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

Whereas T lymphocytes are essential for the initiation of acute graft-versus-host disease (aGVHD), it is not at all clear whether they or other cells or noncellular factors actually mediate the characteristic lesions. This report describes the in vivo effects of human NK cells, T cells, and cytokines on the induction of aGVHD in 4 Gy sublethally irradiated C.B-17 scid/scid (SCID) mice. Human NK and T lymphocytes were obtained separately by antibody- and complement-mediated negative selection from the peripheral blood of normal donors and expanded in medium containing rIL-2 and irradiated autologous feeder cells. The characteristics of the two groups of cells were analyzed before injection into SCID mice. Cytofluorometric phenotyping demonstrated that 70-95% of NK-enriched cells expressed CD3-, CD16+, CD56+, and CD8-dim+; ninety-seven per cent of T cells expressed CD3+, TCR-alpha/beta+, CD4+, or CD8-bright+. Analysis of K562 and Daudi cultured target cell lines demonstrated 40-50% higher cytotoxicity by NK-enriched cells as compared with activated T lymphocytes. TNF-alpha cytokine production was greatly increased in activated NK cells (250 pg/ml) as compared with T cells (25 pg/ml) and fresh PBMC (12.5 pg/ml). IFN-gamma was increased in both NK and T cells. After i.v. injection of 1-5 x 10(7) cells into irradiated SCID mice, minor to severe skin lesions, diarrhea, and weight loss occurred in NK- but not the T cell-injected animals. In NK-injected animals, thinning and focal loss of epithelium with pyknotic nuclear change and degeneration and loss of skin appendages were observed. Single cell necrosis, crypt abscess formation, and loss of glandular epithelium developed in the colon of NK but not in T cell-injected animals. These findings are very similar to allogeneic aGVHD in SCID mice injected with C57BL/6 mouse splenocytes. Immunohistological staining with anti-human CD56, CD3, TNF-alpha, and IFN-gamma antibodies demonstrated CD56+ cells in association with TNF-alpha and IFN-gamma secretion in the bowel of NK-injected animals. CD3+ cells were not found in the same tissues. These findings were not observed in T cell-injected and control mice. In summary, aGVHD-like lesions were induced by transplantation of xenogeneic human activated NK cells into SCID mice. We hypothesize that cytokines released from human NK cells play a central role in the pathogenesis of clinical aGVHD.
 ...
PMID:Acute graft-versus-host-like disease induced by transplantation of human activated natural killer cells into SCID mice. 835 98

IL-1ra is the first described naturally occurring receptor antagonist of any cytokine or hormone-like molecule. IL-1ra is a member of the IL-1 family by three criteria: amino acid sequence homology of 26 to 30% to IL-1 beta and 19% to IL-1 alpha; similarities in gene structure; and common gene localization to human chromosome 2q14. Two structural variants of IL-1ra exist: sIL-1ra, a secretory molecule produced by monocytes, macrophages, neutrophils, fibroblasts, and other cells; and icIL-1ra, an intracellular molecule produced by keratinocytes and other epithelial cells, macrophages, and fibroblasts. IL-1ra production by monocytes, macrophages, and neutrophils may be regulated in a differential fashion with IL-1 beta. Human IL-1ra binds to both human IL-1RIs and IL-1RIIs on cell surfaces, although with 100-fold greater avidity to IL-1RIs. IL-1ra may bind preferentially to soluble IL-1RIs and not at all to soluble IL-1RIIs. IL-1ra competitively inhibits binding of both IL-1 alpha and IL-1 beta to cell surface receptors without inducing any discernible intracellular responses. All three forms of IL-1 may bind to IL-1 receptors in a similar fashion but IL-1ra may lack the secondary interactions necessary to trigger cell responses. A 100-fold or greater excess of IL-1ra over IL-1 may be necessary to inhibit biological responses to IL-1 both in vitro and in vivo. The roles of sIL-1ra and icIL-1ra in normal physiology or in host defense mechanisms remain unclear. The administration of IL-1ra blocks the effects of IL-1 in some animal models of septic shock, inflammatory arthritis, graft-versus-host disease, and inflammatory bowel disease. The preliminary results of clinical trials in humans indicate possible efficacy of IL-1ra in sepsis syndrome, rheumatoid arthritis, and GVHD.
 ...
PMID:Interleukin-1 receptor antagonist. 837 62

Numerous studies have demonstrated that the generation of alloreactive effector cells depends on cytokines. Conversely, there is evidence that cytokine metabolism is altered at the clonal level in tolerant chimaeras. This has led to preclinical and clinical studies using antibodies that antagonize interleukin-2 (IL-2), with the hope of achieving immunosuppression and inducing tolerance. Monoclonal antibodies against the alpha-chain (p55) of the human IL-2 receptor are being applied to prevent transplant rejection and graft-versus-host disease in several clinical trials. The antibodies that have been applied clinically so far antagonize the binding of IL-2 to the IL-2 receptor alpha-chain which is part of the high affinity IL-2 receptor, but they do not deplete the receptor-bearing cells. Our study investigates the immunosuppressive effect of monoclonal antibodies against the alpha-chain (p55) and beta-chain (p75). In mixed lymphocyte cultures the p55 antibody causes a reduction in T-cell proliferation to about 50%. The generation of cytotoxic T cells is reduced more effectively (up to 80%). By additional blocking of the IL-2 receptor beta-chain we achieved an additional but still incomplete immunosuppressive effect. Moreover we show that IL-2 receptor-blocked alloreactive T cells escape suppression by using IL-4 as an alternative stimulating signal. To prevent T lymphocytes benefiting from this alternative and thwarting the immunosuppressive effect, cytotoxic IL-2 receptor antibodies that deplete the high affinity receptor-bearing cells are needed.
 ...
PMID:Interleukin-4 bypass of the immunosuppressive effect mediated by interleukin-2 receptor antibodies. 843 32

The relationship between acute and chronic graft-versus-host disease (GVHD) is not well understood. While both syndromes appear to result from recognition of host antigens by donor T cells, their pathological changes differ markedly. In light of the recent concept that helper T cells (Th) may be divided into two types based on their cytokine secretion profile and their ability to mediate cellular (Th1) or humoral (Th2) immunity, and considering the inflammatory nature of acute GVHD and the occurrence of significant B cell activation in chronic GVHD, we hypothesized that acute and chronic GVHD may be associated with differential cytokine production by activated T cells. To evaluate this hypothesis, we assessed expression of a range of cytokines in (C57BL/6 x DBA/2)F1 (B6D2F1) recipients of C57BL/6 (acute GVHD), DBA/2 (chronic GVHD) or B6D2F1 (control) spleen cells. The results reported here indicate that a wide range of cytokines, including interleukin (IL)-4, IL-10, interferon-gamma, tumor necrosis factor beta and macrophage inflammatory protein-1 alpha, are indeed differentially expressed in acute and chronic GVHD and support the concept that the pathology peculiar to acute or chronic GVHD may arise due to differential cytokine expression by activated T cells.
 ...
PMID:Differential cytokine expression in acute and chronic murine graft-versus-host-disease. 843 68

Peripheral blood mononuclear cells (PBMC) from 17 patients receiving HLA-identical sibling bone marrow grafts were stimulated with host pretransplant PBMC. Cytotoxic T-cell lines (TCL) with specificity for host pretransplant PBMC were obtained from 9 of these patients, all presenting with severe graft-versus-host disease (GVHD), but from none of the remaining cases lacking evidence of disease. Cytotoxic TCL were specific for host targets and failed to lyse donor cells. Monoclonal antibodies (MoAbs) blocking experiments and donor population screening analyses demonstrated that minor histocompatibility antigen (MiHA)-specific lysis of host targets was restricted by class I major histocompatibility complex (MHC) determinants. Whereas hematopoietic cells such as phytohemagglutinin (PHA) blasts or lymphoblastoid cell lines were susceptible to lysis by MiHA-specific TCL, keratinocytes (K) representing the natural targets of GVHD were quite resistant. Quantitative radioimmunometric measurements indicated very low constitutive expression of class I MHC antigens on K targets, which was readily increased by treatment with interferon-gamma (IFN-gamma). IFN-gamma treatment at the same time rendered these cells susceptible to lysis by MiHA-specific TCL. Host leukemic cells of 3 patients were recognized by MiHA-specific TCL in a chromium release assay and in one experiment host leukemic cells were effectively killed and their growth specifically inhibited in a leukemia colony assay by a clone. These data demonstrate that (1) host-specific cytotoxic TCL are detected exclusively in the PB of patients with acute GVHD grades II through IV after allogeneic matched bone marrow transplantation, and (2) their target antigens are simultaneously expressed on several host cell lines, including lymphoblastoid cell lines, PHA blasts, leukemic cells, and K. We also extend previous findings by showing that, besides the expression of the nominal MiHA, the density of the restricting class I MHC elements also crucially determines the extent of TCL lysis. Because of its capacity to enhance class I MHC antigen expression, IFN-gamma represents a key cytokine for determining the susceptibility of MiHA targets for lysis by TCL and clones, and in one patient an MiHA-specific clone recognized host leukemic cells and also inhibited host leukemic cell growth in a colony inhibition assay.
 ...
PMID:Correlation of minor histocompatibility antigen-specific cytotoxic T lymphocytes with graft-versus-host disease status and analyses of tissue distribution of their target antigens. 847 80

The pathological complications of bone marrow transplantation are complex and may affect any organ in the body. The causes are often multifactorial and include the effects of chemotherapy, the conditioning regimen, drugs used in the post-transplant period such as immunosuppressants and antibiotics, graft-versus-host disease (GvHD) and the effects of the primary disease itself. Infections are common and result from the immunosuppressive effects of cytotoxic drugs and irradiation, GvHD and marrow failure. Haemorrhage is not infrequent. Graft-versus-host disease remains a significant problem and can be difficult to diagnose. Some of its histological features simulate the effects of chemoradiation and the diagnostic lesions may not be present early in the disease, when treatment is most effective. Evidence has accumulated that inflammatory cytokines have a key role in the pathogenesis of GvHD. It can be prevented by eliminating T-cells from the donor marrow but this procedure adversely affects marrow engraftment, increases the changes of rejection and results in a higher incidence of leukaemic relapse. Immunohistochemical staining for various cytokine-inducible molecules has led to some improvement in early diagnosis.
 ...
PMID:The pathology of bone marrow transplantation. 849 53

Due to the accumulation of evidence concerning a putative role of nitric oxide (NO) in graft-versus-host disease (GVHD), we performed follow-up measurements of the stable end-products of NO, nitrite/nitrate (NO2-/NO3-) in plasma of patients undergoing allogeneic (n = 16) and autologous (n = 6, as a control) bone marrow transplantation. NO2-/NO3- concentrations were set in relation to the clinical course and to serum levels of soluble tumor necrosis factor receptor 75 (sT-NFrec 75) and neopterin, both of which are known to be sensitive indicators of cellular immune activation phenomena involving macrophages in vivo, and endogenous interleukin (IL)-10, a major T helper cell type 2 (TH-2)-derived cytokine and potent inhibitor of macrophage activation and NO formation. A significant rise of NO2-/NO3- levels was observed in patients with GVHD and preceded the onset of clinical symptoms by up to 3 days. In contrast to indicators of macrophage activation, i.e., neopterin and sT-NFrec75, NO2-/NO3- concentrations were not significantly altered from baseline levels during infectious complications, as NO2-/NO3- concentrations did not fluctuate in patients after autologous engraftment. During episodes of acute GVHD, NO2-/NO3- concentrations showed a strong positive correlation with levels of plasma neopterin and sTNFrec 75, but were also significantly related to IL-10. In non-GVHD patients, a negative correlation between IL-10 and NO2-/NO3- concentrations was evident. Therefore, NO2-/NO3- determination may be a valuable early indicator of the initiation of human GVHD. Our results provide some further insights concerning cytokine-related metabolic changes in the course of human GVHD in vivo which may prove useful in the development of new therapeutic approaches for this disease.
 ...
PMID:Nitric oxide formation as predictive parameter for acute graft-versus-host disease after human allogeneic bone marrow transplantation. 852 17

We show that while interleukin-1 and tumor necrosis factor-alpha antagonists are partially able to inhibit graft-versus-host disease (GVHD) when bone marrow (BM) transplantation is performed in irradiated recipients of minor antigen-disparate donor BM, these same antagonists do not inhibit GVHD when donor BM is fully MHC disparate. This failure in MHC-disparate recipients occurs despite the presence of interleukin-1 and tumor necrosis factor-alpha mRNA in tissues of GVHD mice measured by in situ hybridization and despite escalation of antagonist dosages far beyond those used in previous reports. These findings indicate that a relationship may exist between cytokines that amplify GVHD and target antigens that elicit GVHD. Moreover, when GVHD inhibition was observed in the minor model, it was transient, which suggests that it may be important to target more than one cytokine to effectively inhibit GVHD. These findings suggest that caution is in order in clinical GVHD studies based entirely on anti-proinflammatory cytokine treatment.
 ...
PMID:Interleukin-1 or tumor necrosis factor-alpha antagonists do not inhibit graft-versus-host disease induced across the major histocompatibility barrier in mice. 852 41

Interleukin-1 receptor type 1 (IL-1R), IL-2 receptor alpha subunit (IL-2R) and IL-6 receptor alpha subunit (IL-6R) mRNA expression in peripheral blood mononuclear cells (PBMC) in 17 patients who underwent allogeneic bone marrow transplantation (allo BMT) and 2 patients who underwent autologous transplantation were analyzed using a semiquantitative reverse-transcriptase polymerase chain reaction (RT-PCR). There were several exceptions in some cases and IL-1R expression was found to vary in a rather wide range, however, the expression of IL-2R and IL-6R mRNA tended to increase during the development of graft-versus-host disease (GVHD). In particular, IL-2R mRNA expression was increased in four patients with GVHD and graft failure. In contrast, IL-2R and IL-6R mRNA expression was not increased in autologous (auto) BMT and auto peripheral blood stem cell transplantation (PBSCT) patients. These findings suggest that IL-2R and maybe IL-6R mRNA expression in PBMC play an important role in the development of an allo response and GVHD. Therefore, the analysis of cytokine receptor mRNA expression in PBMC after allo BMT may provide important information concerning the immune response and the cytokine network system in marrow transplants.
 ...
PMID:Cytokine receptor gene expression in peripheral blood mononuclear cells during graft-versus-host disease after allogeneic bone marrow transplantation. 853 20

GVHD in animal models induces severe thymic atrophy as a result of prolonged secretion of high concentrations of adrenal glucocorticoids. In this study we investigated the mechanism responsible for the persistent stimulation of the adrenal glands to secrete glucocorticoids in mice undergoing GVHD. GVHD was induced across the major and multiple minor histocompatibility antigen difference in unirradiated C57Bl/6 x AF1 hybrid mice by the intravenous injection of A strain parental lymphoid cells. Our results showed plasma corticosterone (CS) levels were elevated in association with high concentrations of corticotropin (ACTH) in both the GVHD and control syngeneic (SYN) groups on day 9. By days 16 and 24, plasma CS and ACTH in the SYN mice returned to basal levels. In contrast, plasma CS levels remained elevated in the GVHD animals on days 16 and 24 despite decreasing concentrations of plasma ACTH. Reverse transcription-polymerase chain reaction (RT-PCR) showed several-fold increase in POMC mRNA in the adrenal glands of GVHD mice compared with SYN animals. In addition, high mRNA levels for murine prohormone convertase 1, the enzyme that cleaves POMC into ACTH, were also detected in GVHD adrenals. Histological analysis of GVHD adrenals failed to show any sign of adrenalitis, and RT-PCR of GVHD adrenals also failed to detect mRNA for interferon-gamma (IFN-gamma), a cytokine expressed by activated T and natural killer (NK) cells. However, mRNA for IL-12, a cytokine produced by activated macrophages, was increased in GVHD adrenals, suggesting that resident adrenal macrophages were activated during GVHD. Our findings suggest that persistent elevated levels of plasma glucocorticoids during GVHD could be mediated by intra-adrenal ACTH produced by resident adrenal macrophages activated as a consequence of GVHD.
 ...
PMID:Increased expression of proopiomelanocortin (POMC) mRNA in adrenal glands of mice undergoing graft-versus-host disease (GVHD): association with persistent elevated plasma corticosterone levels. 853 78


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>