Detection of donor-specific anti-HLA antibodies (DSA) has been associated with graft rejection in all forms of transplantation. The mechanism by which DSA increase the risk of graft failure remains unclear. We hypothesized that complement-binding DSA are associated with engraftment failure in hematopoietic stem-cell transplantation and analyzed 122 haploidentical transplant recipients tested prospectively for DSA. Retrospective C1q testing was done on 22 allosensitized recipients. Twenty-two of 122 patients (18%) had DSA, 19 of which were females (86%). Seven patients with DSA (32%) rejected the graft. Median DSA level at transplant for patients who failed to engraft was 10,055 MFI versus 2,065 MFI for those who engrafted (p=0.007). Nine patients with DSA were C1q positive in the initial samples with median DSA level 15,279 MFI (range 1,554-28,615), compared with 7 C1q negative patients with median DSA level 2,471 MFI (665-12,254) (p=0.016). Of 9 patients, who tested positive for C1q in the initial samples, 5 patients remained C1q positive at time of transplant [all with high DSA levels (median 15,279, range 6,487-22,944)] and experienced engraftment failure, while 4 patients became C1q negative pre-transplant and all engrafted the donor cells (p=0.008). In conclusion, patients with high DSA levels (> 5,000 MFI) and complement-binding antibodies (C1q positive) appear to be at much higher risk of primary graft failure. C1q should be assessed in patients with DSA prior to hematopoietic stem-cell transplantation. Reduction of DSA to non-complement binding levels might prevent engraftment failure in hematopoietic stem cell transplantation.
Filgrastim mobilization and apheresis of blood stem cells constitute a safe, well-tolerated, and comparable or less expensive alternative to the traditional marrow harvest.
Targeted drug delivery offers an opportunity for the development of safer and more effective therapies for the treatment of cancer. In this study, we sought to identify short, cell-internalizing peptide ligands that could serve as directive agents for specific drug delivery in hematologic malignancies. By screening of human leukemia cells with a combinatorial phage display peptide library, we isolated a peptide motif, sequence Phe-Phe/TyrAny-Leu-Arg-Ser (F F / Y XLRS), which bound to different leukemia cell lines and to patient-derived bone marrow samples. The motif was internalized through a receptor-mediated pathway, and we next identified the corresponding receptor as the transmembrane glycoprotein neuropilin-1 (NRP-1). Moreover, we observed a potent anti-leukemia cell effect when the targeting motif was synthesized in tandem to the pro-apoptotic sequence D (KLAKLAK) 2 . Finally, our results confirmed increased expression of NRP-1 in representative human leukemia and lymphoma cell lines and in a panel of bone marrow specimens obtained from patients with acute lymphoblastic leukemia or acute myelogenous leukemia compared with normal bone marrow. These results indicate that NRP-1 could potentially be used as a target for liganddirected therapy in human leukemias and lymphomas and that the prototype CGFYWLRSC-GG-D (KLAKLAK) 2 is a promising drug candidate in this setting. (Blood. 2011;117(3):920-927)
IntroductionThe development of targeted drug-delivery strategies for safer and more effective therapy in human hematologic malignancies has been a long-standing goal for clinical and basic investigators. We reasoned that profiling of human leukemia-and lymphoma-derived cell lines with combinatorial libraries might yield ligand peptide sequences that bind to specific internalizing receptors on cell surfaces and may potentially lead to the discovery of new or unrecognized therapeutic targets. Such targeting motifs could also serve as vehicles for the preferential delivery of cytotoxic agents to leukemia and lymphoma cells.Several cell surface-binding peptides recognizing receptors in the membranes of lymphoma and leukemia cell lines have been reported. [1][2][3][4][5] The selected peptide ligands are readily internalized by cells and may therefore be potentially useful in ligand-directed drug delivery. Recently, we described an arginine-rich motif that is internalized into leukemia and lymphoma cells through the macropinocytotic pathway; however, the precise cell surface receptor has yet to be identified. 6 In effect, there is currently a relative lack of well-defined ligand-receptor systems for targeting human leukemia or lymphoma cells. The identification and validation of ligandreceptor pairs for these hematologic cancer cells relative to normal leukocytes would potentially represent a differential strategy and perhaps even improve disease outcomes.In this study, we used a combinatorial phage display-based subtractive selection 7-9 to identify ligand motifs that bind to specific cell surface receptors on human leuk...
Neutropenia-related fungal infections can be life-threateningand efficacy of rG-CSF-elicited WBC transfusions in patients despite antifungal therapy. We evaluated the role of recombiwith neutropenia-related fungal infections that were refractory nant granulocyte colony-stimulating factor (rG-CSF)-elicited to therapy with amphotericin B. acute branching septated hyphae but the culture evaluation
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.