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)

Twelve patients with haematological malignancy received cyclophosphamide 120 mg/kg, fractionated total body irradiation 12 Gy, oral cyclosporin and an HLA-identical sibling marrow transplant depleted of T cells by incubation with monoclonal antibodies directed against the CD2 and CD8 antigens and rabbit complement. The phenotype of the residual T cells in the donor marrow inocula was CD3+, CD4+, CD8-. To exclude the possibility that this represented modulation or blocking of the CD8 antigen, T-depleted and non-depleted marrow aliquots from these donors were bulk-cultured for 10 days with phytohaemagglutinin and interleukin-2. Even after this attempted expansion, only a small proportion of cultured T cells from the depleted aliquots (in contrast to the non-depleted aliquots) expressed the CD8 antigen. Since all patients receiving CD3+, CD4+, CD8- marrow developed mild or moderate acute graft-versus-host disease (GVHD), we conclude that CD4+ T cells are capable of initiating acute GVHD across non-MHC barriers in man.
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PMID:CD4+ T cells appear capable of initiating graft-versus-host disease across non-major histocompatibility complex (MHC) barriers in man. 290 76

It has previously been demonstrated that graft-versus-host disease can be overcome in patients receiving HLA-mismatched bone marrow transplants by prior in vitro depletion of T lymphocytes from the marrow. In this report we describe the use of monoclonal antibodies and magnetic microspheres for the depletion of T cells from peripheral blood and bone marrow. The target cells are sensitized with antibodies directed against the CD2, CD3, CD4 and/or CD8 cell surface antigens, captured by magnetic beads coated with sheep anti-mouse IgG antibody and collected by placing the cell suspension in a magnetic field. This simple, rapid procedure results in the efficient removal of T cells from peripheral blood and from bone marrow without affecting the colony-forming potential of normal hematopoietic stem cells. The procedure is capable of being scaled up for the treatment of larger volumes of marrow that are required for clinical transplantation.
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PMID:T lymphocyte depletion of human peripheral blood and bone marrow using monoclonal antibodies and magnetic microspheres. 290 78

An in vitro skin explant model for graft-versus-host disease (GVHD) in humans has been used to study the role of effector T cells in the histological pathogenesis of GVHD. In 11 of 12 experiments clear GVHD changes of grades II-IV were induced in HLA-mismatched skin explants cultured with allogeneic T cells sensitized by in vitro mixed lymphocyte culture. The role of effector T cells was investigated by comparing results before and after removal of CD3 positive cells, and CD4 positive and CD8 positive T cell-subsets by antibody and complement cytolysis from responder populations. Only total removal of CD3 positive T cells prevented histopathological lesions of GVHD in the skin biopsy specimens. The results also demonstrated that the CD4 positive population caused the greatest degree of GVHD in vitro in skin biopsy specimens and direct infiltration into skin by cells is not required for changes to become evident. These results confirm the early results on animal models and demonstrate the use of the skin explant model as a tool for studying the biology of GVHD in humans.
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PMID:Skin explant culture as a model for cutaneous graft-versus-host disease in humans. 297 10

The regeneration of T cell subsets was studied with double immunofluorescence marker methods in 37 patients who received HLA matched T lymphocyte depleted bone marrow transplants (BMT) as part of the treatment for their haematological disease. A cocktail of anti-pan-T (CD6: MBG6) and anti-suppressor/cytotoxic-T cell (CD8: RFT8) monoclonal antibodies was used with rabbit serum as a source of cytolytic complement to achieve selective T cell lysis. The T8+ cells reached low normal values around 60 days post-transplant and remained within the normal range throughout the study (greater than 150 days). This observation is in contrast to our previously published results in patients who, after receiving BMT without efficient T cell depletion, had increased numbers of circulation T8+ cells from 60 days post-transplant. In the present study Leu-7+, RFT8- cells reached normal values rapidly but the reconstitution of T4+ lymphocytes was slow: low normal levels were reached only around day 150 following BMT. The degree of graft-versus-host disease (GVHD) seemed to be related to the number of residual T cells infused: two of the three patients who received the highest numbers of T cells developed Grade II III; otherwise GVHD was minimal. Among the clinical parameters studied cytomegalovirus (CMV) immune status moderately influenced reconstitution: at 55-90 days post-transplant T8+ cells were present at the upper normal levels in seven out of 15 patients receiving BMT from CMV seronegative donors, but in none of the 16 individuals receiving BMT from seropositive donors. CMV related complications were relatively uncommon. Thus the most significant factor in preventing 'T8+ cell overshoot' and T cell imbalance during regeneration appears to be the depletion of T (including T8+) lymphocytes from marrow. The differences of T8+ cell reconstitution in this and previous studies may reflect a different regeneration pattern from T cell precursors as opposed to inoculated mature T cells.
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PMID:T lymphocyte regeneration after transplantation of T cell depleted allogeneic bone marrow. 301 26

Cyclosporine-induced pseudo-graft-versus-host disease (CIPGVHD) in syngeneic or autologous rat marrow chimeras has clinical and histologic features closely resembling classic graft-versus-host disease in the allogeneic chimera. We describe here the pathology and immunopathology of the usual target tissues in CIPGVHD developing in the first week following CsA (early group). The findings are constrasted to the CIPGVHD developing during the second week post-CsA (later group). Six of 9 rats in the early group had acute-type CIPGVHD in the tongue, skin, liver, intestines, and mainstem bronchi. In general, the lymphocytic infiltrates in these tissues were in intimate contact with injured epithelial cells. The intestines had multiple apoptotic lesions. Class II antigen was prominent in the tongue mucosa, but only patchy expression was evident in 2 skin biopsies. All of the lymphocytes infiltrating the mucosa were CD8+(OX-8)/CD4-(W3/25) T cells (OX-19+). Most of the lymphocytes in the lamina propria expressed CD4 as well as CD8 markers, suggesting coexpression. In the later group, 6 of 7 rats had chronic-type CIPGVHD (1 with acute and chronic) while 1 rat had no GVHD (P = .02, Fisher's exact test compared with the early group). These animals had features characteristic of established chronic GVHD in the skin, tongue, liver, intestines, and salivary glands. Fibrosis of the dermis and lamina propria was prominent in the skin and tongue. Submucosal fibrosis was increased in the small intestine. The salivary glands had an interstitial infiltrate and fibrosis with loss of ducts and glands. Class II antigen was prominent in the epidermis of the tongue and skin of all rats. The number of lymphocytes infiltrating the mucosa of the tongue was considerably smaller than seen in the early group. More than 90% of these cells were T cells, as detected by OX-19, and expressed both CD4 and CD8 markers. While most lamina propria lymphocytes expressed the CD4 antigen, there were significantly fewer CD8+ cells, consistent with increased numbers of CD8-/CD4+ helper-phenotype cells. The observations indicate that immediately post-CsA, the CIPGVHD is primarily acute, with epithelial infiltrates of CD8+/CD4- T cells and lamina propria infiltrates that include double-labeled cells consistent with immature thymocytes. There is a rapid transition to established chronic-type CIPGVHD by the second week. The residual mucosal infiltrate is now dominated by double-labeled T cells or thymocytes while the lamina propria infiltrate has more mature helper-phenotype T cells. Induced RT1.B/D antigen could be important in the pathogenesis of the peripheral tissue manifestations.
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PMID:Cyclosporine-induced pseudo-graft-versus-host disease in the early post-cyclosporine period. 304 92

The effect of cyclosporine on a systemic graft-versus-host reaction, cardiac allograft rejection, and a local host-versus-graft reaction in the rat were examined in detail. Therapeutic levels of CsA did not inhibit the early stages of lymphocyte activation but did prevent maturation of the immune response to full effector function--viz., graft rejection or clinical GVH disease. In all three models the phenotype changes in T cells associated with the early stages of activation--i.e., induction of receptors for interleukin 2 (IL-R), induction of MHC class II expression, and coexpression of CD4 and CD8 glycoproteins--were not inhibited by CsA. In the GVH and HVG reactions lymphocyte activation proceeded as far as DNA synthesis. In the systemic GVH model animals showed no sign of GVHD for as long as CsA was administered, but withdrawal of the drug resulted in accelerated lethal GVHD.
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PMID:T cell activation in the presence of cyclosporine in three in vivo allograft models. 304 98

Twelve patients with acute nonlymphoblastic leukemia (ANL, n = 6) or acute lymphoblastic leukemia (ALL, n = 6) in first complete remission received cyclophosphamide 120 mg/kg and total body irradiation (TBI) 12 Gy followed by HLA-identical sibling marrow that had been depleted of T cells by incubation with anti-CD2 (with or without anti-CD8) monoclonal antibody and rabbit complement. These 12 patients were compared historically to 25 patients with ANL (n = 15) or ALL (n = 10) in first remission given cyclophosphamide 120 mg/kg and TBI 12 Gy followed by non-T cell depleted HLA-identical sibling marrow for parameters of relapse and survival. Thirty-six of the 37 patients received cyclosporin as post transplant prophylaxis for graft-versus-host disease (GVHD). All surviving patients have been followed for a minimum of one year from transplant. The actuarial rate of leukemic relapse in the T-depleted group was 62% compared to 37% in the non-depleted group (p less than 0.02). Additionally, relapse occurred significantly earlier post transplant in the T-depleted recipients (p = 0.012). Actuarial survival at two years post transplant was 24% for the T-depleted recipients and 41% at six years post transplant for the non-depleted recipients (not significant, p = 0.37). We have previously shown that GVHD is less severe in patients given T cell depleted transplants. Taken together, these findings suggest that (under the protocol conditions used) a graft-versus-leukemia effect is not separable from a GVHD effect in man.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:High incidence of early leukemic relapse in patients given cyclosporin and T cell depleted HLA-identical sibling marrow transplants for acute leukemia in first remission. 305 4

In vitro depletion of mature pan-T lymphocytes has been widely and successfully used to prevent acute graft-versus-host disease (GVHD) after allogeneic bone-marrow transplantation (BMT). However, this procedure has been associated with a high incidence of graft failure and leukemic relapse. In this pilot study, we evaluated the efficiency of a selective depletion of human marrow T cytotoxic lymphocytes (CD8), a subset essential to induce GVHD in mice. Eleven patients with hematologic malignancies were included (7 HLA-matched BMT, 4 HLA-mismatched BMT). Marrow treatment with 7 anti-CD8 mAbs and rabbit complement resulted in a marked reduction of CD8+ lymphocytes from 15% (median value; range 7%-31%) to 1% (median value; range less than 1%-11%). Acute GVHD was not abolished by this procedure despite postgraft immunosuppression. One patient (HLA-mismatched BMT) rejected his graft and had a full autologous recovery. In conclusion, when compared to the data in the literature, CD8 depletion was shown to be less efficient than pan-T-cell depletion in the prevention of GVHD after allogeneic BMT and was still associated with a major complication associated with this procedure, i.e., graft failure.
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PMID:Selective depletion of marrow-T cytotoxic lymphocytes (CD8) in the prevention of graft-versus-host disease after allogeneic bone-marrow transplantation. 307 87

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

Complement-mediated lysis of (subsets of) T lymphocytes in bone marrow grafts is increasingly used to prevent acute graft-versus-host disease in human bone marrow transplant recipients, especially in case of major immunogenetic disparity between donor and recipient. Since T lymphocyte depletion has resulted in an increased frequency of allogeneic engraftment failures, its effect on hemopoietic reconstitution was measured in rhesus monkeys. The reactivity patterns of commonly used types of antihuman T lymphocyte monoclonal antibodies (MCAs) with rhesus monkey lymphocytes was analyzed using a double-label cytofluorometry technique and found to be very similar to those with human lymphocytes. The antibodies investigated included CAMPATH-1 (recognizing an antigen present on virtually all lymphocytes and monocytes), OKT4 + 4a (CD4, helper/inducer T lymphocytes), B9 (CD8, suppressor/cytotoxic T lymphocytes), WT-1 (CD7, pan-T), and anti-DR MCAs as stem cell toxic controls. Their possible toxicity to hemopoietic stem cells was studied by using a semiquantitative autologous regeneration assay. Cytotoxic lysis of cells in the bone marrow grafts reacting with the T lymphocyte purging MCAs did not result in delayed regeneration compared to untreated autologous grafts. It is concluded that T lymphocyte depletion using anti-T-lymphocyte MCAs does not influence the repopulating capacity of an autologous bone marrow graft.
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PMID:The repopulation capacity of bone marrow grafts following pretreatment with monoclonal antibodies against T lymphocytes in rhesus monkeys. 327 19


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