title: Dipeptidyl peptidase IV (DPPIV/CD26) inhibition does not improve engraftment of unfractionated syngeneic or allogeneic bone marrow after nonmyeloablative conditioning.
abstract: In order to develop minimally toxic bone marrow transplantation (BMT) protocols suitable for use in a wider range of indications, it is important to identify ways to enhance BM engraftment at a given level of recipient conditioning. CXCL12/stromal cell-derived factor-1α plays a crucial physiological role in homing of hematopoietic stem cells to BM. It is regulated by the ectopeptidase dipeptidyl peptidase IV (DPPIV; DPP4) known as CD26, which cleaves dipeptides from the N-terminus of polypeptide chains. Blocking DPPIV enzymatic activity had a beneficial effect on hematopoietic stem cell engraftment in various but very specific experimental settings. Here we investigated whether inhibition of DPPIV enzymatic activity through Diprotin A or sitagliptin (Januvia) improves BM engraftment in nonmyeloablative murine models of syngeneic (i.e., CD45-congenic) and allogeneic (i.e., Balb/c to B6) BMT (1 Gy total body irradiation, 10-15 × 10(6) unseparated BM cells/mouse). Neither Diprotin A administered in vivo at the time of BMT and/or used for in vitro pretreatment of BM nor sitagliptin administered in vivo had a detectable effect on the level of multilineage chimerism (follow-up >20 weeks). Similarly, sitagliptin did not enhance chimerism after allogeneic BMT, even though DPPIV enzymatic activity measured in serum was profoundly inhibited (>98% inhibition at peak exposure). Our results provide evidence that DPPIV inhibition via Diprotin A or sitagliptin does not improve engraftment of unseparated BM in a nonmyeloablative BMT setting.
authors.affiliation: Division of Transplantation, Department of Surgery, Vienna General Hospital, Medical University of Vienna, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schwaiger
authors.forename: Christoph
authors.initials: C
authors.lastname: Klaus
authors.forename: Veerle
authors.initials: V
authors.lastname: Matheeussen
authors.forename: Ulrike
authors.initials: U
authors.lastname: Baranyi
authors.forename: Nina
authors.initials: N
authors.lastname: Pilat
authors.forename: Haley
authors.initials: H
authors.lastname: Ramsey
authors.forename: Stephan
authors.initials: S
authors.lastname: Korom
authors.forename: Ingrid
authors.initials: I
authors.lastname: De Meester
authors.forename: Thomas
authors.initials: T
authors.lastname: Wekerle
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D000068900:Sitagliptin Phosphate; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D009842:Oligopeptides; D011719:Pyrazines; D014230:Triazoles; C041445:diprotin A; D000068900:Sitagliptin Phosphate
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