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)

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

Bone marrow cells from 10 marrow transplant donors were treated with an immunotoxin, which couples A-chain of ricin with a monoclonal anti-T-cell antibody T101 to prevent graft-versus-host disease by the elimination of mature T-cells. Marrow cells treated with the anti human T-cell immunotoxin (IT101) were cultured for erythropoietic colonies, granulocytic colonies, and multilineage hematopoietic colonies (CFU-GEMMT) containing myeloid cells and T-cells, and optimal conditions were defined for the elimination of T-cells present in the harvested donor marrow prior to marrow transplantation. Marrow samples purged with IT101 were examined for residual T-cells by fluorescence activated cell sorting, using anti-T-cell antibodies, [3H]-thymidine incorporation after PHA stimulation, and an assay for clonogenic T-cells. The number of T-cell colonies observed in the treated marrows was less than 5% of the number in comparable unpurged donor marrows. Treatment with IT101 did not alter the plating efficiency of hematopoietic colonies compared to untreated donor marrow cells. These data suggest that multilineage progenitors responsible for the reconstitution of the recipient hematopoietic system are not affected by marrow IT101 purging. The clinical data on 10 patients indicate that the depletion of T-cells in the donor marrow with IT101 is effective in decreasing the severity of acute graft-versus-host disease in allogeneic marrow transplantation and warrants continued investigation.
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PMID:T-cell depletion with ricin A-chain T101 in allogeneic bone marrow transplantation to prevent severe graft-versus-host disease. 328 72

We evaluated the inhibitory effects of two immunotoxins (IT) synthesized by linking two different anti-CD2 (T, p50) murine monoclonal antibodies (MoAb) to intact ricin (R). Pretreatment with 1000 ng ml-1 35.1-R or OKT 11a-R inhibited PHA-induced T-cell proliferation by 93% and 86%, respectively. At this IT concentration generation of alloreactive cytotoxic T-cells (CTL) was inhibited by more than 99% by either IT. 35.1-R and OKT 11a were minimally toxic to natural killer (NK) effectors or pluripotent bone marrow progenitor cells (CFU-GEMM). Blocking experiments suggested that 35.1-R and OKT 11a-R might recognize different epitopes of the CD2 (T, p50) surface determinant. Our findings show that anti-CD2 IT may be useful for T-cell depletion in allogeneic bone marrow transplantation. We compared TU3, an equimolar mixture of T101 [anti-CD5]-R, UCHT-1 [anti-CD3]-R and 35.1 [anti-CD2]-R with the TUT-cocktail (a mixture of T101-R, UCHT-1-R and TA-1 [anti-CDw18]-R. TUT is currently under evaluation in Phase 1 clinical trials as a T-cell depletion regimen for GVHD prophylaxis. TU3 was as effective as TUT-cocktail in inhibition of PHA response and CTL generation but unlike TUT spared NK effectors. Cocktails of immunotoxins directed against subpopulations of lymphocytes may be useful for more effective anti-GVHD strategies, and to circumvent problems of graft failure/rejection associated with current purgation regimens.
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PMID:Anti-CD2 (T, p50) intact ricin immunotoxins for GVHD-prophylaxis in allogeneic bone marrow transplantation. 351 22

Current studies suggest that the depletion of T-lymphocytes from donor marrow is an effective method for preventing acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation in man. To deplete the T-lymphocytes from bone marrow cells we use either monoclonal anti-T-cell antibodies and complement or T101 ricin A-chain immunotoxin. Residual T-lymphocytes are analyzed by their capacity to form clonal T-cell colonies in the presence of phytohemagglutinin (PHA), accessory cells, and recombinant interleukin 2. The method is compared to immediate indirect immunofluorescence (iF) and thymidine incorporation by marrow cells stimulated by PHA. IF is not suitable for evaluating the depletion by immunotoxin, and the interpretation of thymidine incorporation is generally questionable. The results of the colony formation show that the sensitivity of the colony assay is close to that of iF when T cells are depleted by complement lysis, and the sensitivity of the colony assay is not dependent upon the depletion procedure. Therefore, the T-cell colony assay is a simple functional control for the quality of bone marrow T-cell depletion, especially for T-cell depletion by immunotoxin.
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PMID:Clonal T-cell colony formation in agar culture: an attractive assay to test the T-cell depletion from bone marrow. 353 43

Two patients undergoing marrow transplantation for acute lymphocytic leukaemia in third remission received from histocompatible siblings marrow pretreated with a mixture of three anti-T-cell immunotoxins, consisting of murine monoclonal antibodies covalently linked to ricin. This marrow processing effectively eliminated functional T-cell responses while preserving the marrow precursors necessary for sustained haematoimmunopoietic engraftment. No post-transplant immunoprophylaxis was administered. Both patients showed prompt peripheral engraftment and were discharged from hospital within a month of transplantation. No toxic effects or graft-versus-host disease were apparent after the administration of immunotoxin-treated marrow. Ex-vivo immunotoxin pretreatment appears a safe and simple procedure which deserves further clinical testing as a sole method of graft-versus-host disease prophylaxis.
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PMID:Ex-vivo treatment of donor bone marrow with anti-T-cell immunotoxins for prevention of graft-versus-host disease. 614 6

A non-complement-binding monoclonal antibody, TA-1, recognizing determinants on human T lymphocytes, was linked to the plant seed toxin ricin, either the intact molecule or purified ricin A chain. Peripheral blood lymphocytes were pretreated with conjugate for 2 hr, washed, and then measured in vitro for T cell proliferation. Studies showed that antibody-intact ricin conjugates were up to 39-fold more inhibitory than antibody-A-chain conjugates. Killing was selective because an unreactive control antibody linked to toxin had minimal inhibitory effect. Dose response curves obtained in human studies were nearly identical to curves obtained in an animal model n which a monoclonal anti-murine T cell antibody (anti-Thy 1.1) was linked to ricin and ricin A chain. In the human system, longer exposures of peripheral blood cells to conjugates did not alter our findings. TA-1-ricin conjugates were tested against human ALL cell lines. KOPN-1, a cell line bearing the determinant reactive with TA-1 was selectively eliminated within 2 days after pretreatment with 500 ng/ml. Even 10-fold greater concentrations of TA-1-A chain were not adequate for leukemic cell destruction. These findings (1) show for the first time in a human model that monoclonal antibodies, directed against certain differentiation antigens when linked to ricin A chain are not as effective in normal or malignant cell killing as when linked to intact ricin; (2) contribute to the growing body of evidence showing that monoclonal antibody A chain conjugates do not permit the acquisition of levels of toxin sufficient to destroy target cells; and (3) are important relative to increasing interest in use of antibody-toxin conjugates for graft-versus-host disease prophylaxis in allogeneic bone marrow transplantation.
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PMID:Monoclonal antibody-toxin conjugates reactive against human T lymphocytes. A comparison of antibody linked to intact ricin toxin with antibody linked to ricin A chain. 623 50

Three new reagents that react against human T cells were synthesized by covalently linking the toxin ricin to monoclonal antibodies recognizing differentiation antigens on the surface of T lymphocytes. Each of these immunotoxins selectively inhibited T-cell proliferation when the cells were incubated in the presence of lactose. Multipotent human stem cells were inhibited only at much higher concentrations. Mixtures of all three immunotoxins were more effective than any one alone. These reagents have the potential for preventing graft-versus-host disease in man.
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PMID:Anti-T-cell reagents for human bone marrow transplantation: ricin linked to three monoclonal antibodies. 635 79

Three murine anti-human monoclonal antibodies broadly reactive with human T cells were conjugated to intact ricin toxin. The purgative effects of these immunotoxins (IT) on alloreactive T cells after in vitro pretreatment was tested in an in vitro assay measuring the generation of cytotoxic T cells (CTL). Pretreatment was performed in the presence of lactose to block the native binding of ricin, thus rendering IT antibody specific. Blocking studies with free antibody showed that selective toxicity was determined by the antibody moiety of the antibody-toxin conjugate. Our assay system permitted the measurement of significant CTL levels in the bone marrow. Thus, we were able to determine the differential selectivity of IT for T cells as compared with stem cells in the same donor preparation. Our studies show that antibody-intact ricin conjugates have great potential as T cell purgative reagents for GVHD prophylaxis in human BMT.
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PMID:Anti-T cell monoclonal antibodies conjugated to ricin as potential reagents for human GVHD prophylaxis: effect on the generation of cytotoxic T cells in both peripheral blood and bone marrow. 660 76

A new pharmacologic agent, anti-CD3F(ab')2-ricin toxin A chain (RTA), was synthesized for the purpose of targeting T cells and as a means of treating established graft-versus-host disease (GVHD). The Fc region of anti-CD3 monoclonal antibody (MoAb) was removed to prevent its ability to activate T cells. The resulting F(ab')2 fragments were conjugated to deglycosylated RTA (dgRTA), a catalytic and potent phytotoxin. The resulting immunotoxin (IT) was potent (greater than 95% inhibition) and selective in inhibiting T-cell mitogenesis in vitro. In vivo, the IT depleted 80% of T cells in mice receiving bone marrow (BM) transplants. Transplantation in an aggressive acute GVHD model using C57BL/6 donor cells and H-2 disparate B10.BR recipients resulted in an infiltration of CD3-expressing cells and a median survival time (MST) of 20 to 30 days. A 5-day course of anti-CD3F(ab')2-RTA (30 micrograms/d intraperitoneally) beginning 7 days after GVHD induction was beneficial in treating established GVHD in these mice, as evidenced by significantly prolonged survival (MST, greater than 80 days), superior mean weight values, and improved clinical appearance. Neither intact anti-CD3, unconjugated anti-CD3 F(ab')2 fragments, nor a mixture of anti-CD4 and anti-CD8 MoAbs (which are highly effective in prophylactic models) were as effective. F(ab')2 fragments made from anti-Lyt-1 (the murine homologue of human anti-CD5) linked to RTA were also not effective, despite the fact that both anti-CD3F(ab')2-RTA and anti-Lyt-1F(ab')2-RTA had similar half-lives of about 9 hours. The IT also increased MST in two aggressive models of GVHD across non-H-2 minor histocompatibility barriers, indicating that the usefulness of anti-CD3F(ab')2-dgRTA is not limited to a single-strain combination. This agent should be further investigated as an alternative to current strategies for treating steroid refractory GVHD.
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PMID:Therapy for ongoing graft-versus-host disease induced across the major or minor histocompatibility barrier in mice with anti-CD3F(ab')2-ricin toxin A chain immunotoxin. 749 98

Despite the use of conventional chemoprophylaxis regimens, patients receiving unrelated-donor BMT are at high risk of developing severe acute GVHD. We evaluated a prophylactic regimen combining CsA, MTX and anti-CD5-ricin A chain immunotoxin (H65-RTA) in 31 patients; pentoxifylline was also given to reduce the anticipated nephrotoxicity of CsA. In most cases, planned doses of CsA, MTX and H65-RTA were given (i.e. to 77%, 77% and 93% of patients, respectively). Although fluid retention requiring diuretic therapy was frequent, only 1 patient had a > 10% unexplained increase in body weight during the first 21 days post-BMT. Also, while significant increase of the baseline serum creatinine was noted in 7 patients, none required dialysis. One patient suffered a reversible allergic reaction to the immunotoxin; no other side effects attributable to this regimen were observed. All but 2 patients engrafted (1 died of fungemia on d + 19 and the other had persistent leukemia) and no late graft failures were observed. Seventeen patients developed acute GVHD grade > or = II (probability, 58% [95% CI 41-76%]); 7 had grade > or = III (probability, 24% [95% CI 12-43%]). In the 27 patients who achieved stable engraftment and have survived beyond d + 100, the 3-year probability of developing chronic GVHD was 66% (95% CI 48-84%). As of the last follow-up prior to 01 May 1994, 13 patients are alive in CR and one in relapse; 9 of these patients are off all immunosuppressives and well. Four other patients relapsed and died, and 13 died of other transplant-related causes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prophylaxis for acute graft-versus-host disease following unrelated donor bone marrow transplantation. 753 67


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