Depressed mediator release by inflammatory exudate cells in immunized rats following antigen challenge

The aim of the present study was to characterize leukocytes present in a local inflammatory reaction with respect to production of prostaglandin E (PGE) and the release of factors affecting lymphocyte function, which are produced by macrophages (interleukin-1) or stimulated lymphocytes (interleukin-2). Lewis rats immunized against bovine serum albumin (BSA) were challenged by intraperitoneal injection of antigen. The PGE release by peritoneal cells (PEC) was testedin vitro and found to be enhanced in immunized rats before BSA challenge. However, PEC harvested after the injection of antigen showed a marked reduction in prostaglandin production during the first 24 h. When these cells were tested for the secretion of lymphokines (IL-1, IL-2) the same depression was found.     

Differential expression of APO-1 on human thymocytes: Implications for negative selection?

Negative selection during T cell ontogeny involves selective induction of apoptosis in thymocytes. In peripheral lymphoid cells, apoptosis may be mediated via the APO-1 pathway. Here we report that APO-1 is constitutively expressed on the vast majority of human thymocytes but down-regulated at a mature stage of thymocyte development (TCR^hi). This stage of development is characterized by CD28^hi, CD44^hi, CD69^hi and up-regulation of Bcl-2 protein. We define a new thymocyte subpopulation that expresses high levels of APO-1 and intermediate levels of T cell receptor α/β (TCR^im/APO-1^hi). The TCR^im/APO-1^hi population contains a large fraction of dead cells, suggesting that the APO-1 pathway may be involved in negative selection of at least a fraction of thymocytes after intrathymic activation.     

Pelvic and lower extremity arterial imaging: diagnostic performance of three-dimensional contrast-enhanced MR angiography

OBJECTIVE: The diagnostic performance of a three-dimensional MR angiography-based strategy was assessed with regard to its ability to characterize the arterial vasculature from the aortic bifurcation to the lower extremity runoff vessels. A single-injection, two-station protocol in combination with a lower-extremity vascular coil was used. SUBJECTS AND METHODS: Both conventional digital subtraction angiography and three-dimensional contrast-enhanced MR angiography with a dedicated peripheral vascular coil were performed in 61 patients with suspected peripheral vascular disease. In a prospective analysis, one reviewer evaluated the digital subtraction angiographic images and a second reviewer evaluated the MR angiographic images; both were unaware of the results of the other imaging technique. Each vascular segment (29 segments per patient) was evaluated for the presence of occlusive vessel disease. The following grading system was applied: 0, normal; 1, vessel irregularity with a luminal reduction of less than 10%; 2, mild stenosis (lumen reduction, 10-49%); 3, severe stenosis (lumen reduction, 50-99%); and 4, occlusion (lumen reduction, 100%). In 11 patients surgical graft patency was assessed. RESULTS: MR angiography provided an image quality comparable with that of digital subtraction angiography. Overall sensitivity and specificity for MR angiography were 92% and 96.6%, respectively, for the detection of hemodynamically significant disease and 92.3% and 99.4%, respectively, for the detection of occlusions. CONCLUSION: Two-station contrast-enhanced three-dimensional MR angiography with a dedicated lower-extremity vascular coil proved effective enough to consider it as a noninvasive alternative to digital subtraction angiography in the assessment of the pelvic and lower extremity arterial vasculature.     

Phospho-CRKL monitoring for the assessment of BCR-ABL activity in imatinib-resistant chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia patients treated with nilotinib

Actual BCR-ABL kinase inhibition in vivo as determined by phospho-CRKL (pCRKL) monitoring has been recognized as a prognostic parameter in patients with chronic myelogenous leukemia treated with imatinib. We report a biomarker sub-study of the international phase I clinical trial of nilotinib (AMN107) using the established pCRKL assay in imatinib-resistant chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia. A minimum dose (200 mg) required for effective BCR-ABL inhibition in imatinib resistant/intolerant leukemia was determined. The pre-clinical activity profile of nilotinib against mutant BCR-ABL was largely confirmed. Substantial differences between peripheral blood baseline pCRKL/CRKL ratios were observed when comparing chronic myeloid leukemia with Ph+ acute lymphoblastic leukemia. Finally, rapid BCR-ABL-reactivation shortly after starting nilotinib treatment was seen in acute lymphoblastic leukemia patients with progressive disease carrying the P-loop mutations Y253H, E255K, or mutation T315I. Monitoring the actual BCR-ABL inhibition in nilotinib treated patients using pCRKL as a surrogate is a means to establish effective dosing and to characterize resistance mechanisms against nilotinib.     

HLA-haploidentical blood progenitor cell transplantation in osteopetrosis

Infantile osteopetrosis (OP) carries an extremely poor prognosis unless treated early by hematopoietic stem cell transplantation. We explored the use of purified blood progenitor cells from HLA-haploidentical parents in 7 patients lacking suitable matched donors. Blood progenitor cells were purified by positive selection and by additional T-cell depletion using rosette formation. For conditioning, patients received busulfan, thiotepa, and either cyclophosphamide (5 patients) or fludarabine (2 patients). Stable donor engraftment developed in 6 of 7 patients. Graft-versus-host disease was not observed. Three of the 7 patients had no major complications and 4 of 7 had both veno-occlusive disease and respiratory failure. Five of 7 patients survive with complete cure of OP at a median of 4 years. Patients with OP lacking HLA-matched donors can be successfully treated by transplantation of purified blood progenitor cells from HLA-haploidentical donors.