Antibodies to VLA4 Integrin Mobilize Long-Term Repopulating Cells and Augment Cytokine-Induced Mobilization in Primates and Mice

• Published in: Blood Vol. 90; no. 12; pp. 4779 - 4788
• Main Authors: Craddock, Charles F., Nakamoto, Betty, Andrews, Robert G., Priestley, Gregory V., Papayannopoulou, Thalia
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.12.1997; The Americain Society of Hematology
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Antibodies - immunology; Biological and medical sciences; Bone Marrow Transplantation; Bone marrow, stem cells transplantation. Graft versus host reaction; Cell Division; Cytokines - pharmacology; Fluorouracil - pharmacology; Hematopoietic Stem Cell Mobilization; Integrin alpha4beta1; Integrins - physiology; Medical sciences; Mice; Papio; Rats; Receptors, Lymphocyte Homing - physiology; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Animal model; Transfusion; Antibody; Stem cell; Rodentia; Cytokine; Cell adhesion molecule; Monkey; Hematopoietic cell; Mobilization; Vertebrata; Autograft; Mammalia; Integrin; Mouse; Hematopoiesis; Animal; Primates; Graft
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V90.12.4779

Although the use of cytokine-mobilized peripheral blood stem cells has gained a significant momentum in clinical transplantation, the mobilization schemes practiced are guided by a great deal of empiricism. The mechanism(s) by which cytokines or chemokines, alone or in combination, bring about redistribution of stem/progenitor cells from bone marrow to peripheral blood are poorly understood. Likewise the fate of mobilized stem/progenitor cells and their biological properties are incompletely defined. One of the leading hypotheses to explain the mechanism of cytokine-induced mobilization encompasses the view that cytokines disrupt, directly or indirectly, cytoadhesive interactions of stem/progenitor cells with their bone marrow stroma. Compatible with this view are changes in the expression and/or function of several cytoadhesion molecules, especially integrins, postmobilization, and extensive in vitro experimentation supporting the concept of cytokine/integrin interactions. To provide a further insight on the cytokine/integrin interplay in vivo, we have combined cytokine treatments with anti-integrin treatments for mobilization in primates and mice. We found that anti-VLA4 treatment combined with either granulocyte colony-stimulating factor (G-CSF ) treatment or kit ligand treatment leads to significant enhancement of mobilization efficiency (fivefold to eightfold) well above the levels produced by either cytokine alone or anti-VLA4 treatment alone. Similar enhancement was seen when combinations of cytokines, ie, G-CSF plus kit ligand or G-CSF plus Flt3-ligand were used with anti-VLA4 in primates and mice. Furthermore, when anti-VLA4 was given in 5-Fluorouracil–treated primates, significant numbers of progenitor cells were circulating for several days during the recovery period only in the anti-VLA4 treated animals. These data suggest that (1) the effect of anti-VLA4 on mobilization, when used alone, is unlikely to be mediated by secondary cytokine elaboration in vivo; (2) three different cytokines and their combinations do not appear to influence the in vivo responsiveness to anti-VLA4 in coadministration schemes; (3) even if cytokine treatments on their own exert downmodulation of VLA4 function, the target progenitor cells influenced by anti-VLA4 or by cytokines may not necessarily overlap; and (4) augmentation of mobilization in cytokine/anti-VLA4 treatments is most likely caused by an amplification of the pool of target cells on which anti-VLA4 exerts its effects. Because cytokines or anti-VLA4 are each capable of mobilizing long-term repopulating cells and because we show with the present studies that anti-VLA4 in an autologous bone marrow cell transplantation setting does not cause any delay in engraftment, the combination of cytokine/anti-integrin treatment enhancing mobilization may have a clinical use.