Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0018133 (graft-versus-host disease)
18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe a 5-year-old girl with Ph(+) CML who received a cord blood transplant in a second accelerated phase after a very early lymphoid blast crisis. She was induced into CR by ALL-directed chemotherapy and then maintained with IFN-alpha2b together with weekly rotational chemotherapy. Nineteen months after diagnosis, her mother gave birth to an HLA-compatible sibling, whose cord blood was cryopreserved. The patient's second acceleration occurred 22 months after the CML diagnosis. The subsequent conditioning regimen included busulfan 16 mg/kg, Ara-C 12 g/m2 and melphalan 140 mg/m2. In order to prevent GVHD, CsA alone was administered, 3 mg/kg i.v. per day for a total of 40 days. The total number of nucleated cells infused was 0.8 x 108/kg, with CD34+ cells 1.8 x 106/kg and CFU-GM 1 x 104/kg. Engraftment occurred on day +35. Respiratory distress, severe VOD and grade II acute gastrointestinal GVHD complicated the post-transplant period. No chronic GVHD occurred. The girl is alive 23 months after transplantation with complete donor chimerism; both Ph chromosome and bcr/abl RNA are negative. Bone Marrow Transplantation (2000) 25, 213-215.
...
PMID:A successful cord blood transplant in a child with second accelerated phase chronic myeloid leukemia following lymphoid blast crisis. 1067 84

Administration of the immunosuppressive drug cyclosporine after syngeneic or autologous bone marrow transplantation elicits a T-lymphocyte-dependent autoimmune syndrome similar to graft-versus-host disease (GVHD). The onset of this autoaggression syndrome, termed syngeneic GVHD, is associated with the development of a highly restricted repertoire of CD8+ autoreactive T cells that recognize a peptide from the invariant chain, termed CLIP, presented by major histocompatibility complex (MHC) class II molecules. Clonal analysis reveals 2 distinct subsets of autoreactive T cells defined by their activation requirement for either the N-terminal or the C-terminal flanking regions of CLIP and by their cytokine profile. The studies here reveal that the autoreactive T-cell clones requiring the N-terminal flanking region of CLIP produce type 1 cytokines (interferon [IFN]-gamma, interleukin [IL]-2, and tumor necrosis factor-alpha). In contrast, the autoreactive T-cell clones that require the C-terminal flanking region of CLIP produce type 2 cytokines (IL-4, IL-10, transforming growth factor-beta). As assessed in a local graft-versus-host reaction assay, the N-terminal flanking-restricted clones mediate changes consistent with acute GVHD, whereas the clones responsive to the C-terminal flanking region do not. Moreover, the autoreactive T-cell clones restricted by the C-terminal flanking region of CLIP ameliorate the pathogenic potential of the cells responsive to the N-terminal flanking region of CLIP. The mechanism accounting for this regulatory affect appears to be the downregulation of mRNA message for type 1 cytokines (IFN-gamma and IL-2). The C-terminal-restricted autoreactive T-cell clones, however, could manifest disease with dermal changes similar to those seen in chronic syngeneic GVHD, provided that IFN-gamma was present. Consistent with these observations was the demonstration that type 1 cytokines are preferentially detected during the acute phase of syngeneic GVHD, whereas type 2 cytokines dominate during the chronic phase. The results suggest that acute and chronic syngeneic GVHD is mediated by distinct autoreactive T cells, which are separated by their fine specificity for the CLIP-MHC class II complex and by their cytokine profiles.
...
PMID:Complexity of effector mechanisms in cyclosporine-induced syngeneic graft-versus-host disease. 1070 95

Graft-versus-host disease (GVHD) is the most serious complication following bone marrow transplantation, with an incidence of 40-60%. The disease can be fatal in 50% of cases, even in patients receiving marrow from an HLA identical sibling. Several assays have been developed to try to predict the development of GVHD, including mixed lymphocyte culture reaction, cytotoxic T lymphocyte precursor, and helper T lymphocyte precursor frequency assays. This review describes an in vitro skin explant model which has been used since 1988 for both predicting acute GVHD in HLA identical sibling bone marrow transplantation and studying the pathophysiology of the disease. The model involves sensitising donor lymphocytes in vitro in a primary mixed lymphocyte reaction and then evaluating the secondary response on patient skin biopsies by grading the graft-versus-host reactivity (grades I-IV) histopathologically. From analysis of collective data the model is a clear predictor of GVHD and superior to the other assays widely used, with a correlation of 82% with clinical outcome. The skin explant model allows the investigator to study the pathogenesis of GVHD. The cytokines TNF alpha and IFN gamma are shown to be important mediators of cellular damage in graft-versus-host reactions. Recent work has also involved using the model to study the alloreactivity of cord blood. The model is currently being assessed in several bone marrow transplantation centres in Europe on different patient groups including those who receive marrow from haploidentical and matched unrelated donors.
...
PMID:A human skin explant model for predicting graft-versus-host disease following bone marrow transplantation. 1071 Dec 54

The effectiveness of donor-lymphocyte infusion (DLI) for treatment of relapsed chronic myelogenous leukemia (CML) after allogeneic bone marrow transplantation is a clear demonstration of the graft-versus-leukemia (GVL) effect. T cells are critical mediators of GVL, but the antigenic targets of this response are unknown. To determine whether patients who respond to DLI also develop B-cell immunity to CML-associated antigens, we analyzed sera from three patients with relapsed CML who achieved a complete molecular remission after infusion of donor T cells. Sera from these individuals recognized 13 distinct gene products represented in a CML-derived cDNA library. Two proteins, Jkappa-recombination signal-binding protein (RBP-Jkappa) and related adhesion focal tyrosine kinase (RAFTK), were recognized by sera from three of 19 DLI responders. None of these antigens were recognized by sera from healthy donors or patients with chronic graft-versus-host disease. Four gene products were recognized by sera from CML patients treated with hydroxyurea and nine were detected by sera from CML patients who responded to IFN-alpha. Antibody titers specific for RAFTK, but not for RBP-Jkappa, were found to be temporally associated with the response to DLI. These results demonstrate that patients who respond to DLI generate potent antibody responses to CML-associated antigens, suggesting the development of coordinated T- and B-cell immunity. The characterization of B cell-defined antigens may help identify clinically relevant targets of the GVL response in vivo.
...
PMID:Detection of a potent humoral response associated with immune-induced remission of chronic myelogenous leukemia. 1097 24

In a retrospective single center study, we examined the outcome of induced GVHD in leukemia patients relapsing after allogeneic BMT. Thirty-three adult patients with leukemia (15 AML, 3 ALL, and 15 CML) persisting or relapsing 1-36 months (median, 6) after allogeneic BMT underwent various immune manipulations and consequently developed acute and/or chronic GVHD at our center. Immunotherapies to elicit GVHD comprised chemotherapy followed by PBSC (n = 18), non-myeloablative transplant (n = 2), PBL followed by IFN-alpha (n = 5), PBL alone (n = 3), abrupt cessation of CsA (n = 3), and CsA withdrawal combined with IFN-alpha (n = 2). Twenty-four (72.7%) patients obtained a remission including complete hematological or cytogenetic remission, respectively, for acute leukemias or CML. Overall survival of patients, estimated at 3 years using the Kaplan-Meier method, was 33.9% (95% CI, 20-52%). Twelve patients including two patients with ALL remain in complete hematological (n = 5) or cytogenetic remission (n = 7) 3-93 months (median 12) after achieving remission. Twelve (63.2%) of 19 dead patients died due to treatment-related toxicities; five patients from acute GVHD, three from GVHD followed by infections and four from infections. By multivariate Cox analysis, only chronic GVHD resulted in a higher probability of disease-free survival (P = 0.026). Eight patients who had both acute GVHD < or = grade I and chronic GVHD are all alive without leukemia. We conclude that acute GVHD is associated with considerable toxicity while chronic GVHD plays a role in retaining remission in leukemia relapsing after allogeneic BMT.
...
PMID:Effect of induced GVHD in leukemia patients relapsing after allogeneic bone marrow transplantation: single-center experience of 33 adult patients. 1143 12

A novel IFN-like molecule, limitin, was recently identified and revealed to suppress B lymphopoiesis through the IFN-alphabeta receptor, although it lacked growth suppression on myeloid and erythroid progenitors. Here we have studied diverse effects of limitin on T lymphocytes and compared limitin with previously known IFNs. Like IFN-alpha and -beta, limitin modified immunity in the following responses. It suppressed mitogen- and Ag-induced T cell proliferation through inhibiting the responsiveness to exogenous IL-2 rather than suppressing the production of IL-2. In contrast, limitin enhanced cytotoxic T lymphocyte activity associated with the perforin-granzyme pathway. To evaluate the effect of limitin in vivo, a lethal graft-versus-host disease assay was established. Limitin-treatment of host mice resulted in the enhancement of graft-versus-host disease. Limitin did not influence thymocyte development either in fetal thymus organ cultures or in newborn mice injected with limitin-Ig, suggesting that limitin is distinguishable from IFN-alpha and -beta. From these findings, it can be speculated that the human homolog of limitin may be applicable for clinical usage because of its IFN-like activities with low adverse effects on, for example, T lymphopoiesis, erythropoiesis, and myelopoiesis.
...
PMID:A new IFN-like cytokine, limitin, modulates the immune response without influencing thymocyte development. 1154 1

TNF-TNFR2 interactions promote MHC class II-stimulated alloresponses while TNF-TNFR1 interactions promote MHC class I-stimulated alloresponses. The present studies were designed to evaluate whether TNF-TNFR2 interactions were involved in the in vivo generation of CD4(+) T cell-mediated intestinal graft-versus-host disease (GVHD) in the (C57BL/6J (hereafter called B6) --> B6 x B6.C-H-2(bm12) (bm12))F(1) GVHD model. Briefly, 5 x 10(6) splenic CD4(+) T lymphocytes from B6.TNFR2(-/-) or control B6 mice were transferred with 1--2 x 10(6) T cell-depleted B6 bone marrow cells (BMC) to irradiated MHC class II-disparate (bm12 x B6)F(1) mice. Weight loss, intestinal inflammation, and the surface expression of CD45RB (memory marker) on intestinal and splenic lymphocytes were assessed. IL-2 and IFN-alpha mRNA levels in intestinal lymphocytes were assessed by nuclease protection assays. A significant reduction in weight loss and intestinal inflammation was observed in recipients of the TNFR2(-/-)CD4(+) SpC. Similarly, a significant decrease was noted in T cell numbers and in CD45RB(low) (activated/memory) expression on intestinal but not CD4(+) T cells in recipients of TNFR2(-/-)CD4(+) spleen cells. IL-2 and IFN-alpha mRNA levels were reduced in the intestine in the recipients of TNFR2(-/-) splenic CD4(+) T cells. These results indicate that TNF-TNFR2 interactions are important for the development of intestinal inflammation and activation/differentiation of Th1 cytokine responses by intestinal lymphocytes in MHC class II-disparate GVHD while playing an insignificant role in donor T cell activation in the spleen.
...
PMID:TNF-TNFR2 interactions are critical for the development of intestinal graft-versus-host disease in MHC class II-disparate (C57BL/6J-->C57BL/6J x bm12)F1 mice. 1188 80

The authors report two cases of hypereosinophilia as the major presenting sign of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). Tissue biopsies of the skin, salivary gland, gut, and liver showed evidence of acute GVHD (aGVHD). In one case, further investigations have been performed. Elevated levels of interleukin (IL)-5 and soluble IL-2 receptor were found in the blood, and skin biopsy specimens demonstrated high levels of IL-5 messenger ribonucleic acid (mRNA). In contrast, skin biopsy specimens from other patients with aGVHD but without eosinophilia were negative for IL-5 mRNA. The authors also demonstrated the presence of IL-4 and interferon(IFN)-gamma mRNA within the same skin biopsy specimen, suggesting that this case of aGVHD was mediated by both Th1 and Th2 cell type. These two patients were treated by glucocorticoids with resolution of the hypereosinophilia and the symptoms of GVHD. The authors briefly discuss the possible mechanisms of this hypereosinophilia with respect to aGVHD.
...
PMID:Hypereosinophilia as a presenting sign of acute graft-versus-host disease after allogeneic bone marrow transplantation. 1249 2

The role of T cells in eradicating leukemic cells has been well demonstrated for chronic myeloid leukemia (CML). Type 1 (T1) T-cell cytokines play a major role in this antileukemic immune effect. Studies in cancer patients have demonstrated a decreased T1 cytokine production, measured by enzyme-linked immunosorbent assay (ELISA), in cultures of peripheral blood mononuclear cells. This observation of malignancy-related suppressed T1 cytokines also occurs in untreated chronic-phase (CP) CML, raising the question of the influence of different CML treatment regimens on this immunosuppression. Intracellular flow cytometry (ICF) has facilitated the evaluation of cytokines on a single-cell level. This study analyzed T1 (interferon-gamma) cytokine production in purified peripheral blood T cells by ICF, comparing different therapy approaches for CML. Twenty-one newly diagnosed CP CML patients were compared with 24 patients treated with interferon-alpha (IFN-alpha) and to 30 allogeneic bone marrow transplant (BMT) recipients (BCR-ABL negative by reverse-transcriptase polymerase chain reaction, and free of, or having only limited graft-versus-host disease at the time of study). Thirty-seven healthy controls were included. Our results showed a significantly decreased T-cell IFN-gamma synthesis in CP CML patients in relation to healthy controls (P = 0.0007). Treatment with IFN-alpha resulted in a shift from immunosuppression--documented for the group of untreated patients--to immunopotentiation, with an increase of T-cell IFN-gamma production (P = 0.0266). Notably, BMT enhanced IFN-gamma production of T cells to a level not only exceeding untreated patients (P < 0.0001) but also healthy volunteers (P < 0.0001). The observation of T1 cytokine up-regulation with IFN-alpha therapy indicates that enhanced T-cell function may be achievable in patients with CML, even in the absence of an allo-response.
...
PMID:Intracellular cytokine analysis of interferon-gamma in T cells of patients with chronic myeloid leukemia. 1260 98

Donor lymphocyte infusion (DLI) results in complete cytogenetic remission (CCR) of relapsed chronic-phase chronic myeloid leukemia (CML-CP) after allogeneic stem cell transplantation (SCT) in up to 80% of patients. The main complication of DLI is graft-versus-host disease (GVHD). Decreasing the dose of DLI is associated with less GVHD but also with a longer interval between treatment and CCR. We postulated that combining alpha-interferon (alpha-IFN) with DLI would enable us to decrease the dose of DLI, thereby limiting GVHD, and at the same time to decrease the interval between DLI and CCR for patients with either a hematologic or cytogenetic relapse. For molecular relapses, we hypothesized that because of a lower tumor load, very low doses of DLI without alpha-IFN could be an effective treatment. Two groups of CML-CP patients treated with DLI at a very low dose of 0.5 to 1.0 x 10(7) mononuclear cells per kilogram, containing 2 to 6 x 10(6) CD3+ T cells per kilogram, were analyzed: 13 patients with a cytogenetic or a hematologic relapse after allogeneic SCT (group A) were treated with additional alpha-IFN therapy at a dose of 3 x 10(6) U 5 d/wk, and 8 patients with a molecular relapse were treated without alpha-IFN (group B). Twelve patients from group A reached a CCR. The median interval between DLI and CCR was 7 weeks (range, 5-18 weeks) for group A. All patients with a CCR reached complete donor chimerism at a median of 10 weeks after DLI (range, 6-121 weeks). Eleven patients reached molecular remission at a median of 15 weeks after DLI (range, 8-34 weeks). In group B, all patients reached a molecular remission at a median of 14 weeks (range, 12-29 weeks). Five patients from group A developed acute GVHD grade II to IV and extensive chronic GVHD. In group B, 1 patient developed acute GVHD grade II to IV and subsequently developed extensive chronic GVHD. With a median follow-up of 62 months, 10 patients in group A are alive and in continuous CCR. One patient had a molecular relapse, for which she successfully received additional DLI; another patient reached molecular remission only after 5 doses of DLI. Two patients from group A died of a gram-negative sepsis, and 1 died of an acute myocardial infection. In group B, all patients are alive and in molecular remission with a median follow-up of 20 months. One patient's disease progressed but was successfully treated with DLI plus alpha-IFN. In conclusion, very-low-dose DLI in combination with alpha-IFN as treatment for cytogenetic or hematologic relapses of CML-CP after allogeneic SCT reduced the interval to obtain a CCR with acceptable GVHD when compared with the literature. Patients with a CCR also reached complete donor chimerism and complete molecular remissions. For patients with a molecular relapse, very-low-dose DLI alone is sufficient to induce molecular remissions in most patients and is associated with limited GVHD.
...
PMID:Alpha-interferon with very-low-dose donor lymphocyte infusion for hematologic or cytogenetic relapse of chronic myeloid leukemia induces rapid and durable complete remissions and is associated with acceptable graft-versus-host disease. 1499 86


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

---