Porcine endothelial cells and iliac arteries transduced with AdenoIL-4 are intrinsically protected, through Akt activation, against immediate injury caused by human complement.

Vascular endothelial cells (ECs) can be injured in a variety of pathologic processes that involve activated complement. We reported previously that porcine ECs incubated with exogenous IL-4 or IL-13 are protected from cytotoxicity by human complement and also from apoptosis by TNF-alpha. The resistance to complement consists of an intrinsic mechanism that is lost a few days after cytokine removal. In our current study, we investigated whether transfer of the IL-4 gene into porcine ECs in vitro and into porcine vascular tissues in vivo would induce efficient and durable protection from human complement. We found that ECs transduced with adenoIL-4 or adenoIL-13 exhibited continuous production of the cytokine and prolonged protection from complement-mediated killing. IL-4 also protected ECs from activation: ECs incubated with IL-4 did not develop cell retraction and intercellular gaps upon stimulation with sublytic complement. The endothelium and subendothelium of pig iliac arteries that were transduced with the IL-4 gene were effectively protected from complement-dependent immediate injury after perfusion with human blood. However, after similar perfusion, the endothelium was immediately lost from arteries that were transduced with a control adenovirus. The protection was not due to up-regulation of the complement regulators decay accelerating factor, membrane cofactor protein, and CD59, or to reduced complement activation, but required the participation of Akt. Although our studies model protection in pig-to-primate xenotransplantation, our findings of IL-4 induction of Akt-mediated protection may be more broadly applicable to EC injury as manifested in ischemia-reperfusion, allotransplantation, and various vascular diseases.

Progression of chronic myeloid leukemia to blast crisis during treatment with imatinib mesylate.

CONTEXT: Previous investigators have reported discrepancies between hematologic, marrow morphologic, and cytogenetic responses to imatinib mesylate among patients with chronic myeloid leukemia (CML). In addition to disease refractoriness, rare instances of disease progression from chronic phase to blast crisis during imatinib therapy have recently been anecdotally reported. OBJECTIVES: To describe the clinicopathologic features of 3 patients with CML who rapidly progressed from chronic phase to blast crisis while taking imatinib and to perform a review of the literature. DESIGN: Morphologic, immunophenotypic, and cytogenetic analyses were performed on the 3 patients at the time of initial diagnosis, during imatinib therapy, and at blast crisis. RESULTS: The 3 patients were men, aged 39, 42, and 43 years. Two had been treated with hydroxyurea for 16 and 21 months before imatinib therapy, while 1 was started on a regimen of imatinib following diagnosis. Despite a hematologic response in all 3 patients, none of them achieved cytogenetic remission, and all progressed to blast crisis at 7 to 10 months of imatinib therapy. Blood findings during blast transformation were heterogeneous, including normal blood morphologic findings in 1 patient, leukocytosis with circulating blasts and basophilia in 1, and marked pancytopenia in 1. All 3 marrow specimens demonstrated moderate to marked diffuse reticulin fibrosis with more than 20% blasts. Clonal cytogenetic evolution was evident in 2 of the 3 patients and included an extra Philadelphia chromosome in both. All 3 patients underwent allogeneic bone marrow transplantation. One was alive with no evidence of disease at 14 month follow-up, while 2 had residual disease after bone marrow transplantation and died of complications at 4 and 5 months after transplantation. CONCLUSIONS: Blood data did not always reflect marrow status. Therefore, bone marrow follow-up is critical for monitoring of response. Our findings suggest that significant progression of marrow reticulin fibrosis during imatinib therapy can be an indicator for a return or progression of CML and, in some patients with CML, imatinib may promote cytogenetic clonal evolution, resulting in a poor response to treatment.