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

The helper T lymphocyte precursor (HTLp) frequency detected in HLA matched sibling donors is directed against alloantigens and this frequency has been shown to correlate with the development of graft-versus-host disease in the patient after bone marrow transplantation. Using limiting dilution analysis the HTLp frequency is determined by measuring IL-2 using the IL-2-dependent murine cell line CTLL-2. An important factor associated with the successful performance of any bioassay is the reliability of the indicator cell line used. When maintained in continuous culture, however, the overall sensitivity of this cell line is highly variable. To overcome this problem, large batches of CTLL-2 were grown, frozen and tested for their ability to detect low levels of IL-2 (0.01 IU) in dose response assays. Batches meeting this criterion were stored in liquid nitrogen until required. In this study, we investigated the effect of freezing and storing large batches of this cell line, thereby assuring a plentiful supply of sensitive indicator cells.
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PMID:A convenient and reliable IL-2 bioassay using frozen CTLL-2 to improve the detection of helper T lymphocyte precursors. 961 91

Transplant-related mortality (TRM) following allo- geneic bone marrow transplantation (BMT) remains a major concern and early identification of patients at risk may be clinically relevant. In this study we describe a predictive score based on bilirubin and blood urea nitrogen (BUN) levels on day +7 after BMT. The patient population consisted of 309 consecutive patients who underwent BMT from sibling (n = 263) or unrelated donors (n = 46) for hematologic disorders between December 1990 and December 1996. Of 27 laboratory tests taken on day +7 after BMT, serum bilirubin (P = 0.02) and BUN (P = 0.007) were found to be independent predictors of TRM in multivariate analysis. The median levels of bilirubin (0.9 mg/dl) and of BUN (21 mg/dl) were then used as a cut-off and a score of 1 was given for values equal/greater than the median. There were 216 patients with scores 0-1 (low risk) on day +7 (bilirubin <0.9 and/or BUN <21) and 93 patients with score 2 (high risk) (bilirubin >/=0.9 and BUN >/=21): the latter had more grade III-IV acute graft-versus-host disease (P = 0.03), slower neutrophil (P = 0.02) and slower platelet engraftment (P = 0.002). The actuarial 5 year TRM is 22% for low risk vs44% for high risk patients (P = 0.0003). For HLA-identical siblings TRM is 20% vs35% (P = 0.01), for unrelated donors it is 20% vs 65% (P = 0.01). Day +7 score was highly predictive of TRM on multivariate analysis (hazard ratio 1.9, P < 0.01), after adjustment for year of transplant (P < 0.00001), unrelated vs sibling donors (P = 0.001), patient age (P = 0.01) and diagnosis (P = 0.01). These results were validated on an independent group of 82 allogeneic BMT recipients in a pediatric Unit who showed an actuarial TRM of 16% for low risk vs 46% for high risk patients (P = 0.002). This study suggests that it may be possible to identify patients with different risks of TRM on day +7 after BMT: high risk patients could be eligible for programs designed to intensify prophylaxis of post-transplant complications.
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PMID:Early predictors of transplant-related mortality (TRM) after allogeneic bone marrow transplants (BMT): blood urea nitrogen (BUN) and bilirubin. 1049 Jul 32

We have previously shown that patients at high risk of graft-versus-host disease (GVHD) and transplant-related mortality (TRM) can be identified on day +7 following an allogeneic bone marrow transplant (BMT), based on serum bilirubin and blood urea nitrogen levels. One possible approach to reduce the risk of GVHD and TRM, is pre-emptive treatment with T cell antibodies. We report a pilot study testing the feasibility of this approach in 18 high risk patients, with a median age of 41, 83% of whom had advanced disease, undergoing an alternative donor BMT (family mismatched in five and unrelated in 13). The patients received three doses of rabbit antithymocyte globulin (ATG) (Thymoglobuline; Sangstat) 1.25 mg/kg on alternate days, starting at a median interval of 11 days (range 7-13) after BMT. Controls were 20 historical unrelated donor transplants (median age 35, 63% with advanced disease), with a high score from our original publication in 1999. The actuarial 1 year TRM of the ATG-treated patients was 40% compared to 60% for untreated controls (P = 0.06). Severe grade III-IV aGVHD developed in 27% of the ATG-treated patients, and in 55% of the controls (P = 0.08). This study indicates that early pre-emptive treatment of aGVHD in day +7 high risk patients is feasible and may lead to a reduction of aGVHD and TRM. This approach is being tested in a prospective randomized trial.
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PMID:Pre-emptive therapy of acute graft-versus-host disease: a pilot study with antithymocyte globulin (ATG). 1262 70

The treatment of cutaneous T cell lymphoma (CTCL), which includes mycosis fungoides and Sezary syndrome, has been in a state of continual change over recent decades, as new therapies are constantly emerging in the search for more effective treatments for the disease. However, prognosis and survival of patients with CTCL remains dependent upon overall clinical stage (stage IA-IVB) at presentation, as well as response to therapy. Past therapies have been limited by toxicity or the lack of consistently durable responses, and few treatments have been shown to actually alter survival, especially in the late stages of disease. Even aggressive chemotherapy has not been shown to improve overall survival compared to conservative sequential therapy in advanced disease, and adds the risk of immunosuppressive complications. Over the last decade, extracorporeal photopheresis has been the only single treatment that has been shown to improve survival in patients with Sezary syndrome, although its true efficacy and place in combination therapy remain unclear. Much of the focus of current research has been on combinations of skin-directed therapies and biological response modifiers, which improve response rates. The results of various trials over the years have also brought into favor the use of post-remission maintenance therapy with topical corticosteroids, topical mechlorethamine (nitrogen mustard), interferon-alpha, or phototherapy to prevent disease relapse. Recent novel developments in CTCL therapy include oral bexarotene, a retinoid X receptor-selective retinoid that has activity in all stages of CTCL, and the topical gel formulation of bexarotene, which plays a role in treating localized lesions. US Food and Drug Administration (FDA)-approved, oral systemic bexarotene has the advantage of a 48% overall response rate at a dosage of 300 mg/m(2)/day, and avoids immunosuppression and risk of central line and catheter-related infectious complications that are associated with other systemic therapies. Monitoring of triglycerides and use of concomitant lipid-lowering agents and thyroid replacement is required in most patients. Also recently FDA-approved, denileukin diftitox is the first of a novel class of fusion toxin proteins and is selective for interleukin-2R (CD25+) T cells, targeting the malignant T cell clones in CTCL. Denileukin diftitox is associated with capillary leak syndrome in 20 to 30% of patients, which may be ameliorated by hydration and corticosteroids. Higher response rates are possible by combining bexarotene with "statin" drugs and active CTCL therapies. Studies are being conducted on combining bexarotene and denileukin diftitox with other modalities. Biological response modifier therapies that are in current or future investigational trials include topical tazarotene, pegylated interferon, interleukin-2, and interleukin-12. At the forefront of systemic chemotherapy development, pegylated liposomal doxorubicin, gemcitabine, and pentostatin appear to have the greatest potential for success in CTCL therapy. Bone marrow transplantation, which is currently limited by the risk of graft-versus-host disease, offers the greatest potential for disease cure. Further developments for CTCL may include more selective immunomodulatory agents, vaccines, and monoclonal antibodies.
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PMID:Treatment of cutaneous T cell lymphoma: current status and future directions. 1197 40

Clinical transplantation evidence has indication that umbilical cord blood (UCB) can be useful in the hematopoietic reconstitution in the children, but not well in the adult patients because of the low cell count. The purpose of our study was to evaluate a new method for collection of blood cells from human placenta and umbilical cord. We have simultaneously harvested blood cells from umbilical cord (UCB), placenta blood (UPB) and placenta tissue (UPT) for their content of nucleated cells, CD34 (hematopoietic stem progenitor marker) positive cells. Result showed that the nuclear cell (NC) from UPB and UPT has three to four times than that from umbilical cord blood only, (8.3 +/- 1.04) x 10(8) (UCB), (16.33 +/- 5.54) x 10(8) (UPB), and (8.01 +/- 2.64) x 10(8) (UPT). CD34(+) cells are (0.77 +/- 0.01) x 10(6), (1.25 +/- 0.55) x 10(6) and (4.21 +/- 1.90) x 10(6) respectively. The cells from UPB and UPT have more survival ability than the cells from UCB in the long-term cell culture condition. It is clear that the blood stored in the liquid nitrogen did not show large loss of total nucleated cell count and CD34(+) cells. It was observed that UPT and UPB contained more suppressor lymphocytes, which may be important in prevention of graft-versus-host disease. In conclusion, our data may have implications for the development of placental blood collection together with umbilical cord blood banking for the stem cell transplantation.
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PMID:[Rich hematopoietic stem/progenitor cells in the human placenta tissue and placenta blood]. 1251 18

We have previously described a scoring system for patients undergoing hemopoietic stem cell transplantation (HSCT) based on day +7 blood urea nitrogen (BUN) and serum bilirubin levels. We have revised that scoring system using a formal multivariate approach based on a training phase (305 patients) and a validation phase (217 patients). Day +7 BUN, serum cholinesterase (CHE), total proteins (TP), gamma glutamyl transferase (gammaGT), donor type and cell dose at transplant were included in the new score. The score distribution identified three groups of patients in the training set (<25, 25-75, >75 percentile of the score) which were classified as low, intermediate and high risk. Their actuarial risk of transplant-related mortality (TRM) at 6 years was, respectively, 12, 38 and 60%. In the validation set the 6 year actuarial TRM was, respectively, 15, 40 and 69%. High risk patients had more graft-versus-host disease (GvHD) (P <0.0001) and lower platelet counts (P <0.0001). This study confirms that GvHD and TRM can be predicted on day +7 after HSCT: pre-emptive GvHD therapy may be one option for high-risk patients and is being tested in a prospective randomized trial. The score for single patients can be calculated on the web site http://213.26.110.20/lrm/day_seven_score.html.
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PMID:A revised day +7 predictive score for transplant-related mortality: serum cholinesterase, total protein, blood urea nitrogen, gamma glutamyl transferase, donor type and cell dose. 1283 86

Successful clinical small-bowel transplantation is still difficult to achieve. Two features render the small intestine unique among vascularised solid organ grafts. First, the bowel contains a large amount of lymphoid tissue within the Peyer's patches, mesenteric lymph nodes, and intraepithelial lymphocytes, which are thought to mediate graft-versus-host disease and provide a major stimulus for the recipient's immune system. Unfortunately, mere surgical reduction of these tissues, by using segmental allografts, does not furnish any immunological advantage. Second, the small bowel lacks specific serum markers such as blood urea nitrogen (BUN) in the kidney or bilirubin in liver transplantation. Clinical signs such as fever, pain, or tenderness of the abdomen may indicate an already advanced destruction of the graft. Therefore, very potent immunosuppressive regimens are necessary to avoid small-bowel allograft rejection or even to reverse an ongoing rejection process. Cyclosporin was shown in small and large animal models to control rejection reactions sufficiently. However, there are two even more promising immunosuppressive agents currently under investigation. FK506, a macrolide lactone isolated from Streptomyces tsukubaensis, leads to long-term survival of small-bowel allografts in a rodent model and has already been used in a few clinical small-bowel transplantations. RS61443, a mycophenolic acid morpholinoethylester, selectively inhibits T- and B-cell proliferation. We have investigated the use of FK506 and RS61443 for the reversal of small-bowel allograft rejection in a small animal model.
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PMID:The use of FK506 and RS61443 for reversal of small-bowel rejection. 1462

Umbilical cord blood (UCB) is a source of the rare but precious primitive hematopoietic stem cells (HSC) and progenitor cells that can reconstitute the hematopoietic system in patients with malignant and nonmalignant disorders treated with myeloablative therapy. UCB cells possess an enhanced capacity for progenitor cell proliferation and self-renewal in vitro. UCB is usually discarded, and it exists in almost limitless supply. The blood remaining in the delivered placenta is safely and easily collected and stored. The predominant collection procedure currently practiced involves a relatively simple venipuncture, followed by gravity drainage into a standard sterile anti-coagulant-filled blood bag, using a closed system, similar to the one utilized on whole blood collection. After aliquots have been removed for routine testing, the units are cryopreserved and stored in liquid nitrogen. UCB banks are being established throughout the world and UCB units are collected for allogeneic unrelated and related HSC transplantation. In unrelated cord blood banks donated UCB units are collected and stored for allogeneic use in patients who do not have an identified HLA matched relative. UCB banks report available units to national and international donor registries. The second model of UCB banking is referred to as family banking, where UCB is stored for the benefit of the donor or their family members. After more than one decade of clinical experience, it is currently accepted that UCB transplants, related and unrelated, are equivalent to or might compare favorably with bone marrow (BM) transplants, especially in children. Initial studies of long-term survival in children with both malignant and non-malignant hematologic disorders, who were transplanted with UCB from a sibling donor, demonstrated comparable or superior survival to children who received BM transplantation. One factor that limits the use of UCB transplantation in adult patients is the relatively limited number of HSC that may be harvested from umbilical cord, resulting in a slower time to engraftment and higher transplant related mortality, mainly due to the long aplasia period after transplantation and susceptibility to viral and fungal infections. Despite prolonged periods of aplasia, the apparent reduction in the incidence and severity of graft versus host disease (GVHD) may in turn underline comparable rates of survival in some series comparing UCB to adult-donor sources. The "naive" nature of UCB lymphocytes may explain the lower incidence and severity of GVHD encountered in UCB transplantation compared to the allogeneic BM transplant setting. UCB transplantation does not seem to be associated with increased rates of disease relapse. The available data suggest that nucleated cell dose in UK unit should be the primary criterion for donor selection. In 1991, the UCB transplantation program was established at the Zagreb University Hospital Center for related transplants, and until now 4 UCB transplantations have been performed successfully. In order to speed up the engraftment rate, several strategies such as multiple UCB transplants and ex vivo expansion of HSC have been assayed. The current strategies are focused on the development of much more efficient technologies for ex vivo production of progenitor cells, but whether expansion will speed engraftment and improve outcome after UCB remains to be determined. UCB is known to contain extremely immature stem cells. Consequently, such pluripotent or, perhaps, multipotent stem cells have been proposed as elements suitable for cellular therapy and regenerative medicine. Up to date there are no conclusive data regarding these possibilities but preliminary in vitro and animal studies in the field of tissue regeneration suggest some degree of plasticity and/or transdifferentiation. UCB cells are showing their unique qualities and potential, and consequently UCB banks might dramatically increase the scope of their clinical application.
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PMID:[Umbilical cord blood as a source of stem cells]. 1693 34

Bronchiolitis obliterans (BO) following allogeneic haematopoietic stem cell transplantation (HSCT) affects peripheral airways. Detection of BO is presently delayed by the low sensitivity of spirometry. We examined the relationship between peripheral airway function and time since HSCT, and compared it with spirometry and clinical indices in 33 clinically stable allogeneic HSCT recipients. The following measurements were performed: lung function, exhaled nitric oxide, forced oscillatory respiratory system resistance and reactance, acinar (S(acin)) and conductive airways ventilation heterogeneity and lung clearance index (LCI) measured by multiple breath nitrogen washout. 22 patients underwent repeat visits from which short-term changes were examined. Median time post HSCT was 12 months. Eight patients were clinically diagnosed as having BO. In multivariate analysis, time since HSCT was predicted by S(acin) and forced expiratory volume in 1 s % predicted. 20 patients had abnormal S(acin) with normal spirometry, whereas none had airflow obstruction with normal S(acin). S(acin) and LCI were the only measures to change significantly between two visits, with both worsening. Change in S(acin) was the only parameter to correlate with change in chronic graft-versus-host disease grade. In conclusion, peripheral airways ventilation heterogeneity worsens with time after HSCT. S(acin) may be more sensitive than spirometry in detecting BO at an early stage, which needs confirmation in a prospective study.
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PMID:Small airways function declines after allogeneic haematopoietic stem cell transplantation. 2156 12

Mononuclear and polynuclear copper(II) complexes of the alloferons 1 (Allo1) with point mutations (H6A) H(1)GVSGA(6)GQH(9)GVH(12)G-COOH (Allo6A) and (H12A) H(1)GVSGH(6)GQH(9)GVA(12)G-COOH (Allo12A) have been studied by potentiometric, UV-visible, CD, EPR spectroscopic, and mass spectrometry (MS) methods. Complete complex speciation at different metal-to-ligand ratios ranging from 1:1 to 3:1 was obtained. At physiological pH 7.4 and a 1:1 metal-to-ligand molar ratio, the Allo6A and Allo12A peptides form CuL complexes with the 4N {NH2, N(Im)-H(1),2N(Im)} binding mode. The amine nitrogen donor and the imidazole nitrogen atoms (H(9)H(12) or H(6)H(9)) can be considered to be independent metal-binding sites in the species formed for the systems studied. As a consequence, di- and trinuclear complexes for the metal-to-ligand 2:1 and 3:1 molar ratios dominate in solution, respectively. The induction of apoptosis in vivo in Tenebrio molitor cells by the ligands and their copper(II) complexes at pH 7.4 was studied. The biological results show that copper(II) ions in vivo did not cause any apparent apoptotic features. The most active was the Cu(II)-Allo12A complex formed at pH 7.4 with a {NH2, N(Im)-H(1),N(Im)-H(6),N(Im)-H(9)} binding site. It exhibited 123% higher of caspase activity in hemocytes than the native peptide, Allo1.
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PMID:Mono- and polynuclear copper(II) complexes of alloferons 1 with point mutations (H6A) and (H12A): stability structure and cytotoxicity. 2365 65


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