Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have explored the effect of IL-3 and IL-6, each alone and in combination with G-CSF, GM-CSF or IL-1, on neutrophil and platelet recovery in BALB/c mice (H-2d) given 10 Gy total body irradiation followed by 10(7) bone marrow cells and 10(6) spleen cells from C57BL6 donors (H-2b), as well as the effect of IL-3 alone and IL-6 alone on graft-versus-host disease (GVHD) and survival. Neither IL-3 alone nor IL-6 alone significantly increased the circulating absolute neutrophil count (ANC) at day 6 post transplant when compared with mice given saline injections (ANC 0.31 x 10(9)/l). G-CSF and IL-1, each alone, significantly raised the day-6 ANC (0.58 x 10(9)/l, p = 0.02; 0.67 x 10(9)/l, p = 0.007 respectively). However, IL-3, 200 ng twice daily, significantly increased the day-6 ANC when used in combination with GM-CSF (0.49 x 10(9)/l, p = 0.003) or with IL-6 (0.66 x 10(9)/l, p = 0.004), as well as with G-CSF (0.62 x 10(9)/l, p = 0.007) or with IL-1 (0.49 x 10(9)/l, p = 0.003). Apart from the combination with IL-3, IL-6 significantly raised the day-6 ANC only in combination with G-CSF (0.79 x 10(9)/l, p = 0.007). When used alone, both IL-6 and G-CSF raised the day-6 platelet count (312 x 10(9)/l, p = 0.02 and 309 x 10(9)/l, p = 0.01 respectively) compared with control mice (216 x 19(9)/l). IL-3 alone resulted in a platelet count of 303 x 10(9)/l (p = 0.06). In combination, only IL-3 with G-CSF significantly increased the value over that of saline control mice (328 x 10(9)/l, p = 0.02). IL-3 200 ng alone twice daily and IL-6 200 ng alone twice daily for 14 days post transplant resulted in survival not different from that of mice given saline injections. However, IL-3 500 ng twice daily for 14 days resulted in impaired survival and accelerated weight loss. In summary, while neither IL-3 nor IL-6 (nor GM-CSF) used alone accelerated neutrophil recovery post transplant, the combinations of IL-3 plus IL-6 and IL-3 plus GM-CSF did so. IL-6 (and G-CSF) accelerated platelet recovery post transplant, but combining IL-3 or IL-6 with the other cytokines was generally unsuccessful in this regard. Higher-dosage IL-3 appeared to accelerate graft-versus-host disease and impair survival, thus providing indirect evidence of the involvement of this cytokine in the mediation of GVHD.
Cytokines Mol Ther 1995 Mar
PMID:Effect of in vivo administration of IL-3 and IL-6, alone and in combination with G-CSF, GM-CSF or IL-1, on haematopoiesis, graft-versus-host disease and survival after murine haematopoietic stem cell transplantation. 938 63

We treated 12 patients with leukemia relapse after allogenic bone marrow transplantation with a combination of interferon-alpha (IFN-alpha) ((2.5-5.0) x 10(6) u/m2 subcutaneously three times a week) and interleukin-2 (IL-2) ((1.8-3.6) x 10(6) IU/m2 subcutaneously five times a week) to determine the toxicity and efficacy of combination cytokine therapy in this setting. The median age of the patients was 39 years (range: 16-50). There were nine females and three males. The median time to relapse from BMT was 98 days (range: 0-963). At the time of relapse, six patients had AML, four patients had CML (two in blast crisis and two in chronic phase with clonal evolution), and one patient had lymphoblastic lymphoma. Combination cytokine therapy was started a median of 108 days post BMT (range: 37-2404). Nine patients treated at the higher dose level required a 50% dose reduction because of toxicity or GVHD (three CNS, two GVHD, one high fever, one diarrhoea with hypotension, and one pericarditis). At a lower dose level, 2 of 10 patients had their treatment discontinued because of toxicity or GVHD. Six patients developed clinical findings consistent with acute GVHD while on combination cytokine therapy. Two patients responded to combination cytokine therapy: one with CML and one with AML. Combination cytokine therapy is feasible in the setting of relapse post allogeneic BMT. The combination of IL-2 1.8 x 10(6) IU/m2 five times a week with IFN-2 2.5 x 10(6) U/m2 three times a week seems to be tolerable, and merits further study in this setting.
Cytokines Mol Ther 1995 Jun
PMID:Interferon-alpha and interleukin-2 as treatment for leukemia relapse after allogeneic bone marrow transplantation. 938 68

Interferon-gamma (IFN-gamma) is known to be involved in graft rejection of solid organs and acute graft-versus-host disease (GVHD). Its role, and especially that of soluble IFN-gamma receptor (sIFN-gamma R), in bone marrow transplantation (BMT) has not been established. We evaluated the sera of 27 patients following BMT. Fourteen of them underwent uneventful BMT, whereas 13 developed transplant-related complications, including acute GVHD (n = 5), early rejection (n = 4), or relapse of basic disease (n = 4). Soluble IFN-gamma R and IFN levels were evaluated at day -10 (preconditioning), day 0 (day of BMT), day of engraftment, and during BMT-related complications using sIFN-gamma R-specific monoclonal antibodies (McAB) followed by double-sandwich ELISA, and a sensitive radioimmunoassay respectively. In normal controls (n = 80) sIFN-gamma R and IFN-gamma levels in the sera were 0.5 +/- 0.05 and 0.3 +/- 0.04 ng/ml respectively. Soluble IFN-gamma R levels increased in direct correlation with engraftment (0.63 +/- 0.11 ng/ml at the day of BMT to 1.43 +/- 0.16 ng/ml at the day of engraftment; n = 14; P < 0.001). IFN-gamma levels increased in direct correlation with engraftment (0.37 +/- 0.03 ng/ml at the day of BMT to 5.69 +/- 1.64 ng/ml at the day of engraftment; n = 14; P < 0.001). In five patients with GVHD sIFN-gamma R levels increased from 0.43 +/- 0.19 ng/ml at the day of BMT to 1.73 +/- 0.17 ng/ml (P < 0.004) at the time of GVHD. Similarly, IFN-gamma levels increased from 0.43 +/- 0.08 ng/ml at the day of BMT to 3.03 +/- 0.5 ng/ml at the time of GVHD (P < 0.05). Both graft rejection and early relapse were associated with an elevation of IFN-gamma levels. In short, both s-IFN-gamma R and IFN-gamma were found to be significantly elevated during engraftment and GVHD. Hence these cytokines may be used as a tool for assessing engraftment and AGVHD.
Cytokines Cell Mol Ther 1997 Sep
PMID:Soluble interferon-gamma receptor and interferon-gamma in patients undergoing allogeneic bone marrow transplantation for hematological malignancies. 942 73

Pulmonary complications are a major clinical problem following allogeneic bone marrow transplantation (BMT), contributing to more than 30% of transplant-related mortalities. Idiopathic pneumonia syndrome is responsible for significant mortality among BMT patients. However, the etiology of injury to the lung parenchyma by this disease syndrome is unknown and it has been difficult to evaluate the cellular and molecular mechanisms underlying IPS in the absence of a suitable animal model. To study post-BMT lung disease during graft-versus-host disease (GVHD), we have developed a murine model that utilizes a semi-allogeneic parental --> F1 transplant strategy to induce a mild form of GVHD. Progressive inflammatory lung disease developed in animals with mild GVHD, as indicated by changes in immune cell distribution and cytokine expression in the lungs of transplanted animals. Histologic analysis of lung tissue from GVHD mice at 3 wk post-BMT showed minor immunopathologic changes compared with control mice. In contrast, lungs of GVHD mice at 12 wk displayed histopathologic hallmarks of interstitial pneumonitis, such as prominent perilumenal mononuclear cell infiltration and areas of alveolar congestion. Flow cytometric analysis of lung interstitial cells of GVHD mice revealed an increase in CD8+ T-cells at week 3, which decreased to normal levels by week 12 post-BMT. Simultaneously, the percentage of CD4+ T-cells increased progressively above normal levels and peaked at week 7 post-BMT. Analysis of cytokine mRNA expression in lung tissue indicated that steady state levels of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, interferon-gamma, and IL-12 were significantly elevated in lungs of GVHD mice at 3 wk post-BMT compared with untreated controls. Mice that were transplanted with allogeneic bone marrow alone (BMT controls) also displayed elevated expression of these cytokines, although only IL-6 was significantly higher than in untreated controls. In contrast, at 12 wk after transplantation only TNF-alpha and IL-12 levels remained elevated in GVHD mice, suggesting prolonged macrophage activation. On the basis of these findings, we conclude that allogeneic bone marrow transplantation in this mouse model causes a progressive interstitial pneumonitis, which is characterized by an acute influx of CD8+ T-cells, followed in the chronic phase by a prominent accumulation of CD4+ T-cells, and is associated with persistent production of cytokines known to activate macrophages.
Am J Respir Cell Mol Biol 1998 Feb
PMID:Idiopathic pneumonia syndrome in mice after allogeneic bone marrow transplantation. 947 11

Autoantigen-specific CD4+ T cells have been implicated as the causative cell type in: multiple sclerosis, rheumatoid arthritis, autoimmune uveitis, diabetes mellitus, inflammatory bowel disease and graft-versus-host disease. The pathology of a number of experimentally induced autoimmune diseases is also mediated by autoantigen-specific CD4+ T cells. Ideally, treatment of CD4+ T-cell-mediated diseases would eliminate the autoantigen-specific cells, while sparing the remainder of the T-cell repertoire. We have developed an effective therapy that deletes the autoreactive T cells at the site of autoimmune tissue destruction. This approach uses an antibody directed against a cell-surface protein (OX-40, also known as CD134) that is selectively upregulated on activated autoantigen-specific T cells within the inflamed tissue.
Mol Med Today 1998 Feb
PMID:Antibodies to OX-40 (CD134) can identify and eliminate autoreactive T cells: implications for human autoimmune disease. 954 94

Allogeneic cell therapy (allo-CT) is emerging as an effective treatment for patients relapsing after allogeneic bone marrow transplantation (BMT), indicating that tumor cells resisting chemoradiotherapy may still respond to immunocompetent allogeneic lymphocytes. We investigated possible graft-versus-tumor (GVT) effects in six patients with metastatic breast cancer that would be comparable to the graft-versus-leukemia (GVL) phenomenon occurring after allogeneic BMT in hematologic malignancies. The patients were cytoreduced with high-dose chemotherapy and autologous stem cell transplantation (ASCT), and were treated ambulatory with allo-CT consisting of adoptive transfer of HLA-matched donor peripheral blood lymphocytes (PBL) activated in vivo with human recombinant interleukin-2 (rIL-2). If no graft-versus-host disease (GVHD) developed, allo-CT was augmented with infusion of donor PBL, preactivated in vitro with rIL-2. Treatment was well tolerated, with low therapy-related toxicity in all patients. Two patients developed signs and symptoms compatible with GVHD grade I-II, one of whom shows no evidence of disease at more than 34 months out. In the remaining patients, progression-free survival following allo-CT ranged between 7 and 13 months. Allogeneic cell-mediated, cytokine-activated immunotherapy might be utilized for induction of GVT in metastatic breast cancer. A search for techniques to boost chimerism without severe GVHD is indicated.
Cytokines Cell Mol Ther 1998 Mar
PMID:Allogeneic cell-mediated immunotherapy for breast cancer after autologous stem cell transplantation: a clinical pilot study. 955 10

The key factor for the treatment of post-transfusion graft-versus-host disease (PT-GVHD) is the successful eradication of donor-derived cytotoxic T cells (CTLs) which are thought to be a main cause of the disease, with no effects on either peripheral blood mononuclear cells (PBMCs) or tissues of the recipient. In this study, we examined the effect of azidothymidine (AZT: Zidovudine) on resting PBMCs and cultured fibroblast cells which are assumed to be patient cells, and alloreactive CD8(+)-CTL clones which are imagined to be donor-derived activated CTLs, in vitro. We show here that AZT has no effect on resting PBMCs and cultured fibroblast cells, but greatly inhibited the growth of CTL clones.
Res Commun Mol Pathol Pharmacol 1998 May
PMID:Differential effect of azidothymidine on resting and activated cells: potentiality of this drug for treatment of post-transfusion graft-versus-host disease. 966 67

Graft-versus-host disease (GVHD) remains the principal complication limiting the wider application of allogeneic bone marrow transplantation (BMT). Advances in basic immunology during the last decade have demonstrated how interactions between immunologically competent cells are governed by cytokines, and much recent research has focused on the roles of these mediators in the pathogenesis of acute GVHD. This article reviews current evidence that dysregulated cytokine production can be considered a cascade of sequential monocyte and T-cell activation that is responsible for many of the manifestations of acute GVHD. We suggest that cytokine dysregulation can be conceptualized in three phases. Phase 1 is initiated by the conditioning of the host, which induces inflammatory processes in recipient tissues. Donor T-cell activation by host alloantigens and subsequent cytokine secretion in phase 2 is facilitated by the consequences of phase 1. The T-cell-derived cytokines of phase 2 activate distal inflammatory mediators, which, in synergy with T- and NK-cell-mediated cytotoxicity, produce the systemic morbidity of GVHD-associated immunosuppression in phase 3. Data from both experimental and clinical studies involving cytokines and their blockade in the prevention or treatment of GVHD are reviewed.
Cytokines Cell Mol Ther 1997 Dec
PMID:The role of cytokines in acute graft-versus-host disease. 974 Mar 54

The dysregulation of cytokines is thought to play a role in the inflammatory and allospecific components of graft-versus-host disease (GVHD) and graft rejection (GR) post allogeneic bone marrow transplantation (BMT). Both complications occur post unrelated BMT at significantly higher frequencies than post BMT from identical sibling donors. The levels of tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-1beta, IL-6, IL-10 and IL-12 following unrelated BMT were measured to examine cytokine dysregulation involvement in GVHD and GR. Of the 26 patients included in this study, 15 developed GVHD (14 acute; 1 acute and chronic), 5 had GR and 6 had uneventful BMT. TNF-alpha was markedly elevated in 13/15 of the patients with GVHD and in 3/5 patients with GR. IL-6 was elevated in patients with acute GVHD and with GR. IL-12 levels were similar in pre- and post-BMT sera. No correlation was found between HLA-C match and cytokine levels. In conclusion, a positive correlation was found between elevated levels of TNF-alpha, IL-6 and IL-10, and GVHD (p < 0.05, p < 0.005 and p < 0.002 respectively) and GR (p < 0.01).
Cytokines Cell Mol Ther 1998 Sep
PMID:Dysregulation of inflammatory cytokines in unrelated bone marrow transplantation. 982 41

Idiopathic pneumonia syndrome (IPS) is a significant clinical problem encountered among patients treated with bone marrow transplantation (BMT). IPS is identified as an inflammatory lung disease characterized by diffuse interstitial pneumonitis and alveolitis leading to interstitial fibrosis in the absence of an identifiable infectious agent. In an earlier study we characterized a murine model of IPS following allogeneic BMT that exhibits several features of human IPS. In this report we show that the lung represents a unique target of post-BMT disease in this model. The kinetics of developing lung disease were found to be markedly different from the kinetics of graft-versus-host disease in other tissues such as liver, colon, ear, skin, and tongue. Mice transplanted by our standard protocol with T-cell-depleted semiallogeneic donor bone marrow plus donor spleen cells in the absence of pretransplant radiation conditioning did not develop lung inflammation or fibrosis characteristic of IPS. Pretransplant radiation conditioning in the absence of BMT also failed to cause IPS, demonstrating an important role for radiation conditioning in the development of BMT-related IPS. The occurrence of lung disease post-BMT was found to be dependent on radiation conditioning in a dose-dependent manner. Finally, thoracic irradiation alone was demonstrated to be sufficient in causing IPS in mice transplanted with bone marrow plus spleen cells, albeit with reduced severity. Based on these findings, we conclude that pretransplant radiation conditioning plays an important role in the development of IPS following allogeneic BMT.
Am J Respir Cell Mol Biol 1999 Jun
PMID:Idiopathic pneumonia syndrome after allogeneic bone marrow transplantation in mice. Role of pretransplant radiation conditioning. 1034 Sep 30


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