Durable engraftment of AMD3100-mobilized autologous and allogeneic peripheral-blood mononuclear cells in a canine transplantation model

Abstract

Peripheral-blood mononuclear cells (PBMCs) mobilized with AMD3100, a CXCR4 antagonist, combined with granulocyte colony-stimulating factor (G-CSF) have reconstituted autologous hematopoiesis in cancer patients following myeloablative conditioning. The engraftment potential of PBMCs mobilized with AMD3100 alone, however, has remained unproven. We therefore studied AMD3100-mobilized PBMCs in a canine model. Four dogs received 920 cGy total body irradiation (TBI) before infusion of autologous AMD3100-mobilized PBMCs (median CD34 cell count, 3.9 ؋ 10 6 /kg). Neutrophil (> 0.5 ؋ 10 9 /L [500/L]) and platelet (> 20 ؋/10 9 /L [> 20 000/L]) recoveries occurred at medians of 9 (range, 7-10) days and 25 (range, 23-38) days, respectively, after TBI, and all dogs had normal marrow function at 1 year after transplantation. To evaluate the long-term engraftment potential of AMD3100-mobilized PBMCs, 5 dogs were given 920 cGy TBI followed by infusion of AMD3100-mobilized PBMCs (median CD34 cell dose, 4.7 ؋ 10 6 /kg) from their dog leukocyte antigen (DLA)-identical littermates. Neutrophil and platelet recoveries occurred at medians of 8 (range, 8-10) days and 26 (range, 26-37) days, respectively, after TBI. With a median follow-up of 53 (range, 33-61) weeks, recipients' marrow function was normal, and blood-donor chimerism levels were 97% to 100%. In summary, both autologous and allogeneic AMD3100- IntroductionUnder steady-state conditions, CD34 ϩ hematopoietic progenitor and stem cells circulate in the blood of animals and humans at frequencies too low to allow for efficient collection of numbers sufficient to ensure timely hematopoietic reconstitution after myeloablative therapy. The frequencies of CD34 ϩ cells in the blood are considerably increased both in response to various growth factors and during the recovery phase following myelosuppressive chemotherapy. Granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral-blood mononuclear cells (PBMCs) are routinely used as a source of hematopoietic stem cells for transplantation and, owing to the earlier neutrophil and platelet engraftments and shortened hospital stay associated with the use of this product, are often preferred over bone marrow. [1][2][3][4][5][6][7][8] In the setting of autologous hematopoietic cell transplantation (HCT), difficulties in mobilizing and harvesting sufficiently large numbers of hematopoietic stem cells may occur, particularly in patients who have been exposed to repetitive cycles of myelotoxic chemo-and/or radiation therapy. 9 Alternative strategies aimed at improving CD34 ϩ cell mobilization including use of novel growth factors or growth factor combinations have been explored in clinical studies. [10][11][12][13][14][15] With respect to efficacy and/or safety of the mobilization procedure, however, none of these strategies has proven superior to G-CSF used alone or in combination with chemotherapy.Recently, several studies have demonstrated the importance of the interaction between stromal-cell-derived factor-1␣ (SDF-1␣) and its rece...

CXCR4 antagonism as a therapeutic approach to prevent acute kidney injury

“…In agreement with studies in mouse (8), dog (9), and human (40), plerixafor induces a transient leukocytosis in rats (Fig. 1, B-E).…”

Rapid immune reconstitution of SCID-X1 canines after G-CSF/AMD3100 mobilization and in vivo gene therapy

“…52 The bicyclam AMD3100 is a potent, selective, and reversible antagonist of the CXCR4 chemokine receptor that disrupts the binding of CXCR4 to SDF-1, thereby mobilizing HSCs into the blood. 41,53 Kinetics of HSPC mobilization by AMD3100 alone were previously assessed in adult dogs, 54 in which the treatment was well tolerated and circulating CD34…”

“…Circulating lymphocyte and monocyte counts were increased by medians of 1.5-and fourfold, respectively, in mobilized adult canines as compared with untreated controls. 54 In rhesus macaques, AMD3100 increased numbers of B and T lymphocytes, which included CD4 1 and CD8…”

Protective Role of CXC Receptor 4/CXC Ligand 12 Unveils the Importance of Neutrophils in Atherosclerosis

“…8,9 The bicyclam Cxcr4 antagonist AMD3100 induces generalized leukocytosis, releasing hematopoietic progenitors into peripheral blood 6,7,42 and has been used together with granulocyte colony-stimulating factor for autologous reconstitution of hematopoiesis after myeloablation. 43,44 Although CXCR4 regulates the steady-state release of BM neutrophils into peripheral blood, where they exhibit moderate levels of CXCR4 expression and function, their high Cxcr2 expression entails a release and strong chemotactic activity toward inflammatory Cxcr2 ligands. Continuous steady-state exposure to Cxcl12 in the BM stromal niche leads to an incomplete desensitization, which is enhanced by heterologous stimulation with inflammatory Cxcl1 to induce neutrophil release.…”