Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombocytopenia has been characterized in six patients infected with human immunodeficiency virus (HIV) with respect to the delivery of viable platelets into the peripheral circulation (peripheral platelet mass turnover), marrow megakaryocyte mass (product of megakaryocyte number and volume), megakaryocyte progenitor cells, circulating levels of endogenous thrombopoietin (TPO) and platelet TPO receptor number, and serum antiplatelet glycoprotein (GP) IIIa49-66 antibody (GPIIIa49-66Ab), an antibody associated with thrombocytopenia in HIV-infected patients. Peripheral platelet counts in these patients averaged 46 +/- 43 x 10(3)/microL (P = . 0001 compared to normal controls of 250 +/- 40x 10(3)/microL), and the mean platelet volume (MPV) was 10.5 +/- 2.0 fL (P > 0.3 compared with normal control of 9.5 +/- 1.7 fL). The mean life span of autologous 111In-platelets was 87 +/- 39 hours (P = .0001 compared with 232 +/- 38 hours in 20 normal controls), and immediate mean recovery of 111In-platelets injected into the systemic circulation was 33% +/- 16% (P = .0001 compared with 65% +/- 5% in 20 normal controls). The resultant mean peripheral platelet mass turnover was 3.8 +/- 1.5 x 10(5) fL/microL/d versus 3.8 +/- 0.4 x 10(5) fL/microL/d in 20 normal controls (P > .5). The mean endogenous TPO level was 596 +/- 471 pg/mL (P = .0001 compared with 95 +/- 6 pg/mL in 98 normal control subjects), and mean platelet TPO receptor number was 461 +/- 259 receptors/platelet (P = .05 compared with 207 +/- 99 receptors/platelet in nine normal controls). Antiplatelet GPIIIa49-66Ab levels in sera were uniformly increased in HIV thrombocytopenic patients (P < .001). In this cohort of thrombocytopenic HIV patients, marrow megakaryocyte number was increased to 30 +/- 15 x 10(6)/kg (P = .02 compared with 11 +/- 2.1 x 10(6)/kg in 20 normal controls), and marrow megakaryocyte volume was 32 +/- 0.9 x 10(3) fL (P = .05 compared with 28 +/- 4.5 x 10(3) fL in normal controls). Marrow megakaryocyte mass was expanded to 93 +/- 47 x 10(10) fL/kg (P = .007 compared with normal control of 31 +/- 5.3 x 10(10) fL/kg). Marrow megakaryocyte progenitor cells averaged 3.3 (range, 0.4 to 7.3) CFU-Meg/1,000 CD34(+) cells compared with 27 (range, 0.1 to 84) CFU-Meg/1,000 CD34(+) cells in seven normal subjects (P = .02). Thus, thrombocytopenia in these HIV patients was caused by a combination of shortening of platelet life span by two thirds and doubling of splenic platelet sequestration, coupled with ineffective delivery of viable platelets to the peripheral blood, despite a threefold TPO-driven expansion in marrow megakaryocyte mass. We postulate that this disparity between circulating platelet product and marrow platelet substrate results from direct impairment in platelet formation by HIV-infected marrow megakaryocytes.
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PMID:Ineffective platelet production in thrombocytopenic human immunodeficiency virus-infected patients. 955 79

Three chimpanzees experimentally infected with human immunodeficiency virus (HIV) developed significant chronic thrombocytopenia after 5, 4, and 2 years, with peripheral platelet counts averaging 64 +/- 19 x 10(3)/microL (P = .004 compared with 228 +/- 92 x 10(3)/microL in 44 normal control animals), mean platelet volumes of 11.2 +/- 1.8 fL (P > .5 compared with 10.9 +/- 0. 7 fL in normal controls), endogenous thrombopoietin (TPO) levels of 926 +/- 364 pg/mL (P < .001 compared with 324 +/- 256 pg/mL in normal controls), uniformly elevated platelet anti-glycoprotein (GP) IIIa49-66 antibodies, and corresponding viral loads of 534, 260, and 15 x 10(3) RNA viral copies/mL. Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) was administered subcutaneously (25 microg/kg twice weekly for 3 doses) to determine the effects of stimulating platelet production on peripheral platelet concentrations in this cohort of thrombocytopenic HIV-infected chimpanzees. PEG-rHuMGDF therapy increased (1) peripheral platelet counts 10-fold (from 64 +/- 19 to 599 +/- 260 x 10(3) platelets/microL; P = .02); (2) marrow megakaryocyte numbers 30-fold (from 11.7 +/- 6.5 x 10(6)/kg to 353 +/- 255 x 10(6)/kg; P = .04); (3) marrow megakaryocyte progenitor cells fourfold (from a mean of 3.6 +/- 0.6 to 14.1 x 10(3) CFU-Meg/1, 000 CD34(+) marrow cells); and (4) serum levels of Mpl ligand from 926 +/- 364 pg/mL (endogenous TPO) to predosing trough levels of 1, 840 +/- 353 pg/mL PEG-rHuMGDF (P = .02). The peripheral neutrophil counts were also transiently increased from 5.2 +/- 2.6 x 10(3)/microL to 9.9 +/- 5.0 x 10(3)/microL (P = .01), but neither the erythrocyte counts nor the reticulocyte counts were altered significantly (P > .1). The serum levels of antiplatelet GPIIIa49-66 antibodies exhibited reciprocal reductions during periods of thrombocytosis (P < .07). PEG-rHuMGDF therapy did not increase viral loads significantly (395, 189, and 53 x 10(3) RNA viral copies/mL; P > .5 compared with baseline values). The striking increase in peripheral platelet counts produced by PEG-rHuMGDF therapy implies that thrombocytopenia in HIV-infected chimpanzees is attributable to insufficient compensatory expansion in platelet production resulting from HIV-impaired delivery of platelets despite stimulated megakaryocytopoiesis. These data suggest that PEG-rHuMGDF therapy may similarly correct peripheral platelet counts in thrombocytopenic HIV-infected patients.
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PMID:Treatment of thrombocytopenia in chimpanzees infected with human immunodeficiency virus by pegylated recombinant human megakaryocyte growth and development factor. 961 35

Endogenous thrombopoietin (TPO) stimulates platelet production in nonhuman primates by inducing dose-dependent megakaryocyte development from early marrow hematopoietic progenitors and subsequent proliferation and endoreduplication. In nonhuman primates, recombinant human TPO, nonpegylated or pegylated rHu megakaryocyte growth and development factor produce log-linear responses in peak peripheral platelet counts (or peripheral platelet mass turnover) and marrow megakaryocyte volume, ploidy, number, and mass. Mpl ligands can support normal peripheral platelet concentrations after myelosuppressive chemotherapy in baboons, and correct the thrombocytopenia in human immunodeficiency virus-infected chimpanzees. Whereas mpl ligands do not induce platelet aggregation in vitro, mpl ligands enhance aggregatory responsiveness of platelets to physiologic agonists both in vitro and transiently ex vivo after treatment with mpl ligands in nonhuman primates. However, platelet recruitment into forming thrombus is not augmented by these agents when evaluated in quantitative rabbit or baboon models of platelet-dependent thrombus formation, except for the effect of platelet concentration, per se. These findings indicate that appropriate dosing of mpl ligands prevents thrombocytopenia without increasing the risk of platelet-dependent thrombo-occlusive complications.
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PMID:Platelets in thrombotic disorders: quantitative and qualitative platelet disorders predisposing to arterial thrombosis. 968 70

The recent discovery of chemokine receptors as coreceptors for human immunodeficiency virus-type 1 (HIV-1) entry offers new avenues for investigating the pathogenesis of acquired immunodeficiency syndrome (AIDS)-related cytopenias. To this end, we sought to (1) phenotype human hematopoietic cells for CD4 and the HIV-1 coreceptors CXCR4, CCR5, CCR3, and CCR2b; (2) correlate CD4 and chemokine receptor expression with their susceptibility to HIV-1 infection; and (3) examine any potential interplay between inflammatory cytokines released during HIV-1 infection and regulation of chemokine receptor expression. Fluorescence-activated cell sorting (FACS) analysis of bone marrow mononuclear cells (BMMNC), cells derived from serum-free expanded hematopoietic lineages (colony-forming unit-granulocyte-macrophage [CFU-GM], colony-forming unit-megakaryocyte [CFU-Meg], and burst-forming unit-erythroid [BFU-E]), and CD34(+) cells showed differential expression of chemokine receptors and CD4 with some lineage specificity. Significantly, FACS-sorted CXCR4(+)/CD34(+) cells had the same clonogeneic potential as CXCR4(-)/CD34(+) cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of FACS-sorted human candidate stem cells (HSC; CD34(+), c-kit+, Rho123(low)) showed the presence of CXCR4 mRNA but not CD4 mRNA. Infection studies with HIV-1 Env-pseudotyped luciferase reporter viruses indicated that X4 Env (CXCR4-using) pseudotypes infected megakaryocytic cells, whereas R5 Env (CCR5-using) pseudotypes did not. Similarly, R5 but not X4 Env-pseudotyped viruses infected granulocyte-macrophage cells in a CD4/CCR5-dependent manner. Erythroid cells were resistant to R5 or X4 viral infection. Finally, we found that gamma-interferon treatment upregulated CXCR4 expression on primary hematopoietic cells. In summary, the delineation of chemokine receptor expression on primary hematopoietic cells is a first step towards dissecting the chemokine-chemokine receptor axes that may play a role in hematopoietic cell proliferation and homing. Furthermore, susceptibility of hematopoietic cells to HIV-1 infection is likely to be more complicated than the mere physical presence of CD4 and the cognate chemokine receptor. Lastly, our results suggest a potential interplay between gamma-interferon secretion and CXCR4 expression.
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PMID:Coreceptor/chemokine receptor expression on human hematopoietic cells: biological implications for human immunodeficiency virus-type 1 infection. 994 56

The identification of stromal cell-derived factor (SDF)-1alpha as a chemoattractant for human progenitor cells suggests that this chemokine and its receptor might represent critical determinants for the homing, retention, and exit of precursor cells from hematopoietic organs. In this study, we investigated the expression profile of CXCR4 receptor and the biological activity of SDF-1alpha during megakaryocytopoiesis. CD34(+) cells from bone marrow and cord blood were purified and induced to differentiate toward the megakaryocyte lineage by a combination of stem-cell factor (SCF) and recombinant human pegylated megakaryocyte growth and development factor (PEG-rhuMGDF). After 6 days of culture, a time where mature and immature megakaryocytes were present, CD41(+) cells were immunopurified and CXCR4mRNA expression was studied. High transcript levels were detected by a RNase protection assay in cultured megakaryocytes derived from cord blood CD34(+) cells as well as in peripheral blood platelets. The transcript levels were about equivalent to that found in activated T cells. By flow cytometry, a large fraction (ranging from 30% to 100%) of CD41(+) cells showed high levels of CXCR4 antigen on their surface, its expression increasing in parallel with the CD41 antigen during megakaryocytic differentiation. CXCR4 protein was also detected on peripheral blood platelets. SDF-1alpha acts on megakaryocytes by inducing intracellular calcium mobilization and actin polymerization. In addition, in in vitro transmigration experiments, a significant proportion of megakaryocytes was observed to respond to this chemokine. This cell migration was inhibited by pertussis toxin, indicating coupling of this signal to heterotrimeric guanine nucleotide binding proteins. Although a close correlation between CD41a and CXCR4 expession was observed, cell surface markers as well as morphological criteria indicate a preferential attraction of immature megakaryocytes (low level of CD41a and CD42a), suggesting that SDF-1alpha is a potent attractant for immature megakaryocytic cells but is less active on fully mature megakaryocytes. This hypothesis was further supported by the observation that SDF-1alpha induced the migration of colony forming unit-megakaryocyte progenitors (CFU-MK) and the expression of activation-dependent P-selectin (CD62P) surface antigen on early megakaryocytes, although no effect was observed on mature megakaryocytes and platelets. These results indicate that CXCR4 is expressed by human megakaryocytes and platelets. Furthermore, based on the lower responses of mature megakaryocytes and platelets to SDF-1alpha as compared with early precursors, these data suggest a role for this chemokine in the maintenance and homing during early stages of megakaryocyte development. Moreover, because megakaryocytes are also reported to express CD4, it becomes important to reevaluate the role of direct infection of these cells by the human immunodeficiency virus (HIV)-1 in HIV-1-related thrombocytopenia.
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PMID:Phenotypic and functional evidence for the expression of CXCR4 receptor during megakaryocytopoiesis. 1002 79

Thrombocytopenia is a late complication of human immunodeficiency virus (HIV) infection. The chemokine receptor CXCR4 has been shown to be a co-receptor for lymphocyte-tropic HIV-1 strains. CXCR4 is also a natural receptor for the chemokine SDF-1. We have previously shown that CXCR1 and CXCR2 are present on megakaryocytes and platelets. Although interleukin-8 (IL-8) and other chemokines that bind to these two receptors do not activate platelets, they are able to inhibit megakaryocytopoiesis, presumably through these receptors. We therefore examined whether CXCR4 is present on developing and mature megakaryocytes and on platelets. Reverse transcription-polymerase chain reaction (RT-PCR) demonstrated the presence of CXCR4 message. Immature and mature alphaIIbbeta3+ megakaryocytes, and platelets were also positive for CXCR4 by flow cytometric studies using a CXCR4-specific antibody. We then tested whether SDF-1 can affect the biology of these cells. CD34+ cells and immature alphaIIbbeta3+ cells responded to SDF-1 as indicated by Ca2+ mobilization and chemotaxis. However, mature megakaryocytes failed to demonstrate either of these responses, in spite of their continued ability to bind 125I-SDF-1. Further, SDF-1 failed to inhibit megakaryocyte colony growth. Platelets bound 125I-SDF-1 with a K(D) similar to the affinity seen for CXCR4 on other cells, yet SDF-1 did not aggregate washed platelets nor augment aggregation by low-dose ADP or thrombin. SDF-1 also failed to stimulate Ca2+ mobilization, granular release or expression of P-selectin in platelets. Accordingly, although our studies demonstrate that CD34+ precursors, megakaryocytes and platelets all express CXCR4 and bind SDF-1, biological effects were only demonstrable of SDF-1 on CD34+ precursors. The potential biological implications of CXCR4 expression on maturing megakaryocytes and platelets in normal individuals and following HIV infection are discussed.
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PMID:Megakaryocyte precursors, megakaryocytes and platelets express the HIV co-receptor CXCR4 on their surface: determination of response to stromal-derived factor-1 by megakaryocytes and platelets. 1005 Jul 1

Thrombocytopenia is a consistent finding and one of the earliest hematological abnormalities in horses acutely infected with equine infectious anemia virus (EIAV), a lentivirus closely related to human immunodeficiency virus. Multifactorial mechanisms, including immune-mediated platelet destruction and impaired platelet production, are implicated in the pathogenesis of EIAV-associated thrombocytopenia. This study was undertaken to investigate whether regenerative thrombopoiesis and platelet destruction occurred in ponies acutely infected with EIAV. Circulating large, immature platelets were increased in ponies acutely infected with EIAV late in the infection when platelet count was at a nadir. Morphometric analysis of bone marrow from acutely infected ponies revealed significant increased in megakaryocyte area and megakaryocyte nuclear area. A trend toward increased numbers of megakaryocytes was also observed. Platelets from acutely infected ponies had increased surface-bound fibrinogen and ultrastructural changes consistent with in vivo platelet activation. Platelets also had hypofunctional aggregation responses to three agonists in vitro. We conclude that thrombocytopenia in ponies acutely infected with EIAV is regenerative and suggest that bone marrow platelet production is not severely compromised in these ponies. Our findings reveal that in vivo platelet activation occurs in ponies acutely infected with EIAV, and as a result platelets are hypofunctional in vitro. Activation of platelets in vivo may cause platelet degranulation or formation of platelet aggregates, which would result in removal of these damages platelets from circulation. This may represent a form of nonimmune-mediated platelet destruction in ponies acutely infected with EIAV.
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PMID:Platelets from thrombocytopenic ponies acutely infected with equine infectious anemia virus are activated in vivo and hypofunctional. 1036 85

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder in which there is a deregulated amplification of CML progenitors at intermediate stages of their differentiation along the myeloid, erythroid and megakaryocyte pathways. Such cell populations are routinely quantified using standard in vitro colony-forming cell (CFC) assays. The excessive production of leukemic CFC that is seen in most CML patients at diagnosis may be explained at least in part by their increased proliferative activity. An anomalous cycling behavior in vivo has also been found to extend to more primitive CML progenitor populations detectable as long-term culture-initiating cells (LTC-IC). Although the molecular basis of these changes in CML progenitor regulation is not fully understood at the level of the primitive CFC compartment, a selective inability of CML progenitors to be inhibited by certain -C-C-type chemokines has been demonstrated. Failure of the CML stem cell compartment to expand in vivo at the same rate as later progenitor cell types may be explained by their unique additional possession of an intrinsically upregulated probability of differentiation. Such a mechanism would be consistent with the observed loss of LTC-IC activity by CML cells incubated in vitro under conditions that sustain or expand normal LTC-IC populations. Initial clinical studies undertaken at our center established the feasibility of exploiting the differential behavior of primitive normal and CML cells in vitro as a potential purging strategy for reducing the leukemic stem cell content of CML marrow autografts. The results of a larger, second trial now in progress on a group of unselected patients are encouraging. Future studies of nonobese diabetic/severe-combined immunodeficiency mice engrafted with CML cells should provide another useful preclinical model for evaluating treatments that may more effectively eradicate the neoplastic clone in vivo.
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PMID:Differences between normal and CML stem cells: potential targets for clinical exploitation. 1101 49

Thrombocytopenia is a common medical problem for which the main treatment is platelet transfusion. Given the increasing use of platelets and the declining donor population, identification of a safe and effective platelet growth factor could improve the management of thrombocytopenia. Thrombopoietin (TPO), the c-Mpl ligand, is the primary physiologic regulator of megakaryocyte and platelet development. Since the purification of TPO in 1994, 2 recombinant forms of the c-Mpl ligand--recombinant human thrombopoietin (rhTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF)--have undergone extensive clinical investigation. Both have been shown to be potent stimulators of megakaryocyte growth and platelet production and are biologically active in reducing the thrombocytopenia of nonmyeloablative chemotherapy. However, neither TPO has demonstrated benefit in stem cell transplantation or leukemia chemotherapy. Other clinical studies have investigated the use of TPO in treating chronic nonchemotherapy-induced thrombocytopenia associated with myelodysplastic syndromes, idiopathic thrombocytopenic purpura, thrombocytopenia due to human immunodeficiency virus, and liver disease. Based solely on animal studies, TPO may be effective in reducing surgical thrombocytopenia and bleeding, ex vivo expansion of pluripotent stem cells, and as a radioprotectant. Ongoing and future studies will help define the clinical role of recombinant TPO and TPO mimetics in the treatment of chemotherapy- and nonchemotherapy-induced thrombocytopenia.
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PMID:Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. 1241 15

Pluripotent, self-renewing, hematopoietic stem cells are considered good targets for gene modification to treat a wide variety of disorders. However, as many genes are expressed in a stage-specific manner during the course of hematopoietic development, it is necessary to establish a lineage-specific gene expression system to ensure the proper expression of transduced genes in hematopoietic stem cells. In this study, we constructed a VSV-G-pseudotyped, human immunodeficiency virus type 1-based, self-inactivating lentivirus vector that expressed green fluorescent protein (GFP) under the control of the human CD41 (glycoprotein 2b; GP2b) promoter; this activity is restricted to megakaryocytic lineage cells. The recombinant virus was used to infect human peripheral blood CD34+ (hematopoietic stem/progenitor) cells, and lineage-specific gene expression was monitored with GFP measurements. The analysis by FACS determined that GFP expression driven by the GP2b promoter was restricted to megakaryocytic progenitors and was not present in erythrocytes. Furthermore, in the hematopoietic colony-forming assay, GFP expression was restricted to colony-forming units-megakaryocyte (CFU-Meg) colonies under the control of the GP2b promoter, whereas all myeloid colonies (burst-forming units-erythroid, colony-forming units-granulocyte-macrophage, and CFU-Meg) expressed GFP when the transgene was regulated by the cytomegalovirus promoter. These results demonstrated lineage-specific expression after gene transduction of hematopoietic stem cells. The application of this vector system should provide a useful tool for gene therapy to treat disorders associated with megakaryocyte (platelet) dysfunction.
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PMID:HIV-1-derived self-inactivating lentivirus vector induces megakaryocyte lineage-specific gene expression. 1572 86


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