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

Natural suppressor (NS) cells, which nonspecifically suppress immune responses, are present in the spleen following exposure to radiation, chronic graft-versus-host disease, or cancer and in normal bone marrow. A model system is described which allows the study of cytokines activating and inhibiting NS cells, cytokines mediating NS activity, and NS effects on cytokine synthesis. Recombinant interleukin-3 (rIL-3) and granulocyte-macrophage colony-stimulating factor (rGM-CSF) efficiently activated NS cells present in normal bone marrow and were effective at concentrations as low as 5 U/ml. At high concentrations, GM-CSF, but not IL-3, did not activate NS cells. Recombinant interferon-gamma (rIFN-gamma) blocked the activation of bone marrow NS cells by rIL-3, but did not down-regulate NS cells once activated. The NS cells secreted one or more soluble suppressor factors, which blocked IL-2 synthesis and also inhibited IL-2-dependent T cell proliferation in the presence of excess IL-2.
 ...
PMID:Cytokine regulation of bone marrow natural suppressor cell activity in the suppression of lymphocyte function. 153 70

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

A human skin explant model was used to investigate the role of cytokines in graft-versus-host reactions (GVHR). Responder cells from HLA mismatched mixed lymphocyte cultures (MLC) produced GVHR (Grades I-III) in skin explant assays. Cell-free supernatants from these experiments also induced similar histopathological changes in the skin. The greatest degree of correlation between the GVHR observed with responder cells and the supernatant was shown with CD4 enriched MLC (p less than 0.001). Supernatants were assayed for tumour necrosis factor-alpha (TNF alpha) and interferon-gamma (IFN gamma) and CD4 enriched MLC populations produced high levels of these cytokines. These results correlated with the grade of GVHR observed in skin explant assays. The GVHR produced by the supernatant alone could be inhibited by both anti-IFN gamma and anti-TNF alpha polyclonal antibodies. The results suggest that TNF alpha and IFN gamma are directly involved in tissue damage during graft-versus-host disease in allogeneic transplant in man.
 ...
PMID:Demonstration of direct involvement of cytokines in graft-versus-host reactions using an in vitro human skin explant model. 182 87

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

Serum levels of interferon-gamma and the IFN-dependent marker molecules neopterin and beta 2-microglobulin were assessed in BMT recipients. Concentrations of the latter two markers were corrected for creatinine levels in order to eliminate the impact of alteration of kidney function. Serum levels were assessed daily using commercially available radioimmunoassays. Twelve patients were studied during the early phase of allogeneic bone marrow transplantation and eleven additional patients during complications of BMT. Results indicated that both the conditioning regimen for BMT as well as major clinical complications such as infection and acute graft-versus-host disease strongly influence the endogenous patterns of the lymphokine and its secondary messages. During allogeneic BMT IFN-gamma and neopterin levels exhibited a biphasic pattern with a first peak during conditioning with high-dose cyclophosphamide and a second still higher peak at the time of hemopoietic regeneration. beta-2-microglobulin ratios increased during conditioning and remained elevated throughout observation. Serious infections of bacterial and viral origin as well as GvHD were accompanied by elevated levels of all three serum parameters studied. The kinetics of enhanced endogenous production, however, differed between infectious complications and GvHD. Increasing concentrations were observed during infections subsequent to clinical manifestation, whereas they preceded disease manifestation in GvHD.
 ...
PMID:Endogenous IFN-gamma during human bone marrow transplantation. Analysis of serum levels of interferon and interferon-dependent secondary messages. 217 Nov 63

We report four cases of Omenn's syndrome (OS), an autosomal recessive disease characterized by early erythrodermia, protracted diarrhea, severe infections, lymphadenopathy, hepatosplenomegaly, failure to thrive, and leukocytosis with marked eosinophilia. The immunological investigations revealed B lymphopenia with increased levels of serum IgE and marked depression of T-cell activation, not restored by the addition of exogenous interleukin 2 (IL-2). IL-2 and interferon-gamma (IFN-gamma) production in vitro were very low or absent. One patient was treated with HLA-identical bone marrow transplant with a complete remission of the clinical picture and the immunological defect. The infant died of graft versus host disease 4 months after the graft. For the remaining three infants the outcome was also fatal within the first year of life. In conclusion, OS should be considered a severe combined immunodeficiency disease with peculiar clinical, immunological, and histological findings.
 ...
PMID:Clinical and immunological findings in four infants with Omenn's syndrome: a form of severe combined immunodeficiency with phenotypically normal T cells, elevated IgE, and eosinophilia. 311 64

Injection of parental strain rat lymphocytes under the kidney capsule of semi-allogeneic F1 recipients causes a local graft-versus-host reaction (GVHR) characterized by a heavy mononuclear cell infiltrate and renal tubular destruction. Since the cellular events involved may have relevance to allogeneic tissue damage in GVH disease and allograft rejection, a detailed analysis of the rat renal GVH reaction was performed. A purified CD4+ lymphocyte subpopulation was as effective in mediating a local GVHR as unfractionated parental lymphocytes, but neither naive CD8+ nor specifically sensitized CD8+ lymphocytes produced a detectable renal GVHR. Mononuclear cells harvested from renal GVHR lesions induced by CD4+ lymphocytes were able to lyse natural killer (NK)-sensitive targets when tested in vitro, but showed no allospecific cell-mediated cytotoxicity. Experiments using recombinant PVG rats demonstrated that the ability of the injected cells to cause a GVHR was dependent upon a disparity in MHC class II antigens and that an isolated disparity of MHC class I antigens alone was not a sufficient stimulus to provoke a response. The use of chimaeric rats demonstrated that F1 MHC alloantigens present on kidney parenchyma (but absent on bone marrow-derived cells) were not sufficient to stimulate injected parental lymphocytes, even in the presence of markedly increased amounts of MHC antigens on vascular endothelium and renal tubular cells following in vivo administration of interferon-gamma (IFN-gamma). These results suggest that the renal GVHR in the rat is mediated principally by the interaction of parental CD4+ lymphocytes recognizing and responding to class II F1 alloantigens on bone marrow-derived cells. The resulting tissue damage is most likely a result of a delayed-type hypersensitivity (DTH) phenomenon.
 ...
PMID:The cellular basis of the local graft-versus-host reaction in rat kidney. 326 45

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

Interleukin-12 (IL-12) is a potent immunostimulatory cytokine and an inducer of type-1 T-helper cell activity and of cytotoxic T lymphocyte and natural killer cell function. We report here the paradoxical observation that a single injection of 4,900 IU of recombinant murine IL-12 inhibits acute graft-versus-host disease (GVHD) in a fully major histocompatibility complex (MHC) plus multiple minor antigen-mismatched bone marrow transplantation (BMT) model (A/J-->B10). The protective effect was enhanced by administration of T-cell-depleted host-type BM cells, and complete donor-type lymphohematopoietic reconstitution was observed in most animals. Treatment with a protective course of IL-12 led to increased serum interferon-gamma (IFN-gamma) levels as compared with those for GVHD controls at early time points, when IFN-gamma was produced predominantly by host-type natural killer cells, but led to almost complete inhibition of the later GVHD-associated increase in serum IFN-gamma levels, when IFN-gamma is produced predominantly by CD4+ T cells. Furthermore, IL-12 treatment was associated with marked alterations in the kinetics of donor T-cell expansion. Reductions in donor CD4+ and CD8+ T cells were observed in the spleen on day 4 post-BMT, but a marked increase in donor CD8+ cells was observed on day 7. Unlike broadly immunosuppressive methods for inhibiting GVHD, which are associated with loss of antileukemic effects, IL-12 has the potential to mediate antileukemic effects of its own; therefore, the GVHD-inhibitory effects of IL-12 described here suggest a potential application for this cytokine in clinical BMT.
 ...
PMID:Interleukin-12 inhibits murine graft-versus-host disease. 766 91


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