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)

The potential involvement of cytokines in acute graft-versus-host disease led us to analyze interleukin-6 in serial serum sets from 22 allogeneic marrow recipients who developed either grade 3 or 4 GVHD (n = 10), grade 2 GVHD (n = 6), or grade 1 or no diagnosed GVHD (n = 6). A total of 279 serial serum samples taken three times weekly before day 35 were analyzed. Maximum IL-6 levels were greater than 40 U/ml (range, 40-1536 U/ml), 11-40 U/ml, and less than or equal to 10 U/ml for six, eleven, and five patients, respectively. Serum IL-6 peaks were temporally related to onset of GVHD, onset of a syndrome of hepatorenal dysfunction (HRD), or bilateral lung infiltration. Eight of ten patients who developed grade 3 or 4 GVHD overall had IL-6 maxima of greater than 10 U/ml an average of 1.5 +/- 1.8 days before the clinical onset. Fifteen of 17 patients with peak IL-6 levels greater than 10 U/ml developed symptoms of hepatic and renal dysfunction within three days of the peak, while none of five patients with less than or equal to 10 U/ml of Il-6 developed HRD. Regression analysis demonstrated a linkage between the log magnitudes of the serum IL-6 peaks and onset of either GVHD or HRD within three days (P = 0.001). Furthermore, IL-6 peaks tended to precede GVHD onset for the 10 patients whose GVHD onset and IL-6 peak were within three days of each other (P = 0.02). These results, confirmed by both specific bioassay and by IL-6 ELISA, support the idea that acute GVHD in humans involves a cytokine cascade that includes production of IL-6 in addition to the previously reported involvement of tumor necrosis factor alpha and interferon-gamma.
 ...
PMID:The relationship of serum IL-6 levels to acute graft-versus-host disease and hepatorenal disease after human bone marrow transplantation. 141 27

Cyclosporin A (CsA) is a potent inhibitor of cytokine (IL-2-IL-6, IFN gamma) production by CD4+ T lymphocytes stimulated via the T cell antigen receptor pathway. This action results in indirect inhibitory effects on the growth and differentiation of B lymphocytes (IL-4 and IL-6). Using experimental models, it has also been shown that the functional activities of mononuclear phagocytes (IFN-gamma) and other antigen-presenting cells, production of mast cells (IL-3) and eosinophils (IL-5) and the activity of natural killer (NK) cells may be inhibited indirectly by CsA. In addition, however, CsA blocks B cell responses to Ca(2+)-dependent signals (e.g., anti-IgM) downstream of phosphatidyl inositol diphosphate hydrolysis; Ca(2+)-independent responses (e.g., to LPS or IL-4) are largely unaffected. In general terms, the functions of macrophages are unchanged or reduced in the presence of CsA. These include phagocytic activity in vitro and in vivo, chemotactic migration, superoxide and H2O2 production, protein (including monokine) secretion and MHC gene product expression. Antigen presentation (e.g., by epidermal Langerhans cells) may be affected, especially at high drug concentrations. There is recent evidence that CsA inhibits mediator (histamine and prostaglandin) release from human mast cells and that mucosal mast cell numbers may be diminished in CsA-treated animals exhibiting graft-versus-host disease or helminth infections.
 ...
PMID:The effects of cyclosporin A on non-T cell components of the immune system. 150 9

These studies examined the role of cytokines in chronic autoimmune graft-versus-host disease (GVHD) in B6D2F1 mice injected with lymphoid cells from DBA/2 mice. Anti-interleukin (IL)-4 and anti-interferon (IFN)-gamma mAb, or IFN-gamma, were used in vivo to modulate B cell hyperactivity and disease. Kinetic experiments showed that, 2-3 weeks after induction, GVH mice had 100x elevated serum IgE, while IgG1 and IgG2a were 10x above normal. Early treatment with anti-IL-4 mAb or IFN-gamma decreased serum IgE and IgG1 and had no effect on IgG2a. Anti-IFN-gamma mAb treatment increased serum IgE and IgG1 while reducing IgG2a. This increase in serum immunoglobulins could be correlated with an increased spontaneous secretion of IL-4, IL-5, and IL-6 in spleen cell cultures from anti-IFN-gamma mAb-treated GVH mice. While neither anti-IFN-gamma nor IFN-gamma treatments altered the disease course, anti-IL-4 treatment delayed proteinuria and death in GVH mice. These observations suggest an important role for IL-4 in immune complex-mediated glomerulonephritis in chronic GVHD.
 ...
PMID:Effects of in vivo administration of interferon (IFN)-gamma, anti-IFN-gamma, or anti-interleukin-4 monoclonal antibodies in chronic autoimmune graft-versus-host disease. 159 85

The pteridine neopterin is a marker of immunological activation and has been shown to be a useful marker of graft-versus-host disease (GVHD) in bone marrow transplant patients. High levels of both neopterin and interferon-gamma (IFN-gamma) were produced in vitro during mixed lymphocyte responses, which may be considered to be a model of the primary events leading to GVHD. Neopterin was shown to be produced by monocytes in response to stimulation with IFN-gamma, but not other cytokines. However, the interleukins IL-1 alpha, IL-1 beta, IL-2, and tumour necrosis factor (TNF) alpha and beta, but not IL-6, stimulated neopterin production by unfractionated peripheral blood mononuclear cells (PBMC), and culture supernatants from PBMC stimulated with IL-1 alpha, IL-1 beta, IL-2 and IL-6, but not TNF-alpha or TNF-beta induced neopterin production following transfer to fresh monocyte cultures. It therefore appears that cytokines may generate neopterin by induction of IFN-gamma, by synergy with low levels of induced IFN-gamma, or by non-IFN-gamma-dependent mechanisms.
 ...
PMID:Cytokine induction of neopterin production. 182 41

The role of cytokines in the development of acute graft-vs-host disease (GVHD) was investigated in B6AF1 mice that were injected with parental A/J lymphocytes. Splenocytes from GVH mice exhibited an increased capacity to produce interleukin (IL)-1, IL-6, and TNF-a when stimulated in culture with lipopolysaccharide (LPS). This enhanced capacity was diminished following in vivo treatment with immunosuppressive drugs. Concanavalin A-stimulated GVH spleen cells produced significantly lower levels of IL-2 but higher levels of interferon-gamma (IFN-gamma) than did syngeneic spleen cells. Immunosuppressive therapy in vivo increased the capacity of GVH spleen cells to produce IL-2. However, immunosuppressants differed in their effects on IFN-gamma production. Sch 24937 (6-bromo-5-chloro-2-[1-(methylsulfonyl)acetyl] 3-(2-pyridyl)indole) enhanced or had no effect while cyclosporin A consistently decreased the capacity of splenocytes to produce this lymphokine. These results indicate that the capacity of GVH splenocytes for cytokine production can be differentially affected by the actions of some pharmacological agents. The data also indicate that there may be differential regulation of the production of IL-2 and IFN-gamma by the Th1 subset in the GVH spleen.
 ...
PMID:A study of cytokine production in acute graft-vs-host disease. 190 99

After bone marrow transplantation many T-lymphocyte functions, including the production of cytokines (CK), such as interleukin 2, are severely depressed for months. The monocyte-derived cytokines tumor necrosis factor alpha and interleukin 6 are molecules central to immune functions. Moreover, they may be involved in graft-versus-host disease and in graft-versus-leukemia reaction. Hence, we have studied the reappearance of these CKs after BMT by analyzing whole blood cultures stimulated in vitro with lipopolysaccharide for 6 hr, followed by testing for the secretion of TNF in the WEHI 164/actinomycin D cytotoxicity bioassay and for IL-6 in the 7 TD 1 proliferation assay. We performed sequential studies in 6 children who were transplanted for aplastic anemia or leukemia with allogeneic bone marrow. We found that the production of both CKs can be induced as early as 10-14 days post BMT at the very beginning of engraftment, indicating that the regenerating monocyte system is recovering rapidly after BMT. Depletion and neutralization experiments confirmed that monocytes are the cellular source of the LPS-induced CK secretion after BMT. Control levels were reached 3 to 4 weeks post BMT. When analyzing the endotoxin-induced CK production in a larger panel of BMT patients after complete reconstitution, we could not detect any impact of acute or chronic GvHD, or of allogeneic or autologous BMT, nor did treatment with cyclosporine A (CsA) show any suppressive effect. Thus, our data show that the CK production of the monocyte/macrophage lineage is quite resistant to factors that do influence other cell lineages of the immune system during BMT. The coincident appearance of monocyte-derived cytokines and of GvHD suggests a role for these cytokines in GvHD in man.
 ...
PMID:Recovery of monocytes after bone marrow transplantation--rapid reappearance of tumor necrosis factor alpha and interleukin 6 production. 192 48

Although acute graft-versus-host disease (GVHD) is a common complication after allogeneic bone marrow transplantation (BMT), the specific pathophysiology of tissue damage has not been elucidated. We have previously described an infiltrate of CD2+, CD8+, alpha/beta receptor+ T lymphocytes, and the upregulation of ICAM-1 in tissues with acute GVHD. We hypothesized that these infiltrating lymphocytes may secrete cytokines that could contribute to tissue damage. In the current study, we used reverse transcription (RT) polymerase chain reaction (PCR) to explore the mRNA expression of candidate inflammatory cytokines IL-1 alpha, IL-2, IL-4, IL-6, TNF-alpha, and interferon-gamma (IFN-gamma) in peripheral blood mononuclear cells (PBMC) and skin biopsies of allogeneic BMT patients with GVHD and controls. In post-BMT control PBMC (n = 10); IL-2 RNA was infrequent (20% of samples) but was significantly more frequently detectable (71%; P < 0.05) after development of acute GVHD (n = 7). IL-4 expression was also more common in PBMC from patients with acute GVHD (57% vs. 30%; P < 0.05). Consistent with the PBMC data, IL-2 and IL-4 RNA were also more frequently detectable in skin biopsies with GVHD (n = 10): 70% of samples expressed IL-2 vs. 25% of normal controls (n = 8; P < 0.05); 60% had detectable IL-4 RNA vs. 0% of controls (P < 0.05). IFN-gamma detectability (40% vs. 12%; P < 0.05) was also more frequent in GVH skin. For both PBMC and skin, IL-1 alpha expression was infrequent in GVHD and controls, whereas TNF-alpha and IL-6 were expressed in nearly all samples. These data suggest that upregulated expression of IL-2, IL-4, and IFN-gamma may be part of the inflammatory cascade of human acute GVHD, while IL-1 alpha, TNF-alpha, and IL-6 are not discriminatory for the inflammation observed at the time of initial GVHD diagnosis.
 ...
PMID:The tissue expression of cytokines in human acute cutaneous graft-versus-host disease. 765 63

TNF alpha levels were determined by ELISA in serum from 112 BMT patients during pre-transplant conditioning. Patients who developed post-transplant complications had significantly higher TNF alpha levels than those without complications (mean 620 pg/ml vs 440 pg/ml, P = 0.04). In particular this effect is associated with patients who developed grade II-IV acute GVHD (mean 960 pg/ml, P < 0.001) and chronic GVHD (mean 724 pg/ml, P = 0.001). High TNF alpha levels were the only statistically significant risk factor for acute GVHD. IL-1 beta and IL-6 levels were not correlated with TNF alpha levels or posttransplantation complications. In multivariate analysis of chronic GVHD, patient age > 17 years and CMV disease were the only statistically significant risk factors. Relapse was associated with low levels of TNF alpha during conditioning (mean 318 pg/ml, P = 0.02). In multivariate analysis, high risk disease was the only factor that correlated with relapse. Low risk patients had significantly higher levels than high risk patients (551 vs 377, P= 0.04). CML and MDS patients had higher TNF alpha levels than acute leukemia patients. There was no difference in TNF alpha levels between patients conditioned with BU/CY and CY/TBI. We conclude that determination of TNF alpha levels during conditioning may be useful in the prediction of acute GVHD.
 ...
PMID:TNF alpha levels are increased during bone marrow transplantation conditioning in patients who develop acute GVHD. 774 64

Cytokines play a key role in the pathogenesis of chronic Graft versus Host Disease (cGVHD) and various studies have shown abberant production of cytokines by immune cells from GVHD patients. Based on these findings and others showing that high TNF levels precede the development of GVHD, we evaluated inflammatory cytokine levels following BMT and during the development of cGVHD. In this study, patients undergoing bone marrow transplantation (BMT) who consequently developed chronic GVHD were analyzed as to their cytokine production during cGVHD and this was correlated with their clinical manifestations. A positive correlation was found between the severity as well as the number of major clinical complications and high levels of inflammatory cytokines (IL-1 beta IL-6 and TNF alpha) compared to control patients or to normal donors. Patients undergoing BMT who did not develop GVHD, did not produce high levels of IL-1 beta IL-6 or TNF. High levels of cytokines may be used as a tool for assessing novel therapeutic modalities and response to GVHD treatment.
 ...
PMID:Cytokine dysregulation in chronic graft versus host disease. 777 55

Cytokines produced by T lymphocytes, monocytes/macrophages, and fibroblasts play a central role in the immune response and in the development of graft-versus-host disease (GVHD). Also, it has been reported that dysregulated production of cytokines maybe the primary mediator of clinical manifestation of acute GVHD. Regarding cytokine gene expression after human allogeneic bone marrow transplantation (allo BMT), we have demonstrated increased IL-1 beta, IL-6, and TNF-alpha mRNA expression in peripheral blood mononuclear cells during the development of acute and chronic GVHD and that the degree of the increase was dependent on the severity of the disease. Furthermore, overexpression of these cytokine mRNAs could be detected before the clinical manifestations of GVHD developed. In contrast, IL-2 mRNA expression was not detected in peripheral blood mononuclear cells in GVHD patients. On the other hand, we have reported that increased mRNA expression and protein product of IL-2 and IFN-gamma were evident in the mixed lymphocyte culture of the cases who developed severe lethal transplantation-related complications. Therefore, the detection of increased IL-2 and IFN-gamma gene expression in MLC appeared to be useful for predicting transplantation-related complications in BMT patients. Furthermore, we found increased IL-2 receptor alpha subunit mRNA expression in the peripheral blood mononuclear cells during GVHD. These findings may indicate the important role of inflammatory cytokines such as IL-1 beta, IL-6 and TNF-alpha in the development of the clinical manifestation of GVHD and also may be indicative of the important role of IL-2 and the IL-2 receptor in allo response perhaps mainly as an autocrine effect.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Cytokine gene expression after allogeneic bone marrow transplantation. 778 51


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