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D H Dockrell

Publications and source records attributed to D H Dockrell.

27 records · Page 2Linked to original sources
PubMed1998

In vivo analysis of Fas/FasL interactions in HIV-infected patients.

Recent insights into the pharmacological control of HIV replication and the molecular mechanisms of peripheral T cells homeostasis allowed us to investigate in vivo the mechanisms mediating T cell depletion in HIV-infected patients. Before the initiation of highly active antiretroviral therapy (HAART), a high degree of lymphoid tissue apoptosis is present, which is reduced upon HAART initiation (P < 0.001) and directly correlates with reduction of viral load and increases of peripheral T lymphocytes (P < 0.01). Because Fas/FasL interactions play a key role in peripheral T lymphocyte homeostasis, we investigated the susceptibility to Fas-mediated apoptosis in peripheral T lymphocytes and of FasL expression in lymphoid tissue before and during HAART. High levels of Fas-susceptibility found in peripheral CD4 T lymphocytes before HAART were significantly reduced after HAART, coinciding with decreases in viral load (P = 0.018) and increases in peripheral CD4 T lymphocyte counts (P < 0.01). However, the increased FasL expression in the lymphoid tissue of HIV-infected individuals was not reduced after HAART. These results demonstrate that lymphoid tissue apoptosis directly correlates with viral load and peripheral T lymphocyte numbers, and suggest that HIV-induced susceptibility to Fas-dependent apoptosis may play a key role in the regulation of T cell homeostasis in HIV-infected individuals.

Anti-HIV Agents↗
PubMed1998

The expression of Fas Ligand by macrophages and its upregulation by human immunodeficiency virus infection.

Fas/Fas Ligand (FasL) interactions play a significant role in peripheral T lymphocyte homeostasis and in certain pathological states characterized by T cell depletion. In this study, we demonstrate that antigen-presenting cells such as monocyte-derived human macrophages (MDM) but not monocyte-derived dendritic cells express basal levels of FasL. HIV infection of MDM increases FasL protein expression independent of posttranslational mechanisms, thus highlighting the virus-induced transcriptional upregulation of FasL. The in vitro relevance of these observations is confirmed in human lymphoid tissue. FasL protein expression is constitutive and restricted to tissue macrophages and not dendritic cells. Moreover, a significant increase in macrophage-associated FasL is observed in lymphoid tissue from HIV (+) individuals (P < 0.001), which is further supported by increased levels of FasL mRNA using in situ hybridization. The degree of FasL protein expression in vivo correlates with the degree of tissue apoptosis (r = 0.761, P < 0. 001), which is significantly increased in tissue from HIV-infected patients (P < 0.001). These results identify human tissue macrophages as a relevant source for FasL expression in vitro and in vivo and highlight the potential role of FasL expression in the immunopathogenesis of HIV infection.

Apoptosis↗
PubMed1998

CD4 regulates susceptibility to Fas ligand- and tumor necrosis factor-mediated apoptosis.

The current knowledge of CD4 function is limited to its role as a necessary coreceptor in TCR-initiated signaling. We have investigated whether CD4 regulates additional T cell functions. Using human primary resting CD4+ T cells, we demonstrate that CD4 activation is sufficient to induce lymphocyte death. Immediately after CD4 cross-linking, CD4+ T cells are rendered susceptible to apoptosis mediated by TNF or FasL. This, together with the concomitant induction of FasL within the same population, results in significant CD4+ T cell death in vitro. The CD4-dependent induction of susceptibility to apoptosis that is mediated by TNF or FasL is protein synthesis independent but phosphorylation dependent. After CD4 activation, PKC regulates susceptibility to apoptosis mediated by FasL but not the induction of susceptibility to TNF-dependent apoptosis. Moreover, significant differences between CD3 and CD4 activation were observed with regards to the kinetics of induction of CD4+ T cell susceptibility to FasL- and TNF-mediated apoptosis. Altogether, these results provide a model with which to study the molecular mechanisms regulating lymphocyte survival after CD4 activation, and highlight the potential role of CD4 in controlling lymphocyte apoptosis under physiological conditions or in disease states such as HIV infection.

Apoptosis↗
PubMed1998

Epstein-Barr virus-induced T cell lymphoma in solid organ transplant recipients.

Epstein-Barr virus (EBV) infection in transplant recipients can lead to lymphomas termed posttransplantation lymphoproliferative disorders (PTLDs). Most PTLDs are malignancies of B lymphocytes and are linked to EBV infection, but the rare T lymphocyte PTLDs have been inconsistently linked to EBV infection. Although the B lymphocyte is the main host cell of EBV, it has been suggested that T lymphocytes may also become infected by EBV. A review of EBV-induced PTLDs at our institution identified one of 61 cases that was restricted to T lymphocytes. Of 36 cases of T cell PTLD identified through a literature review, 21 were investigated for the presence of EBV, and eight (38%) were documented to be EBV-induced. We compared the features of EBV-positive and EBV-negative T cell PTLDs and concluded that cases of EBV-positive T cell PTLD have some distinctive clinical features.

Heart Transplantation↗
PubMed1997

Organizing pneumonia. Features and prognosis of cryptogenic, secondary, and focal variants.

BACKGROUND: Organizing pneumonia (OP) is a non-specific response to many types of lung injury. Clinicians frequently encounter pathology reports of OP in patients with no underlying condition (cryptogenic OP, also known as BOOP or bronchiolitis obliterans OP) or in association with drugs or nonpulmonary disease. The goals of this study are to describe the clinical course and outcomes in patients with 3 clinical variants of OP. METHODS: A retrospective study of patients with OP seen at the Mayo Clinic, Rochester, Minn, from January 1, 1984, through June 30, 1994, was conducted. Initial features were obtained from medical records. Chest radiographs and pathology specimens were reviewed for this study. Resolution, relapse, and survival were obtained from medical records and a follow-up patient questionnaire. RESULTS: Seventy-four patients had pathologically confirmed OP. Organizing pneumonia was classified into 3 clinical groups: symptomatic cryptogenic OP; symptomatic OP related to underlying hematologic malignant neoplasm, collagen vascular disease, or drugs (secondary OP); and asymptomatic OP presenting as a focal nodule (focal OP). Thirty-seven patients (50%) had cryptogenic OP and 27 patients (36%) had secondary OP. No difference was found between cryptogenic and secondary OP in type or severity of symptoms, signs, laboratory and pulmonary function tests, or radiologic or pathologic findings. Corticosteroids were given at a similar initial dose (prednisone, about 50 mg/d). Resolution of symptoms was more frequent in patients with cryptogenic OP than those with secondary OP. Relapse was infrequent in both of these groups. Five-year survival was higher in patients with cryptogenic OP (73%) than in secondary OP (44%), and respiratory-related deaths were more frequent in patients with secondary OP. Organizing pneumonia was an asymptomatic focal rounded opacity in 10 patients (14%), most often detected on chest radiograph and diagnosed on lung biopsy done for suspicion of lung cancer. Patients with focal OP required no treatment and had no relapse or respiratory-related deaths. CONCLUSIONS: Clinical classification of OP is useful to predict clinical course and outcome. Cryptogenic OP most often was a symptomatic bilateral lung process that had an overall favorable prognosis with prolonged corticosteroid therapy. Patients with secondary OP had a high mortality rate when the disease was associated with predisposing conditions or drugs. Patients with asymptomatic focal OP had an excellent prognosis.

Aged↗
PubMed1997

Hypercalcemia in a patient with hypoparathyroidism and Nocardia asteroides infection: a novel observation.

Hypercalcemia is associated with numerous chronic granulomatous processes and chronic infections. Increased production of 1,25-dihydroxyvitamin D by activated macrophages has been shown to be the cause in most cases. In this article, we describe a case of hypercalcemia related to infection with Nocardia asteroides. In a 34-year-old woman who previously had hypocalcemia, acute hypercalcemia developed coincident with Nocardia pericarditis. The hypercalcemia resolved after treatment of N. asteroides with sulfisoxazole. Parathyroid hormone and phosphorus levels were within normal limits, and total 25-hydroxyvitamin D levels were only mildly increased. After successful treatment of the Nocardia infection, the patient required supplemental calcium and vitamin D. Her hypercalcemia was temporally related to the duration of the N. asteroides infection. We believe this is the first reported case of hypercalcemia associated with N. asteroides infection.

Adult↗
PubMed1997

Seroconversion to human herpesvirus 6 following liver transplantation is a marker of cytomegalovirus disease.

Human herpesvirus 6 (HHV-6) infection is common after transplantation; HHV-6 is known to interact with other viruses and induce immunosuppression. Whether HHV-6 plays a role in the occurrence of cytomegalovirus (CMV) infection after transplantation was investigated. In a cohort of 247 liver transplant recipients, HHV-6 seroconversion was identified as a significant risk factor for development of symptomatic CMV infection (P < .001), including CMV organ involvement (P < .001), even in the presence of the other significant risk factors: D+/R- CMV serologic status (P < .001) or use of OKT3 after transplantation (P = .002). Subgroup analysis indicated that HHV-6 seroconversion was significantly associated with symptomatic CMV infection in the D+/R+ but not in the D+/R- CMV serologic group (P < .001 and P = .11, respectively). These results indicate that HHV-6 seroconversion is a marker for CMV disease after transplantation and suggest that additional studies using more sensitive diagnostic techniques are warranted to determine the relationship between HHV-6 and CMV infection after transplantation.

Adult↗
PubMedDate not supplied

Human herpesvirus-6 and -7 in transplantation.

Infections with the beta-herpesviruses human herpesvirus-6 (HHV-6) and human herpesvirus-7 (HHV-7) are ubiquitous in childhood. The immunosuppression secondary to organ or bone marrow transplantation together with posttransplantation management may favour viral replication and reactivation. HHV-6 and -7 induce immunosuppression by targeting lymphocytes, natural killer cells and monocytes. HHV-6 is commonly detected posttransplantation but variability in definitions of clinical syndromes related to this virus and detection methods have complicated understanding of the clinical relevance of HHV-6 posttransplantation. Clinical symptoms associated with HHV-6 include febrile illness, pneumonitis, hepatitis, encephalitis and bone marrow suppression. However, the majority of HHV-6 infections are asymptomatic. The incidence of HHV-7 infection and its clinical manifestations posttransplantation are even less well characterised. In addition, HHV-6 and HHV-7 are related to CMV disease or acute graft-versus-host disease and, indirectly, to increases in resource utilisation. Based on the potential relevance of these two beta-herpesviruses in transplant recipients, further studies are required to establish their real impact in transplantation. For this, sensitive and specific molecular diagnostic techniques allowing for the rapid detection and quantitation of virus and for the analysis of susceptibility to current antiviral agents are required.

Bone Marrow Diseases↗