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)

In patients undergoing bone marrow transplantation cryptococcosis is rarely encountered. We report a fatal case of Cryptococcus meningitis in a 12-year-old girl with acute lymphoblastic leukemia (ALL) in second remission who had a transplant from a human leukocyte antigen (HLA)-identical unrelated bone marrow donor. The conditioning regimen was thiotepa, cyclophosphamide, and total body irradiation (TBI); graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A, methotrexate, and antilymphocyte globulin (ALG). The patient experienced stage III GVHD responsive to high-dose corticosteroids. On day +54 a thrombotic microangiopathy occurred. On day +64 neurological status worsened; a brain computed tomographic (CT) scan showed hyperdense lesions suggesting fungal infection. Detection of cryptococcal antigen by latex agglutination was positive but India ink stain and culture were negative. Despite treatment with amphotericin B, 5-flucytosine, and granulocyte-macrophage colony-stimulating factor, the patient died 13 days after the diagnosis.
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PMID:Cryptococcal meningitis following a thrombotic microangiopathy in an unrelated donor bone marrow transplant recipient. 926 80

CD40 signaling has been implicated in various pathogenic processes such as chronic inflammatory disease, graft-versus-host disease, autoimmune disease and cancer. We previously demonstrated in an in vitro system that the CD40/CD40L pathway mediates late interleukin (IL) 12 production in response to Cryptococcus neoformans. The purpose of this study was to examine the course of C. neoformans infection in the absence of CD40/CD40L costimulation. We compared infection in mice genetically lacking CD40L (CD40L(-/-)) and in the wild-type counterpart. The animals were injected intratracheally with C. neoformans and monitored for clearance of the organism and the development of cellular immune response. CD40L(-/-) mice exhibited an exacerbation of infection, evaluated as scarce inflammatory response in the lung, that mirrored an increase of fungal burden. This correlated with impairment of nitrite production and antimicrobial activity by macrophages against C. neoformans and unrelated microorganisms such as Candida albicans. Moreover, IL-12 production by splenic macrophages was diminished in CD40L(-/-) mice and interferon-gamma production by CD4 and CD8 T cells was decreased. CD4 T cells retained the ability to express a costimulatory molecule, CTLA-4, but showed a decrease in CD28 expression. This latter molecule is implicated in a positive effect on proliferation, cytokine production and survival of T cells. Collectively these data demonstrate that absence of CD40L correlates with (i) reduced antimicrobial activity of natural effector cells; (ii) reduction of the magnitude of T cell response; and (iii) increase of fungal growth in the brain. These findings suggest that disruption of CD40/CD40L may be deleterious for development of an efficient immune response to C. neoformans and may identify potential molecular targets for novel immunotherapeutic approaches
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PMID:Disruption of CD40/CD40L interaction influences the course of Cryptococcus neoformans infection. 1473 88

Intradermal inoculation of cloned self-reactive alphabeta T cells into the footpads of mice induced cutaneous graft-versus-host disease (GVHD), and after recovery from GVHD, the epidermis became resistant to subsequent attempts to induce GVHD. Resistance to GVHD was not induced in the epidermis of T-cell receptor delta-deficient (TCRdelta(-/-)) mice that lacked gammadelta T cells bearing canonical Vgamma5/Vdelta1(+)gammadeltaTCRs, known as dendritic epidermal T cells (DETCs), and resistance was restored by reconstitution of these mutant mice with precursors of Vgamma5(+) DETCs. Pulmonary infection by Cryptococcus neoformans induced an increase of gammadelta T cells in the lung, and in comparison with wildtype mice, TCRdelta(-/-) mice eliminated C. neoformans more rapidly and synthesized more interferon-gamma in the lung. In the mouse small intestine, the absence of gammadelta T cells is associated with a reduction in epithelial cell turnover and downregulation of the expression of major histocompatibility complex class II molecules. The protective role of gammadelta T cells was verified in a dextran sodium sulfate-induced inflammatory bowel disease (IBD) model, whereas in a spontaneous model of IBD, gammadelta T cells were involved in the exacerbation of colitis in TCRalpha(-/-) mice. Taken together, in addition to the homeostatic regulation of epithelial tissues, gammadelta T cells appear to play a pivotal role in the modification of inflammatory responses induced in many organs containing epithelia.
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PMID:gammadelta T cells: firefighters or fire boosters in the front lines of inflammatory responses. 1729 Dec 82

The last twenty years, the incidence of invasive fungal infections (IFI) has risen dramatically due to the prolongation of survival of patients with multiple risk factors for fungal infections. Amphotericin B was for more than 40 years the gold standard for almost all IFI, but toxicity and resistance, especially of new and emerging pathogens remained important issues. Fluconazole and itraconazole have also the same disadvantage of resistance. Voriconazole, a new triazole antifungal has offered an additional option, but the problem of resistant aspergillosis, and zygomycosis remains. Echinocandins (caspofungin, micafungin and anidulafungin) are active only against Candida and Aspergillus spp., but not against Fusarium, Scedosporium and Zygomycetes. Posaconazole is the most recently approved triazole with broad spectrum activity against Candida spp., Aspergillus spp., Cryptococcus neoformans, Zygomycetes, dermatiaceous, dimorphic, and other fungal pathogens. Interestingly, posaconazole is active against Candida spp., resistant to fluconazole and itraconazole, and Aspergillus fumigatus resistant to fluconazole itraconazole, amphotericin B, and voriconazole. The results from clinical trials of posaconazole as salvage treatment are encouraging. Multicenter clinical trials have also established its role in the prophylaxis of (IFI) in the severely immunocompromised patients such as those after hematopoietic stem cell transplantation (HSCT) who developed graft versus host disease (GVHD), as well as the neutropenic patients with an acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after myeloablative chemotherapy. Posaconazole has pharmacokinetic advantages and low side effect profile, which are very important, especially in the seriously ill population.
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PMID:Posaconazole: a new antifungal weapon. 2168 87

Posaconazole is a triazole antifungal agent that has broad-spectrum activity against many yeasts and filamentous fungi, including Candida species, Cryptococcus neoformans, Aspergillus species, and Zygomycetes. This drug has been approved for the prevention of invasive fungal infections in patients with neutropenia and for the treatment of invasive fungal infections in hematopoietic stem cell transplant recipients with graft-versus-host disease. Studies on the clinical efficacy, safety, tolerability, and cost-effectiveness of posaconazole therapy were performed using the oral suspension form of the drug. Pharmacokinetic studies have found that the oral suspension form of posaconazole has problemeatic bioavailability: its absorption is affected by concomitant medication and food. This article discusses the pharmacokinetic properties of the newly developed posaconazole delayed-release tablet formulation and reviews the efficacy, safety, and cost-effectiveness of both the oral suspension and the new tablet formulation. In conclusion, the posaconazole tablet formulation has better systemic bioavailability, thereby enabling once-daily administration and better absorption in the presence of concomitant medication and food. However, well-designed clinical studies are needed to evaluate the use of the tablet formulation in real-life settings.
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PMID:Prevention of invasive fungal infections in immunocompromised patients: the role of delayed-release posaconazole. 2639 81