in vitro as well as normal cat sera. Furthermore, there was no evidence that these sera contained complement-fixing antibodies that recognized hematopoietic progenitors. Therefore, these data show that the in vitro behavior of hematopoietic progenitors is not affected by FIV infection alone, and they are in agreement with recent evidence that human progenitors are not a major target of HIV infection. It is likely that factors associated with progressive immunodeficiency, opportunistic infections, nutritional deficiencies, or malignancies play significant roles in the cytopenias that develop during the symptomatic disease induced by FIV, and by analogy, HIV. Prospective marrow culture studies of FIV-infected cats that develop hematologic abnormalities should provide a valuable animal model of acquired immunodeficiency syndrome-associated hematologic disorders.

Animals↗
PubMed1991

Retrovirus-induced feline pure red blood cell aplasia: pathogenesis and response to suramin.

Feline leukemia virus, subgroup C/Sarma (FeLV-C/Sarma) induces pure red blood cell aplasia in cats. Although erythroid (BFU-E and CFU-E) and granulocyte/macrophage (CFU-GM) progenitors are infected with this virus, only erythropoiesis is impaired. Two to 3 weeks before the onset of anemia, CFU-E become undetectable in marrow cultures while earlier erythroid progenitors (BFU-E) persist, suggesting that FeLV-C/Sarma (presumably via its envelope glycoprotein gp70) inhibits the differentiation of BFU-E to CFU-E in vivo. To correlate in vitro observations with the progression of disease, prospective studies were performed in six cats. These studies showed that at the time that the frequencies of CFU-E decreased in marrow cultures, BFU-E no longer responded to hematopoietic growth factor(s), although the responses of CFU-GM were unchanged. In further studies, anemic cats received suramin, a reverse-transcriptase inhibitor with other diverse effects. Within 4 to 14 days, erythropoiesis improved and up to 1,616 CFU-E were detected per 10(5) marrow mononuclear cells. However, progenitor cells remained infected, suggesting that suramin modulated erythroid differentiation without inhibiting progenitor infection. These observations led to the hypothesis that the gp70 of FeLV-C/Sarma impairs BFU-E differentiation by interference with ligand/receptor interactions or signal transduction pathways unique to erythroid cells. Understanding this mechanism should provide insights into the interactions controlling early erythropoiesis.

Amino Acid Sequence↗
PubMed1990

Persistent B19 parvovirus infection in patients infected with human immunodeficiency virus type 1 (HIV-1): a treatable cause of anemia in AIDS.

OBJECTIVE: To determine the role of B19 parvovirus in red cell aplasia of patients infected with human immunodeficiency virus type 1 (HIV-1). DESIGN: Uncontrolled clinical trial, with assay of serum, peripheral blood cells, and bone marrow for virus using DNA hybridization and immunocytochemistry techniques; these assays were then correlated with clinical findings, results of immunoassays for antivirus antibodies, and with immunoglobulin (Ig) therapy. SETTING: Government medical referral center, and university and private hospitals. PATIENTS: Seven patients with pure red cell aplasia and serologic evidence of infection with HIV-1. MEASUREMENTS AND MAIN RESULTS: All patients had giant pronormoblasts in the bone marrow (present in transient aplastic crisis caused by acute B19 parvovirus infection). High concentrations of B19 parvovirus were demonstrated in sera, in several cases in samples separated by weeks or months. Viral DNA and capsid protein were present in the bone marrow of three patients studied, and active viral replication was detected by southern analysis. There was no antivirus IgG in capture immunoassay and no or very low levels of antivirus IgM. The patients did not have symptoms of fifth disease, the illness caused by this virus in immunologically normal persons. Six patients were treated with a regimen of intravenous commercial immunoglobulin. In all cases, this therapy resulted in rapid reduction in serum virus concentrations and full recovery of erythropoiesis. Relapses in two cases were predicted by DNA hybridization studies, and these cases were successfully retreated. CONCLUSIONS: The B19 parvovirus is a remediable cause of severe chronic anemia in HIV-infected patients. Recognition of and therapy for parvovirus in this population will avoid erythrocyte transfusion and should prevent transmission of the virus to other persons, including immunosuppressed persons and women of child-bearing age.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Hematologic manifestations of feline immunodeficiency virus infection.

Studies were done on 53 cats with community-acquired infection with the feline immunodeficiency virus (FIV) to determine if hematologic abnormalities were comparable with those observed in patients seropositive for the human immunodeficiency virus (HIV). Nine cats were asymptomatic, 24 had clinical symptoms equivalent to AIDS-related complex (ARC), and 20 had AIDS-like disease. Hematologic abnormalities were detected in 75% (40 of 53) of FIV-seropositive cats, and multiple concurrent cytopenias were common. Anemia, lymphopenia, neutropenia, and thrombocytopenia occurred in 36%, 53%, 34%, and 8% of FIV-seropositive cats, respectively. Cytopenias were seen only in symptomatic (ARC or AIDS) cats. The occurrence of cytopenias and the distribution of clinical stages were similar in cats with concurrent feline leukemia virus (FeLV) infection and those with FIV alone, suggesting that these abnormalities were a direct consequence of FIV infection. In addition, abnormalities were noted in 72% of marrows from symptomatic cats and included hyperplasia of individual cell lineages and dysmorphic features. Our results demonstrate that the hematologic manifestations of FIV infection are strikingly similar to those reported in HIV-seropositive patients. Thus, FIV infection in cats is an excellent animal model to study the pathogenesis of blood and marrow abnormalities in AIDS, as well as to evaluate the hematologic toxicities of drug therapies.

Acquired Immunodeficiency Syndrome↗