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Biomedical subjects

C Sieff

Publications and source records attributed to C Sieff.

At least 19 recordsLinked to original sources
PubMed1996

Complete blockade of B7 family-mediated costimulation is necessary to induce human alloantigen-specific anergy: a method to ameliorate graft-versus-host disease and extend the donor pool.

Graft-versus-host disease (GVHD) is initiated by adoptively transferred donor T cells that recognize host alloantigens. Whereas the absence of donor T-cell proliferation to host alloantigens in a mixed-leukocyte reaction does not predict freedom from GVHD, the frequency of alloreactive precursor helper T lymphocytes (pHTL) is predictive. Complete blockade of 87 family-mediated costimulation, but not of major histocompatibility complex recognition or adhesion, induces host alloantigenic-specific energy by reducing cytokine production below threshold levels necessary for common gamma chain signaling. The associated reduction of alloreactive pHTL frequency below that predictive for GVHD, without depletion of either nonallospecific T cells or hematopoietic progenitors, has led us to embark upon human clinical trials of haplomismatched allogeneic bone marrow transplantation.

Abatacept↗
PubMed1995

The collection and evaluation of peripheral blood progenitor cells sufficient for repetitive cycles of high-dose chemotherapy support.

BACKGROUND: The development of an optimized peripheral blood progenitor cell (PBPC) harvest protocol to provide support for repetitive chemotherapy cycles is described. STUDY DESIGN AND METHODS: PBPCs mobilized by cyclophosphamide plus granulocyte-colony-stimulating factor (G-CSF) were studied in 163 leukapheresis harvests from 26 lymphoma patients. Harvested cells were transfused with two chemotherapy cycles and with an autologous bone marrow transplant. Progenitor cell content was examined in the context of hematopoietic engraftment. RESULTS: Mobilization allowed the harvest of large numbers of PBPCs. Peak harvests tended to occur after the recovering white cell count exceeded 10 x 10(9) per L. CD34+ lymphomononuclear cell (MNC) and colony-forming units-granulocyte-macrophage (CFU-GM) counts correlated poorly, but both measures peaked within 24 hours of each other in 21 of 26 patients, which demonstrated PBPC mobilization. Engraftment of platelets (> 50 x 10(9)/L) and granulocytes (> 500 x 10(6)/L) was achieved in a median of 20.5 and 16 days, respectively. A minimum number of progenitors necessary to ensure engraftment could be derived. CONCLUSION: Cyclophosphamide and G-CSF allowed the harvest of sufficient PBPCs to support multiple rounds of chemotherapy. Harvest should commence when the recovery white cell count exceeds 10 x 10(9) per L. PBPC harvest CD34+MNC counts are as useful as CFU-GM results in the assessment of PBPC content, and they may allow harvest protocols to be tailored to individual patients.

Adult↗
PubMed1994

Synergistic effects of interleukin-11 with other growth factors on the expansion of murine hematopoietic progenitors and maintenance of stem cells in liquid culture.

The effect of interleukin-11 (IL-11), alone and in combination with other hematopoietic growth factors, was studied in liquid suspension cultures of murine bone marrow. Stem and progenitor cell contents of input bone marrow 2 days after 5-fluorouracil (5-FU) treatment (FU2dBM) and lineage-depleted, Sca-1-positive FU2dBM (Lin-Sca+Fu2dBM) were compared with output values obtained after 6 days in different growth factor combinations. Stem and progenitor cell recoveries were measured by long-term in vivo competitive repopulation, spleen colony-forming unit (CFU-S), and in vitro limiting dilution long-term bone marrow culture (cobblestone area-forming cell [CAFC]) assays. IL-11, IL-3, IL-6, and Steel factor (SF) were tested separately and in combinations of two, three, and four factors. IL-11 was incapable of maintaining the survival of stem or progenitor cells as a single agent but synergized with either IL-3 or SF to expand progenitor cell output in cultures of FU2dBM. IL-11 greatly enhanced progenitor cell expansion from FU2dBM when added to two- and three-factor combinations of SF, IL-3, and IL-6. The recovery of long-term repopulating ability was enhanced four-fold by incubation in SF plus IL-11 compared to SF alone. IL-11 in combination with SF, IL-3, and IL-6 stimulated a 24,000-fold expansion of progenitor cells from stem cell-enriched Lin-Sca+FU2dBM. Overall, the results indicate that IL-11 is a potent synergistic factor for stem cell proliferation and expansion of progenitors in liquid culture.

Animals↗
PubMed1993

In vitro enhancement of erythropoiesis by steel factor in Diamond-Blackfan anemia and treatment of other congenital cytopenias with recombinant interleukin 3/granulocyte-macrophage colony stimulating factor.

Recombinant cytokines were used to investigate the pathophysiology of Diamond-Blackfan anemia (DBA) and to treat patients with Fanconi's anemia (FA) and amegakaryocytic thrombocytopenic purpura (AMT). We compared the erythroid burst forming units (BFU-E) colony growth of six DBA patients with four normal controls. BFU-E showed erythropoietin (Epo) dose dependence in all patients, although colony numbers were reduced in comparison with normals. The number and size of BFU-E were increased with the addition to Epo of interleukin 3 (IL-3) or Steel factor (SF), but IL-3 + SF was not synergistic. SF increased the nonadherent cell production in DBA long-term bone marrow cultures, and stromal cells from DBA patients showed normal SF mRNA transcripts. These data suggest that SF is not involved in the pathogenesis of DBA, although it may be useful in treatment. A small group of patients with FA and bone marrow failure were treated with daily s.c. granulocyte-macrophage colony stimulating factor (GM-CSF). Toxicity was minimal, and the majority of the patients responded with significant, sustained increase in neutrophils. Multilineage response was rare. GM-CSF may thus be palliative in patients with FA. Five patients with AMT were treated with IL-3 or IL-3 followed by GM-CSF in a phase I/II study. There was minimal toxicity, and IL-3, but not GM-CSF, resulted in improved platelet counts in two patients and decreased platelet transfusion requirements in the other three. Prolonged IL-3 treatment resulted in platelet increases in two of the latter patients. Thus, IL-3 may contribute to the treatment of patients with AMT.

Adult↗
PubMed1991

Selective depletion of bone marrow T lymphocytes with anti-CD5 monoclonal antibodies: effective prophylaxis for graft-versus-host disease in patients with hematologic malignancies.

Seventy-one patients with hematologic malignancies received bone marrow from a histocompatible sibling (n = 48) or a partially matched relative (n = 23) that had been depleted of CD5+ T cells with either an anti-CD5 mooclonal antibody (MoAb) plus complement (anti-Leu1 + C) or an anti-CD5 MoAb conjugated to ricin A chain (ST1 immunotoxin [ST1-IT]). These patients received intensive chemoradiotherapy consisting of cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Both anti-Leu1 + C and ST1-IT ex vivo treatments effectively depleted bone marrow of T cells (97% and 95%, respectively). Overall, primary and late graft failure each occurred in 4% of evaluable patients. The diagnosis of myelodysplasia was a significant risk factor for graft failure (P less than .001), and if myelodysplastic patients were excluded, there were no graft failures in major histocompatibility complex (MHC)-matched patients and 2 of 23 (8.7%) in MHC-mismatched patients. The actuarial risk of grade 2 to 4 acute graft-versus-host disease (GVHD) was 23% in MHC-matched patients and 50% in MHC-mismatched patients. In MHC-matched patients, acute GVHD tended to be mild and treatable with corticosteroids. Chronic GVHD was observed in 6 of 36 (17%) MHC-matched patients and none of 11 MHC-mismatched patients. There were no deaths attributable to GVHD in the MHC-matched group. Epstein-Barr virus-associated lymphoproliferative disorders were observed in 3 of 23 MHC-mismatched patients. The actuarial event-free survival was 38% in the MHC-matched patients versus 21% in the MHC-mismatched patients. However, if outcome is analyzed by risk of relapse, low-risk patients had a 62% actuarial survival compared with 11% in high-risk patients. These data indicate that the use of anti-CD5 MoAbs can effectively control GVHD in histocompatible patients, and that additional strategies are required in MHC-mismatched and high-risk patients.

Adolescent↗
PubMed1991

Inhibition of interleukin-1 by an interleukin-1 receptor antagonist prevents graft-versus-host disease.

Graft-versus-host disease (GVHD) is the major complication of allogeneic bone marrow transplantation (BMT). Dysregulation of inflammatory monokines such as tumor necrosis factor alpha (TNF alpha) has been noted in both clinical and experimental GVHD. We present evidence that interleukin-1 (IL-1), another inflammatory monokine, is an important mediator of GVHD. Expression of the gene for IL-1 alpha as well as the gene for TNF alpha is increased in the skin of mice with GVHD. Inhibition of IL-1 function by the in vivo administration of IL-1 receptor antagonist (IL-1ra) reduces the immunosuppression and mortality of GVHD without impairing the engraftment of hematopoietic stem cells. GVHD thus appears to be a systemic inflammatory process in which monokines, especially IL-1, appear to be important mediators. Inhibition of IL-1 by IL-1ra represents a novel approach to the understanding and control of GVHD.

Animals↗
PubMed1987

Gamma-interferon alters globin gene expression in neonatal and adult erythroid cells.

Interferons have the ability to enhance or diminish the expression of specific genes and have been shown to affect the proliferation of certain cells. Here, the effect of gamma-interferon on fetal hemoglobin synthesis by purified cord blood, fetal liver, and adult bone marrow erythroid progenitors was studied with a radioligand assay to measure hemoglobin production by BFU-E-derived erythroblasts. Coculture with recombinant gamma-interferon resulted in a significant and dose-dependent decrease in fetal hemoglobin production by neonatal and adult, but not fetal, BFU-E-derived erythroblasts. Accumulation of fetal hemoglobin by cord blood BFU-E-derived erythroblasts decreased up to 38.1% of control cultures (erythropoietin only). Synthesis of both G gamma/A gamma globin was decreased, since the G gamma/A gamma ratio was unchanged. Picograms fetal hemoglobin per cell was decreased by gamma-interferon addition, but picograms total hemoglobin was unchanged, demonstrating that a reciprocal increase in beta-globin production occurred in cultures treated with gamma-interferon. No toxic effect of gamma-interferon on colony growth was noted. The addition of gamma-interferon to cultures resulted in a decrease in the percentage of HbF produced by adult BFU-E-derived cells to 45.6% of control. Fetal hemoglobin production by cord blood, fetal liver, and adult bone marrow erythroid progenitors, was not significantly affected by the addition of recombinant GM-CSF, recombinant interleukin 1 (IL-1), recombinant IL-2, or recombinant alpha-interferon. Although fetal progenitor cells appear unable to alter their fetal hemoglobin program in response to any of the growth factors added here, the interaction of neonatal and adult erythroid progenitors with gamma-interferon results in an altered expression of globin genes. This supports the concept that developmental globin gene switching can be regulated by environmental factors.

Erythrocytes↗
PubMed1986

Successful haploidentical mismatched bone marrow transplantation in severe combined immunodeficiency: T cell removal using CAMPATH-I monoclonal antibody and E-rosetting.

Six patients with severe combined immunodeficiency were transplanted with bone marrow from their HLA haploidentical parents. T-lymphocytes were removed by complement mediated lysis with a monoclonal antibody (CAMPATH-I) followed by rosetting with sheep erythrocytes. The patients were pre-conditioned with marrow ablative chemotherapy, using busulphan and cyclophosphamide. There was graft take in five patients, with evidence of transient acute graft-versus-host disease only. Three patients are alive and well greater than 5 months after transplant, and one who is 12 months post graft has full reconstitution of cell mediated and humoral immunity, including specific antibody response to immunization. Transplantation across major histocompatibility barriers can be successfully achieved using this method of treatment of donor marrow.

Antibodies, Monoclonal↗
PubMed1983

Monoclonal antiglycophorin as a probe for erythroleukemias.

A monoclonal antibody (LICR.LON.R10) specific for the major sialoglycoprotein of the erythroid cell membrane, glycophorin A (alpha), has been used to test the possibility that "cryptic" erythroleukemia may be diagnosed as acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML). In addition to 27 overt erythroleukemias, 724 leukemias, including 329 ALL (103 in relapse), 205 AML, and 109 blast crises of Ph1-positive chronic myeloid leukemia, were analyzed. Twenty cases with a significant proportion of glycophorin-A-positive (gA+) cells were found; 8 of these (5 AML and 3 blast crises of chronic myeloid leukemia, CML) had an obvious erythroid component, but 12 others were diagnosed as AML (2), AMML (1), CML in myeloid blast crisis (4) or megakaryoblastic blast crisis (1), acute megakaryoblastic leukemia (2), or acute lymphoblastic leukemia (2). The latter two patients had no immunologic evidence supporting a diagnosis of ALL and were resistant to chemotherapy. We conclude that AML and ALL only very rarely express gA, and these are probably genuine "cryptic" erythroleukemias. Other gA+ leukemias (megakaryoblastic and CML blast crises) may arise from bi- or pluripotent stem cells and contain distinct and separable blast cell populations.

Antibodies, Monoclonal↗
PubMed1982

Changes in cell surface antigen expression during hemopoietic differentiation.

Human bone marrow cells were separated on a fluorescence activated cell sorter (FACS) according to their binding of a series of monoclonal antibodies; the positive and negative fractions were cloned for erythroid burst and colony-forming units (BFU-E and CFU-E) and myeloid colony-forming units (CFU-GM), and cytocentrifuge slides were prepared for microscopy of maturing precursors. The pattern of antigen expression on hemopoietic progenitor and precursor populations has been established using antibodies defining blood group (A, I/i), HLA-associated (*A, B, C, DR, DC1), lineage specific, and transferrin receptor antigens. Like monomorphic HLA-DR, the antigen defined by monoclonal antibody OKT10 is expressed on the earliest progenitors and lost during differentiation, suggesting a role in interactions regulating the differentiation of these cells. The HLA-linked DC1 determinant, in contrast to HLA-DR, is not expressed at a detectable level on progenitor cells. Although a lineage-specific early antigen has not been identified, the transferrin receptor is expressed on the majority of erythroid progenitors, but only weakly on myeloid progenitors, and may provide an approach to isolating erythroid progenitors. These and earlier studies with monoclonal antibodies against HLA-DR and glycophorin now provide a detailed "map" of antigen expression during hemopoietic differentiation.

ABO Blood-Group System↗
PubMed1981

Expression of cell-surface HLA-DR, HLA-ABC and glycophorin during erythroid differentiation.

The unexpected discovery that Ia-like (HLA-DR) antigens in humans were present on blast cells from acute myeloblastic leukaemia led to the finding that normal granulocytic progenitors, in contrast to their mature descendents, also expressed HLA-DR antigens. Thus, anti-Ia sera stain a proportion of myeloblasts in normal bone marrow, inhibit myeloid progenitor (CFU-GM) colony formation in the presence of complement and can be used to label and separate CFU-GM on a fluorescence-activated cell sorter (FACS). Winchester et al. subsequently reported that erythroid progenitors (BFU-E and CFU-E) were also inhibited or killed by anti-Ia (p28,37) and complement. These observations raised the possibility that HLA-DR (or presumptive I-region equivalent) products might have a regulatory role in early haematopoiesis. We have now analysed HLA-DR and HLA-ABC antigen expression on normal erythroid progenitors using monoclonal antibodies to non-polymorphic determinants and fluorescence-activated cell sorting. In parallel experiments, we tested a monoclonal antibody to glycophorin, a well defined erythroid-specific cell-surface membrane glycoprotein. We report that HLA-DR, HLA-ABC and glycophorin are all expressed at various stages during erythroid differentiation.

Bone Marrow↗
PubMed1981

Mapping cell surface antigen expression of haemopoietic progenitor cells using monoclonal antibodies.

A library of monoclonal antibodies which show selective reactivity with particular cells or gene products (e.g. HLA-DR, glycophorin) of different cell lineages in the haemopoietic system has been compiled. Using these probes in conjunction with the fluorescence-activated cell sorter (FACS) the pattern and sequence of cell surface antigenic expression on haemopoietic progenitor cells have been mapped. A cell is identified in bone marrow which has a unique membrane phenotype and the nuclear enzyme terminal deoxynucleotidyl transferase. Its composite phenotype is identical to that seen in the common variant of acute lymphoblastic leukaemia (ALL). It is suggested that this cell is a putative B lineage progenitor which provides the major target for ALL. Detailed analysis of erythroid differentiation with monoclonal antibodies on the FACS reveals an intriguing pattern of antigenic expression in which HLA-DR, glycophorin and band III appear in sequence. HLA-DR (Ia-like antigen) may be present on all or most committed haemopoietic progenitor cells and could play an important role in cell interactions regulating early haemopoiesis.

Animals↗
PubMed1981

Cellular immune defects to Epstein-Barr virus-determined antigens in young males.

Three males with the X-linked lymphoproliferative syndrome (XLP) with hypo- or agammaglobulinemia following Epstein-Barr virus (EBV) infection and two males with the chronic mononucleosis syndrome were investigated for immune responses to EBV-determined antigens. Males with XLP showed profound cellular immune defects. Markedly diminished responses of natural killer cell and interferon-activated killer cell activities and impaired leukocyte migration inhibition responses to phytohemagglutinin were determined in patients with XLP. The two patients with chronic mononucleosis showed less severe defects. All patients showed partial or complete impairment of their EBV-specific immune responses as measured by leukocyte migration inhibition. EBV-specific antibodies were markedly diminished against EBV-associated nuclear antigen, early antigen, and viral capsid antigen in males with XLP. In contrast, patients with chronic mononucleosis had elevated antibodies to most EBV-specific antigens. Individuals with life-threatening EBV-induced lymphoproliferative disorders may exhibit multiple defective immune mechanisms against the virus.

Adolescent↗