Browsing by Subject "Dipeptidylpeptidase 4"

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    DPP4 Truncated GM-CSF & IL-3 Manifest Distinct Receptor Binding & Regulatory Functions Compared to their Full Length Forms
    (Nature Publishing group, 2017-11) O’Leary, Heather Ann; Capitano, Maegan; Cooper, Scott; Mantel, Charlie; Boswell, H. Scott; Kapur, Reuben; Ramdas, Baskar; Chan, Rebecca; Deng, Lisa; Qu, Cheng-Kui; Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    Dipeptidylpeptidase 4 (DPP4/CD26) enzymatically cleaves select penultimate amino acids of proteins, including colony stimulating factors (CSFs), and has been implicated in cellular regulation. To better understand the role of DPP4 regulation of hematopoiesis, we analyzed the activity of DPP4 on the surface of immature blood cells and then comparatively assessed the interactions and functional effects of full-length (FL) and DPP4 truncated factors [(T)-GM-CSF and- IL-3] on both in vitro and in vivo models of normal and leukemic cells. T-GM-CSF and T-IL-3 had enhanced receptor binding, but decreased CSF activity, compared to their FL forms. Importantly, T-GM-CSF and T-IL-3 significantly, and reciprocally, blunted receptor binding and myeloid progenitor cell proliferation activity of both FL-GM-CSF and FL-IL-3 in vitro and in vivo. Similar effects were apparent in vitro using cluster forming cells from patients with Acute Myeloid Leukemia (AML) regardless of cytogenetic or molecular alterations and in vivo utilizing animal models of leukemia. This suggests that DPP4 T-molecules have modified binding and functions compared to their FL counterparts and may serve regulatory roles in normal and malignant hematopoiesis.
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    Enhancing the efficacy of engraftment of cord blood for hematopoietic cell transplantation
    (Elsevier, 2016-06) Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    Clinical cord blood (CB) hematopoietic cell transplantation (HCT) has progressed well since the initial successful CB HCT that saved the life of a young boy with Fanconi anemia. The recipient is alive and well now 28 years out since that first transplant with CB cells from his HLA-matched sister. CB HCT has now been used to treat over 35,000 patients with various malignant and non-malignant disorders mainly using HLA-matched or partially HLA-disparate allogeneic CB cells. There are advantages and disadvantages to using CB for HCT compared to other sources of transplantable hematopoietic stem (HSC) and progenitor (HPC) cells. One disadvantage of the use of CB as a source of transplantable HSC and HPC is the limited number of these cells in a single CB collected, and slower time to neutrophil, platelet and immune cell recovery. This review describes current attempts to: increase the collection of HSC/HPC from CB, enhance the homing of the infused cells, ex-vivo expand numbers of collected HSC/HPC and increase production of the infused CB cells that reach the marrow. The ultimate goal is to manipulate efficiency and efficacy for safe and economical use of single unit CB HCT.
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    Inhibition of DPP4/CD26 and dmPGE2 treatment enhances engraftment of mouse bone marrow hematopoietic stem cells
    (Elsevier B.V., 2014-06) Broxmeyer, Hal E.; Pelus, Louis M.; Department of Microbiology & Immunology, IU School of Medicine
    Enhancing the engraftment of hematopoietic stem cells (HSC) is especially important when times to engraftment are prolonged due either to limiting numbers of HSC in the donor graft or to intrinsic slower engrafting time of the tissue sources of HSC. Both inhibition of Dipeptidylpeptidase (DPP) 4/CD26 and treatment of cells with 16,16 dimethyl prostaglandin E2 (dmPGE2) have been shown to enhance hematopoietic stem cell engraftment in murine transplantation models and have been evaluated in clinical settings for their influence on engraftment of cord blood cells, a tissue source of HSC known to manifest an extended time to engraftment of donor cells compared to that of bone marrow (BM) and mobilized peripheral blood for hematopoietic cell transplantation (HCT). Herein, we present new experimental data, using a CD45+ head-to head congenic model of donor mouse BM cells for engraftment of lethally-irradiated mice, demonstrating that similar levels of enhanced engraftment are detected by pulsing donor BM cells with Diprotin A, a DPP4 inhibitor, or with dmPGE2 prior to infusion, or by pretreating recipient mice with sitagliptin, also a DPP4 inhibitor, by oral gavage. Moreover, the combined effects of pretreating the donor BM cells with dmPGE2 in context of pretreating the recipient mice with sitagliptin after administration of a lethal dose of radiation resulted in significantly enhanced competitively repopulating HCT compared to either treatment alone. This information is highly relevant to the goal of enhancing engraftment in human clinical HCT.