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)

We have investigated the effects of the in vitro depletion of LFA1 positive cytolytic T lymphocytes, natural killer (NK) cells, and monocytes on the afferent phase of graft-versus-host disease (GVHD). Lethal GVHD was induced across the murine major histocompatibility complex by injecting C57BL/6 (H-2b) bone marrow (BM) cells (a source of stem cells) and splenocytes (S) (a source of T cells) into lethally irradiated B10.BR (H-2k) recipients. Because anti-LFA1 does not bind complement (C') effectively, we conjugated anti-LFA1 alpha chain monoclonal antibody (MoAb) to ricin toxin A chain (RTA) as a means of facilitating target cell elimination. A 2-hour preincubation of C57BL/6 bone marrow/spleen (BMS) with anti-LFA1-RTA in the presence of ammonium chloride (a potentiator of immunotoxin toxicity), but not a control immunotoxin (IT), reduced CTL activity by greater than 2 logs, significantly reduced NK cell activity, and prevented B10.BR mice from developing GVHD. Depletion of target cells by toxin-labeled-MoAb and not the blockade of the LFA1 molecule by the anti-LFA1 MoAb accounted for our results, because incubating cells with IT in the absence of a potentiator had no effect on GVHD prevention. In contrast, C57BL/6 recipients of C3H BMS grafts only partially benefited from anti-LFA1-RTA preincubation, demonstrating that in this system, different cells not expressing LFA1 were involved in GVHD generation. The same findings observed with anti-LFA1-RTA preincubation were observed with preincubation with L-leucyl-L-leucine methyl ester, a chemical compound eliminating cytolytic cells, providing further support that GVHD induction in the C3H/HeJ into C57BL/6 system is not entirely mediated by classical cytolytic T cells. We next tested anti-LFA1-RTA in a model devised to measure its effect on alloengraftment (B10.BR recipients given lower doses of irradiation). Anti-LFA1-RTA BM preincubation selectively reduced alloengraftment in the model. This observation, combined with experiments showing that LFA1-RTA preincubation, but not anti-Thy 1.2 + C' or control IT preincubation, reduced colony-forming unit-spleen formation, indicates that anti-LFA1 alpha chain IT may remove accessory cells or stem cells critical to engraftment. Still, anti-LFA1-RTA may be useful for clinical GVHD prevention when combined with positive selection techniques designed to enrich for stem cells.
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PMID:Prevention of murine graft-versus-host disease and bone marrow alloengraftment across the major histocompatibility barrier after donor graft preincubation with anti-LFA1 immunotoxin. 195 95

We studied optimal conditions for ex vivo elimination of mature T cells from human bone marrow by T101 immunotoxin (T101-IT) with criteria applicable to graft-versus-host disease (GVHD) prophylaxis prior to allogeneic marrow transplantation. T101-IT consisted of T101 anti-CD5 monoclonal antibody conjugated to purified ricin A-chain toxin. Marrow mononuclear cells isolated by Ficoll-Hypaque or by fractionation with soybean lectin (SBA- cells) were incubated with T101-IT at 37 degrees C with or without ammonium chloride and/or verapamil as potential enhancers of immunotoxin potency. As controls, competitive inhibition studies with unconjugated T101 or irrelevant IgG2a antibody were carried out. Residual T cells were quantified by limiting dilution in phytohemagglutinin (PHA)-interleukin 2 (IL-2) feeder-cell-containing microcultures and hematopoietic progenitors by CFU-GM assay. We demonstrated that T101-IT in the range of 1-100 nM does not affect early total cell viability; that its delayed cytotoxicity is T-cell-specific, greatly enhanced by ammonium chloride, and moderately by verapamil--which also is not synergistic with ammonium chloride; and that 10 nM X 3 fractionated doses (i.e., added at 0, 1.5, and 3 hr of incubation) in the presence of 10 mM ammonium chloride for 4 hr at pH 7.8 consistently induces 2 log T cell depletion. In addition, if the same T101-IT treatment is preceded by fractionation with soybean lectin (i.e., T101-IT treatment of SBA- marrow cells), 3 log T cell depletion is accomplished. We conclude that T101-IT is highly effective in eliminating T cells from donor grafts. However, data presented here indicate that T101-IT should be associated with additional methods, such as soybean lectin fractionation, to ensure more effective ex vivo T cell depletion and acute GVHD prevention.
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PMID:Specific ex-vivo depletion of human bone marrow T lymphocytes by an anti-pan-T cell (CD5) ricin A-chain immunotoxin. 310 75

Graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) is initiated by immunocompetent T cells present in the graft. Selective elimination of distinct T-cell subsets or a sufficient, but not complete T-cell depletion, might abolish severe GVHD without graft rejection and loss of the anti-tumour potential. In this study we analysed the efficacy of different monoclonal antibodies (MoAb) WT32 (CD3), OKT4 (CD4), T101 (CD5), WT1 (CD7), and WT82 (CD8) with respect to their cytotoxicity to T cells either as immunotoxin (IT) or in combination with complement. The cytotoxic potential was assessed by protein synthesis inhibition and clonogenic assays. The ricin A conjugated MoAb exerted only a minor effect on blood or bone marrow T cells, although they were highly inhibitory to T-cell lines. However, in the presence of 20 mM ammonium chloride, IT directed against CD3, CD5, and CD7 were highly cytotoxic. IT directed against CD4 and CD8 were less effective, due to a low internalization. The complement-mediated cytotoxicity was efficient for all antigens used. The natural killer (NK) activity, as measured by cytotoxicity to K562, was hardly depressed by anti-CD3, anti-CD4, anti-CD5, and anti-CD8, but was eliminated by anti-CD7. All procedures used had only a minimal effect on haematopoietic progenitors as measured by CFU-GM and BFU-E assays. We concluded that, although the T-cell population can be eliminated with the combination of anti-CD3, anti-CD5, and anti-CD7 antibodies plus complement, IT with 20 mM NH4Cl appear to kill higher amounts of T cells. Selective elimination of CD4- and CD8-positive cells is effectively obtained by MoAb with complement.
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PMID:Human T lymphocyte differentiation antigens as target for immunotoxins or complement-mediated cytotoxicity. 326 84

Using different isolation procedures (after acidification and saturation with 3 M ammonium sulphate) three fractions were isolated from bull seminal vesicle fluid and assayed for their effects on cell immunity in vitro and in vivo. Two of these preparations (ZS RNase and AS RNase) possessing a high level of ribonuclease activity at concentrations of 50 micrograms/ml showed inhibitory effects (up to 80%) on 3H-thymidine incorporation into the DNA of mitogen-or antigen-stimulated human lymphocytes. The third preparation (3M-P) possessing low ribonuclease activity showed lesser inhibitory effects. The potency of mouse spleen cells to cause regional GVH reaction was significantly decreased after preincubation of spleen cells to cause of 1 mg per AS RNase or ZS RNase whereas 3M-P was ineffective in this test. A single dose of 1 mg per mouse of ZS RNase or 3M-P administered i.p. on day 4 after skin transplantation significantly prolonged graft rejection. Both preparations at this dose potentiated the effect of cyclophosphamide on skin graft survival. All tested preparations preincubated with mouse bone marrow cells had no adverse effects on their colony-forming activity (in the spleens of irradiated mice). The possibility of utilizing the preparations with ribonuclease activity isolated from vesicle fluid in clinical bone marrow transplantation is discussed.
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PMID:Immunosuppressive effects of bovine seminal fluid fractions with ribonuclease activity. 634 32

In the 1980s, attempts were made to use placenta-eluted gamma globulins (PEGG) in patients with graft-versus-host disease (GVHD) after bone marrow transplantation (BMT). Because production of PEGG had been discontinued for many years, we aimed to reestablish a method of production and further explore the mechanisms of the effect of these globulins on GVHD. PEGG were prepared by elution at acid pH from extensively washed human placenta followed by precipitation with saturated ammonium sulfate and absorption on a protein A Sepharose column. In vitro study showed PEGG significantly inhibited both the proliferative response of T-cells to phytohemagglutinin (PHA) and the mixed lymphocyte reaction (MLR). Results of flow cytometric analysis indicated that PEGG down-regulated the expression of CD25 and CD69 on T-cells stimulated by PHA. Cytokine quantification in MLR supernatant showed that PEGG decreased secretion of interferon 3 (IFN-3) but increased production of interleukin 4. In a murine GVHD model, we investigated the preventive effect of PEGG on lethal GVHD in irradiated recipients of allogeneic bone marrow cells and spleen cell transplants by in vivo administration. Compared with controls, recipients treated with PEGG had a markedly increased survival rate with less histopathological evidence of GVHD. These results suggest that PEGG may be a potent therapeutic agent for GVHD.
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PMID:Purification of placenta-eluted gamma globulins and their strong effect against graft-versus-host reactions in vitro and in vivo. 1614 51