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)

T cell clones (n = 456) were derived from 9 patients following allogeneic bone marrow transplantation (BMT) with or without acute graft versus host disease (aGVHD) and from 4 healthy donors. The cloning efficiency was 63.2% in controls, 13.2% and 12.1% in patients with or without aGVHD. Once established, T cell clones were typed for surface markers (CD3, CD4, CD8) and tested for production of IL-2 and expression of cytolytic activities in a lectin-dependent cellular cytotoxicity assay (LDCC) and against the K562 target cell line to detect natural killer activity. We found the expected imbalance of CD4/CD8 clones in BMT patients, as compared to controls. A higher proportion of IL-2-producing clones was observed in patients with aGVHD (83.5%; P less than 0.02) as compared to patients without aGVHD (64.8%) and controls (68.5%). No major differences were found in terms of LDCC, whereas an increased percentage of clones with NK-like activity was found in patients with aGVHD (34.7%, P less than 0.05) as compared to patients without aGVHD (29.5%) and controls (21.3%). The clones were also tested for inhibition of IL-2 production mediated by cyclosporine. Such inhibition could be obtained in virtually all clones both in patients with or without aGVHD, suggesting that the latter is probably not due to the emergence of CsA-resistant clones. In conclusion, this study demonstrates a low cloning efficiency in BMT patients associated with the well-known CD4/CD8 imbalance. A higher production of IL-2, an increased NK activity, but not the presence of CsA-resistant clones appear to differentiate patients with from patients without aGVHD.
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PMID:Phenotypic and functional characterization of T cell clones following allogeneic bone marrow transplantation. 265 22

Nine children with poor prognosis neuroblastoma have been treated by continuous infusion of IL-2 and autologous LAK cells, as described previously by West et al. in adult patients. Six patients were in relapse after high-dose chemotherapy and autologous BMT and three presented with primary refractory disease after conventional therapy. Although patients were very young (median age 6 years; average weight 17 kg), infusion of IL-2, cytapheresis and reinjection of LAK cells appeared feasible with the usual and transient complications observed with IL-2. Haematological toxicity, although reversible, was more important than usually described and due to the presence of bone-marrow metastases in 8 of the 9 patients. Life-threatening toxicity was observed in only one of the admission centres and was probably due to the rapid reinjection of a very large number of activated cells. Two patients presenting with very active disease after high-dose chemotherapy and autologous or allogeneic BMT received IL-2 alone, at 120 days and at 90 days after the graft. The reactivation of grade-II GVHD was the major complication in the patient treated after an allograft, whereas no BMT-related toxicity was observed in the patient treated after the autologous BMT. Immunological modifications induced by IL-2 were very different between these patients. As expected, a preferential outgrowth of NK cells with both NK and LAK activity was observed in the patient treated just after the autograft. In contrast, in the patient treated after an allograft and in the 9 patients in relapse, T lymphocytes remained the major mononuclear cell population with a very large excess of CD8+ T cells. All patients progressed after the first induction cycle with the exception of the only patient treated after autologous BMT who reached a very good partial remission with disappearance of the local tumor and bone metastases. Although very preliminary, these data clearly show that the efficacy of IL-2 largely depends on the patient's immunological status with the optimal effect being observed when IL-2 is given in the first few months following an autograft.
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PMID:A phase-II study of adoptive immunotherapy with continuous infusion of interleukin-2 in children with advanced neuroblastoma. A report on 11 cases. 267 Feb 9

We compared the case like acute GVHD (graft versus host disease) induced by blood transfusion with the cases after open heart surgery which received blood transfusion by the measurement of cell-mediated immunity. Furthermore, we investigated the etiology of GVHD in comparison with cases according to age. Seventy-three cases (under 60 years old: 55 cases, over 60 years old: 18 cases) underwent open heart surgery and the mean blood transfusion volume was 2368cc and the mean age was 52.8 years old. After open heart surgery the rate of peripheral OKT3+ and OKT4+ cells, lymphocyte transformation and IL-2 (interleukin 2 product) were significantly decreased at postoperative day (POD) 1 and recovered to preoperative value until POD 14. However, in the cases like GVHD the rate of OKT4+ cell was decreased in contrast with the change of OKT8+ cell, and lymphocyte transformation and IL-2 production did not recover to normal range postoperatively. In conclusion, in the cases like GVHD the postoperative charge of cell-immunity is similar to the acute GVHD induced after bone marrow transplantation and we must take care about the blood transfusion to the older patients after open heart surgery because there is a possibility that cell-mediated immunity may be more depressed in the elder patient pre and postoperatively.
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PMID:[Studies of pathogenicity of GVHD induced by blood transfusion after open heart surgery]. 279 63

Longitudinal in vitro assays related to cell-mediated immunity were performed in patients following allogeneic (32) or autologous (15) bone marrow transplantation (BMT). In both groups of reconstituted patients, low CD4+/CD8+ T cell ratio and weak allogeneic mixed lymphocyte reactions were found in the first 6 months after BMT, progressively reaching values similar to controls (bone marrow donors or unrelated individuals). In contrast, a strong generation of allogeneic cytotoxic cells, assessed by the number of lytic units per 10(6) cells, was frequently found (18/38 patients tested in both groups) in the first 4 months, despite the quantitative deficit of the CD4+ subset. This in vitro differentiation was found to be independent of in vivo acute graft-versus-host disease (GVHD) and chronic GVHD in allo-transplanted patients. As also documented in autologous recipients, this observation suggests that this phenomenon could be, at least partially, related to the transplantation per se. Preliminary characterization of the effector cells indicates that they belong to the CD8+ subset and that their differentiation is interleukin-2-dependent. Experimental depletion of the CD4+ subset in normal subjects did not increase the number of lytic units in allogeneic cultures. This implies qualitative differences between BMT recipients and normal subjects, namely in CD8+ subset: i.e. that following BMT early CD8+ T cells appear to produce their own growth factor (IL-2), while in normal adult individuals, such autocrine CD8+ T cells, if present, are very rare.
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PMID:Generation of CD8 cytolytic T cells early after autologous or allogeneic bone marrow transplantation. 290 79

Previous investigations have revealed that dietary nucleotide restriction delays the onset of primary murine cardiac allograft rejection and acute graft-versus-host disease followed H-2-incompatible bone marrow transplantation, suppresses sensitization to intradermally injected antigens and suppresses in vivo and in vitro lymphocyte proliferation to alloantigen or lectin stimulation. To determine the mechanisms responsible for these phenomena, BALB/c mice were placed on chow (F), nucleotide free (NF) diet, or NF diet supplemented with 0.25% RNA (NFR), with 0.6% adenine (NFA), or with 0.06% uracil (NFU). Following four weeks of dietary equilibrium, splenic lymphocytes harvested from naive or immunostimulated mice in the various dietary groups were stained with monoclonal antibodies directed Lyt 1, Lyt 2, 3, or surface mouse immunoglobulin (IgG) surface markers. While naive animals demonstrated no differences in lymphocyte subpopulations between groups, following complete Freund's adjuvant (CFA) stimulation, splenic lymphocytes for NF mice demonstrated 27.3 +/- 1.7% Lyt 1+ cells compared with F (32.6 +/- .04%) and NFR mice (33.2 +/- 1.2%) (P less than 0.02). Restriction of dietary nucleotides affected not only phenotypes of T lymphocytes, but also T cell function. Following conconavalin A stimulation of irradiated splenic lymphocytes, IL-2 production was decreased in NF mice compared with the F control group (P less than 0.01). The RNA-repleted diet maintained normal IL-2 production, while addition of adenine or uracil alone did not. Finally, NF diets adversely affected host resistance to the opportunistic pathogen Candida albicans. Following inoculation with 0.25 X 10(6) organisms NF or NFA-fed hosts succumbed more rapidly than F, NFR, or NFU fed hosts (P less than 0.001). These data suggest that helper/inducer T lymphocytes require exogenous nucleotides to respond normally following immune stimulation. Uracil may be the critical substrate, based upon the studies of Candida resistance. By understanding the metabolic basis of NFD-induced immunosuppression, the role of dietary nucleotides in combatting infection and alloantigen rejection can be more clearly defined.
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PMID:Dietary nucleotides, a requirement for helper/inducer T lymphocytes. 293 55

C3H/HeSlc (C3H, H-2k) spleen cells were made tolerant in vitro to C57BL/6CrSlc (B6, H-2b) at the cell-mediated cytotoxicity (CMC) level by in vitro stimulation for 48 hr with mitomycin C (MMC)-treated B6 spleen cells, and treatment with 5 micrograms/ml of 5-fluorouracil for a further 9 hr. These cells were given intraperitoneally to neonate (C3HxB6) F1 mice to examine whether these tolerized spleen cells would cause lethal graft-versus-host disease (GVHD). Despite the lack of CMC, the tolerized C3H spleen cells caused lethal GVHD in most of the neonate F1 mice. Evaluating from various immune parameters, it was evident that T cell populations responsible for IL-2 production, cytostasis, and delayed footpad reaction (DFR) were retained intact after in vitro tolerance induction, probably because of their less-proliferative characteristics in response to fully allogeneic antigen stimulation, and were considered to be responsible for lethal GVHD. Contribution of natural killer (NK) cells to lethal GVHD was not ruled out.
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PMID:Drug-induced in vitro tolerance to allogeneic antigens. II. Further analysis of in vitro-tolerized spleen cells in a fully allogeneic murine combination. 296 9

Cyclosporin A (Sandimmun) has gained wide acceptance by most transplant physicians as the immunosuppressant of choice for preventing rejection of solid organ grafts and graft-versus-host disease. The drug has a specific effect on T-lymphocytes in which it seems to prevent the transcription of genes for several lymphokines. The reduction in IL-2 prevents the clonal expansion of T-lymphocytes and their differentiation into effector T-cells. The reduction in IFN-tau interrupts the feedback mechanism between T-cells and macrophages and the aberrant expression of MHC class II molecules. Through these mechanisms Sandimmun exerts an immunosuppressive and anti-inflammatory effect. Considerable evidence has accumulated to suggest that rheumatoid arthritis (RA) is an auto-immune disease. Activated T-lymphocytes interrelate with macrophages, other inflammatory cells and effector cells in joint tissue, leading to symptoms of inflammation accompanied by joint destruction. Immunosuppressive treatment is already well established in this disease and several trials have already taken place using Sandimmun. A total of 224 patients with RA refractory to conventional disease-modifying drugs have participated in 11 published clinical studies. A review of these studies concludes that Sandimmun is efficacious in controlling inflammatory and functional symptoms, although this improvement is no generally accompanied by reductions in ESR and rheumatoid factor. The frequency of adverse events is comparable to that of other treatments but nephropathy remains the principal factor limiting the use of Sandimmun. Recent evidence suggests that with a strict dosage strategy and good monitoring this problem is controllable and reversible. Further studies are under way to confirm these claims.
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PMID:Sandimmun (cyclosporin A): mode of action and clinical results in rheumatoid arthritis. 307 82

Immunosuppression is a well-characterized consequence of chronic graft-versus-host disease (GVHD). We have previously shown that interferon (IFN) is produced in high levels during acute GVHD. Our objective in this study was to determine if IFN, as a cytokine with known immunosuppressive qualities, could be detected in mice experiencing chronic GVHD-induced immunosuppression. Two different experimental models were used to induce chronic GVHD. The first model involved the injection of parental strain spleen cells into adult F1 hybrids (AJ----B6AF1), while the second model utilized GVHD induced across minor histocompatibility barriers (B10.D2----BALB/c). Results indicated that significant levels of serum IFN-alpha/beta are present in mice undergoing chronic GVHD. Spleen cells from chronic GVHD mice were also shown to produce significant levels of IFN-alpha/beta upon in vitro culture in medium only. This IFN-alpha/beta production was greatly increased when GVHD spleen cells were cultured with either concanavalin A (Con A) or IL-2. In contrast, IFN-gamma production was undetectable in these Con A- or IL-2-containing cultures. Additionally, these same spleen cells which produced high levels of IFN-alpha/beta were immunosuppressed as measured by mitogen-induced cell proliferation. These results suggest that IFN-gamma production is defective in GVHD spleen cells, and that the presence of high IFN-alpha/beta production by GVHD mice may contribute to the immunosuppression associated with chronic GVHD.
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PMID:Enhanced interferon-alpha/beta (IFN-alpha/beta) and defective IFN-gamma production in chronic graft versus host disease: a potential mechanism for immunosuppression. 311 28

We have shown previously that high levels of IFN-beta were generated in vitro from spleen cells obtained from mice experiencing graft vs host disease (GVHD). However, very little or no IFN-gamma was found in these cultures even when IL-2 or Con A was added as a stimulant of IFN-gamma production. This study was undertaken to determine if the IFNs were similarly produced in vivo during the GVH reaction and to further explore the inability of GVHD spleen cells to produce IFN-gamma in vitro. GVHD was induced across minor histocompatibilities by the i.v. injection of B10.D2 spleen cells into sub-lethally irradiated BALB/c mice. Using cytoplasmic immunofluorescence to detect IFN-beta and -gamma, both IFNs were readily detectable in vivo in spleens of mice undergoing GVHD. IFN-gamma demonstrated a distinct distribution pattern, localizing in the peri-arteriolar lymphoid regions of the spleen, whereas IFN-beta immunofluorescence appeared diffusely in all areas. Expression of both IFN-beta and -gamma was shown to be dependent on the GVH reaction, inasmuch as syngeneic controls and mice given T cell-depleted donor cells had little immunofluorescence. These results contradict in vitro data in that IFN-gamma cannot be found in GVHD spleen cell cultures even in the presence of Con A. This in vitro unresponsiveness appeared to be due to the mixing of different cell populations as a result of preparing splenic single-cell suspensions. Percoll gradient fractionation of GVH spleen cells yielded a cell population which, when stimulated with Con A, produced IFN-gamma and underwent cell proliferation. This study represents the first description of the in vivo splenic distributions of IFN-beta and -gamma during GVHD, and presents data that suggest that in vitro results may not truly reflect in vivo immune responsiveness. Thus, the IFNs may play a critical role in the complex events leading to the GVHD syndrome.
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PMID:In vivo and in vitro production of IFN-beta and IFN-gamma during graft vs host disease. 314 98

Impairment in T cell proliferation in response to E. coli and in CML to unrelated alloantigens was usually observed in patients early after marrow grafting and persisted in long-term patients with chronic GVHD but not in those without chronic GVHD. We analyzed various cellular functions in the pathway of T cell activation and found that in patients with immunodeficiency, (1) their M phi usually could process and present antigens to normal T cells, (2) their T cells did not proliferate even in the presence of normal antigen-pulsed M phi, (3) IL-2 production by T cells was deficient, and (4) exogenous IL-2 restored CML activity in cells of most patients early after grafting but not in cells of most patients with chronic GVHD. Therefore, failure to induce proliferation and cytotoxicity in T cells of marrow recipients is not likely due to M phi defects but because of ineffective communication among T cell subsets, probably related to impaired IL-2 production and/or unresponsiveness to IL-2.
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PMID:Ineffective cellular interaction and interleukin 2 deficiency causing T cell defects in human allogeneic marrow recipients early after grafting and in those with chronic graft-versus-host disease. 639 Aug 48


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