Stromal Cell Derived Factor-1 (SDF-1/CXCL12), CXCR4, CD26, and Hematopoietic Stem Cell Mobilization and Homing/Engraftment

HE Broxmeyer PhD^a, W Clapp MD^a, G Bridger PhD^a, E Srour PhD^a, C Orschell PhD^a, G Hangoc DVM^a, S Cooper BS^a, K Christopherson PhD^b

^aDepartment of Microbiology and Immunology, the Walther Oncology Center, Indiana University School of Medicine, Indiana, IN, Indianapolis, ^bAnorMed Corp, Langley, British Columbia, Canada

Aim: Our goal was to enhance the mobilization of hematopoietic (HSC) and progenitor (HPC) cells to the blood for preclinical and clinical HSC/HPC transplantation, to understand mechanisms involved in this mobilization, and to enhance the homing efficiency and engraftment/hematopoietic repopulation of limiting numbers of HSC/HPC. Methods: AMD3100, a specific antagonist of the binding of the chemokine, Stromal Cell Derived Factor-1 (SDF-1/CXCL12) to its receptor, CXCR4 was injected into mice, alone or in combination with granulocyte-colony stimulating factor (G-CSF). We then assessed the mobilization to blood of granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) progenitor cells, as well as long-term marrow competitive and non-competitive repopulating stem cells. Progenitor cells were analyzed in vitro by colony assays and stem cells were determined in vivo in lethally irradiated CD45 congenic mice. We used inhibition of CD26 dipeptidylpeptidase (DPP) IV or functional deletion of CD26 to determine if homing and engraftment/repopulation of CD26 inactivated or deleted HSC was enhanced. Results: AMD3100 induced HSC/HPC mobilization, and synergized with G-CSF to enhance mobilization to a greater extent than with G-CSF alone. Inactivation or deletion of CD26 resulted in enhanced homing and engraftment/repopulation of HSC. Conclusions: AMD3100 is a potent mobilizing agent for HSC and HPC, especially when used with G-CSF, and in the context of poor responders to G-CSF-induced mobilization. Clinical trials of AMD3100 with and without G-CSF are already ongoing and showing success. Inactivation of CD26 DPPIV activity may allow enhanced engraftment of HSC, information especially of value when limiting numbers of HSC, as in the case with HSC collected from umbilical cord blood, are available for transplantation. The mechanisms of action of AMD3100 and inhibitors of CD26 DPPIV activity appear to reflect modification of SDF-1/CXCL12-CXCR4 interactions.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in plenary session 901 (Immunobiology).