Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antithymocyte and antilymphocyte globulins (ALG) are currently used as immunosuppressive agents in organ transplantation and for the treatment of acute graft-versus-host disease and aplastic anemia. Since any type of immunosuppressive treatment is known to carry the risk of developing B-cell lymphoproliferative disorders, we investigated the in vitro effect of ALG on human B-cell activation and proliferation. The data demonstrate that whatever the source of lymphocytes used for ALG preparation (thymocytes, thoracic duct lymphocytes, B- or T-cell lines), (1) ALG react with both B- and T-cell lines, and (2) ALG contain antibodies specific for B cells (eg, CD21) or common to T and B cells (eg anti-beta 2-microglobulin, anti-HLA-DR, CD18, CD11a) in addition to T-cell-specific antibodies. Unlike all other T-cell mitogens tested (Concanavalin A [Con A], Pokeweek mitogen [PWM], CD3 and CD2 antibodies), ALG do not trigger B-cell differentiation into immunoglobulin-secreting cells at concentrations which induce maximum T-cell proliferation. This effect could be attributed to a direct interaction of ALG with B lymphocytes as shown by the capacity of ALG to block the response of purified B cells to a variety of activators. Furthermore, all the ALG tested were shown to inhibit the proliferation of six of the seven Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines and six of the seven Burkitt's lymphoma cell lines studied. This selective B-cell antiproliferative property of ALG was not reproduced with CD11a, CD18, CD21, CD24, or anti-HLA-DR monoclonal antibodies (MoAbs). These results suggest that, although suppressing T-cell responses, ALG treatment may directly control B cell proliferation to some extent, in keeping with the relatively low risk of posttransplant lymphoproliferative disorders reported with ALG.
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PMID:Antiproliferative effect of antilymphocyte globulins on B cells and B-cell lines. 156 43

CD18 antibodies react with the common beta chain of the human leukocyte function antigen (LFA1)* and thus block the functions mediated by the three identified molecules in humans. A murine CD18 monoclonal antibody was infused in 8 leukemic patients receiving allogeneic T-depleted bone marrow transplantation in order to prevent graft rejection. This was part of the conditioning, including total-body irradiation and high-dose chemotherapy, given to all patients. To prevent graft-versus-host disease the donor bone marrow T cells were depleted using complement-mediated cytolysis or a ricin A conjugate immunotoxin, and cyclosporine or methotrexate were given posttransplant. A persistent level of free circulating anti-LFA1 antibody was detected in 5/8 patients. Despite this, 5 graft failures occurred, with 2 patients experiencing late rejection (days 60 and 97) following HLA-identical transplantation and 3 patients having no engraftment following haplo-mismatched transplant. One other patient died of early sepsis. Only 2 patients (who differed at 1 HLA locus from their donor) are alive with long-term complete chimerism (300 and 315 days). Transient inhibition of recipients' leukocyte functions with an anti-LFA1 antibody did not appear to facilitate engraftment of allogeneic T-depleted marrow transplantation for leukemias.
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PMID:Failure of a CD18/anti-LFA1 monoclonal antibody infusion to prevent graft rejection in leukemic patients receiving T-depleted allogeneic bone marrow transplantation. 256 20

Seven patients with immunodeficiencies (Wiskott-Aldrich syndrome, combined immunodeficiency, and osteopetrosis) were given a mouse monoclonal antibody against the alpha subunit of human leucocyte functional antigen (HLFA-1; CD18) to facilitate the engraftment of mismatched haploidentical related-donor bone marrow. Other conditioning included busulphan, cyclophosphamide, and antilymphocyte globulin. To prevent graft-versus-host disease the bone-marrow T cells were depleted with sheep erythrocyte rosetting and cyclosporin therapy was given. HLFA-1 antibody injections were well tolerated without side-effects except slight, transient fever (38-40 degrees) after the first injection. Engraftment was rapid in all seven patients. The regenerating leucocytes were of donor origin in all cases, and two patients have a mixed chimera. Two patients died from infections. The others are alive and well 60-395 days after transplantation. In a historical control group given the same treatment without anti-HLFA-1 infusion, only one of seven transplants partially engrafted; only two patients remain alive with autologous reconstitution but with uncorrected immunodeficiency.
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PMID:Prevention of graft failure by an anti-HLFA-1 monoclonal antibody in HLA-mismatched bone-marrow transplantation. 287 23

It has been suggested that cord blood T cells may be less able to mediate GVHD than marrow-derived T cells due to their naive status. A decreased potential for GVHD may be advantageous for allogeneic transplant, but this benefit might be counteracted by loss of the GVHD associated graft-versus-leukemia (GVL) effect. The GVL potential of cord blood could be doubly compromised since cord blood NK cell activity is also decreased. To assess these issues we have performed extensive comparative functional and immunophenotypic evaluations of cord and adult mononuclear cells. We found a somewhat reduced alloproliferative, allostimulatory and allocytolytic capacity of cord blood mononuclear cells in bulk assays but not by limiting dilution assays. Immunophenotyping revealed no significant differences in the proportion of major lymphocyte subsets with the exception of the previously recognized predominance of CD45RA+ cells in both CD4 and CD8 cord blood T cells. Cord blood T cells expressed normal percentages of the cellular adhesion molecules, CD11a, CD18 and LFA-3; however, the antigen density of each of these molecules was less than that found on adult T cells. Fewer resting cord blood T cells expressed CD54, the ligand for LFA-1. Cord blood B cells and monocytes expressed normal levels of HLA-class I and HLA class II DR, DP and DQ antigens, suggesting that the decreased expression of cellular adhesion molecules or their receptors rather than a decrease in expression of HLA might have contributed to the lower alloreactivity of cord blood. Although the percentages of NK cells and NK cell subsets in adult and cord blood were similar our data confirmed that cord blood has very low NK lytic activity. In contrast, LAK activity was much more readily induced in cord blood compared with adult PBMC, a finding which could be explained in part by a higher frequency of LAK precursors and a more rapid expansion of NK cells in response to culture with medium containing of NK cells in response to culture with medium containing IL-2. Cord blood LAK cells were readily able to lyse fresh leukemia targets from patients with ALL, AML and CML. The data indicate that although the alloreactive potential of cord blood cells may be somewhat decreased, it is not absent and must be considered a factor in cord blood transplants. LAKp with the potential to lyse leukemia are present in increased numbers in cord blood and might contribute to the GVL effect of a cord blood transplant.
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PMID:Characterization of the alloreactivity and anti-leukemia reactivity of cord blood mononuclear cells. 759 66

Polyclonal antithymocyte globulin (ATG)/antilymphocyte and antilymphoblast globulins (ALG) antibodies have been used successfully in transplantation, aplastic anemia and graft-versus-host disease. Flow cytometry has been used to analyze peripheral blood lymphocyte populations in transplant patients receiving polyclonal ATG/ALG preparations for immunosuppression. Recent reports have indicated clinical dose adjustment based on levels of patient's cells expressing various CD antigens. In vitro analysis of individual polyclonal ATG/ALG CD antigen specificity could identify appropriate antigens for clinical monitoring as well as provide useful in vitro activity data. Therefore, a flow cytometry based assay to characterize and compare activities to specific CD antigens found on the surface of peripheral blood lymphocytes has been developed. Activities found in four lots each of horse ATG (ATGAM, Upjohn), rabbit and horse ATG (thymoglobulin and lymphoglobulin, Merieux), horse ALG (Minnesota), and rabbit ATG (Fresenius) have been compared for CD2, CD3, CD4, CD5, CD7, CD8, CD11a, CD18, CD28, CD44, CD45, and TCR-alpha/beta antigens. Quantitation is achieved by measuring the concentration of ATG/ALG required to give 50% inhibition of antigen specific fluorescent-labeled monoclonal antibody relative to buffer controls. The three horse products tested have similar activity to most antigens tested. However, Fresenius rabbit ATG has the lowest activity for almost all antigens tested whereas the Merieux rabbit ATG has activities closer to the horse products. This technique allows for rapid in vitro comparison of reactivities to individual lymphocyte antigens as well as in vitro analysis of consistency.
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PMID:Comparative polyclonal antithymocyte globulin and antilymphocyte/antilymphoblast globulin anti-CD antigen analysis by flow cytometry. 773 66

Dendritic cells (DC) are the main stimulators of primary T cell responses. Very little is known about DC in cord blood (CB), and whether they are involved in the low incidence and severity of GVHD following CB transplantation. Here, CBDC were identified as a HLA-DR+/lineage marker (lin; CD3, CD11b, CD14, CD16, CD19, CD34, CD56 and glycophorin A antigens) negative population, representing 0.3 +/- 0.1% (mean +/- s.d.; n = 15) of CB mononuclear cells. CBDC expressed the CD4, CD11a, CD18, CD45RA, CD50 and CD54 antigens but revealed no expression of the CD1a, CD11c, CD40, CD45R0, CD58, CD83, CD86 and CD102 antigens. Immunomagnetically enriched CBDC showed potent allostimulatory activity for CB T cells. Thus, CBDC are functionally competent and resemble in their immature/resting state CD11c- DC in peripheral blood.
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PMID:Functional competence of dendritic cells in human umbilical cord blood. 971 87

Dendritic cells (DC) are the main stimulators of primary T-cell responses and, thus, probably play a role in the immune reactions after stem cell transplantation. Very little is known about DC in cord blood (CB) and about their potential involvement in the low incidence and severity of acute graft-versus-host disease after CB transplantation. Here, CBDC were identified as a HLA-DR+ cell population, lacking the CD3, CD11b, CD14, CD16, CD19, CD34, CD56, and glycophorin A lineage markers (lin). This lin-/HLA-DR+ population represented 0.3% +/- 0.1% (mean +/- SD; range, 0.1% to 0. 6%; n = 15) of CB mononuclear cells, and CB contained 5.4 +/- 3.2 x 10(3) CBDC/mL (1.8 to 13.0 x 10(3); n = 15). CBDC expressed CD4, CD11a, CD18, CD45RA, CD50, CD54, and CD123, but showed no expression of CD1a, CD11c, CD33, CD40, CD45R0, CD80, CD83, and CD86 and only limited expression of CD58, CD102, and CD116. Despite this immature phenotype, immunomagnetically lin--enriched CBDC were potent stimulators of allogeneic CB T cells. As few as 266 +/- 107 (193 to 530; n = 10) lin-/HLA-DR+ CBDC stimulated a significant response. However, CBDC failed to take up protein or peptide antigens. Thus, in CB there is a prevalence of a DC subpopulation, resembling the CD11c- DC identified in tonsils, the so-called plasmacytoid T cells, which may exert a function distinct from the CD11c+ DC subpopulation.
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PMID:Identification of cord blood dendritic cells as an immature CD11c- population. 1009 Sep 40

Umbilical cord blood (CB) transplantations are associated with a lower risk of severe graft-versus-host disease (GVHD) compared to BMT. GVHD is an immune reaction that involves interaction between cell surface molecules resulting in cell activation and release of many cytokines. Monocytes are known to be an important source of cell adhesion (CAM) and co-stimulatory molecules which play a crucial role in the efficient activation of T and B cells. We analyzed the phenotype of CB monocytes in the presence or absence of an inflammatory signal (rIFN-gamma) and compared them to adult blood (AB); the expression of HLA-DR and 17 different markers (CD11a, CD11b, CD11c, CD18, CD29, CD40, CD44, CD49a, CD49d, CD49e, CD49f, CD54, CD58, CD62L, CD80, CD86 and CD102) was measured by flow cytometry. Statistical analysis showed that, compared to AB, CB monocytes did not express CD11b, CD11c, CD49d and after stimulation with rIFNgamma, they lost the expression of CD58 and CD102, whereas CD80 and CD86 expression was induced. The analysis of fluorescence intensity (MFI) revealed that CB monocytes expressed some CAM (CD29, CD54, CD102) with a lower intensity than AB monocytes except CD44. In conclusion, absence and reduced expression of some markers argue for a different phenotypic profile of CB monocytes compared to AB monocytes, which might partly contribute to their impaired immune response and to the low incidence of GVHD observed after CB transplantations. However, CB monocytes expressed CD80 and CD86 co-stimulatory molecules, but this expression did not prove a normal co-stimulatory function.
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PMID:Expression of HLA-DR, CAM and co-stimulatory molecules on cord blood monocytes. 1116 18

Leukocyte adhesion deficiency (LAD) is an autosomal recessive immunodeficiency disease characterized by severe, recurrent bacterial infections. In patients with LAD, the leukocytes, particularly the neutrophils, fail to adhere to the endothelial cell wall and migrate to the site of infection. LAD results from heterogeneous molecular defects in the leukocyte integrin CD18, which prevent CD11/CD18 heterodimer formation and surface expression. To date, hematopoietic stem cell transplantation remains the only curative treatment for LAD, however, this approach is limited by transplant-related toxicities and graft-versus-host disease. During the course of the preceding decade we have conducted extensive experimental studies demonstrating that gene transfer of the CD18 subunit corrects the structural and functional defect in LAD leukocytes. These studies provided the support for the initiation of a clinical trial of retroviral-mediated gene transfer of CD18 in two patients with the severe deficiency phenotype or LAD. This review will present an overview of LAD, preclinical CD18 gene transfer studies and the initial results from the current clinical trial.
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PMID:Gene therapy for leukocyte adhesion deficiency. 1124 68

The severe form of leukocyte adhesion deficiency type I (LAD-I) usually leads to death early in life. Allogeneic haematopoietic transplantation is the only cure. Unrelated transplantation has been reported only once. We describe three children with LAD-I transplanted with T cell non-depleted bone marrow from unrelated HLA-matched donors. All patients engrafted, one of them at second transplant. One patient developed grade I and one grade II acute GVHD. Two patients are alive, one of them with a decrease in CD11/CD18 expression. Early referral for HLA-matched unrelated BMT is a reasonable option for patients with LAD-I lacking an HLA-matched related donor.
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PMID:Unrelated bone marrow transplantation for leukocyte adhesion deficiency. 1247 95


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