Long-Term Effects of In Vivo Administration of An Anti-VLA-4 Antibody (natalizumab) on Mobilization of Committed and Primitive Hematopoietic Progenitor Cells In Humans

Abstract 2264

The alpha4 beta1 integrin (VLA-4) exert a critical role on hematopoiesis by confining hematopoietic stem cells (HSC) and progenitor cells (HPC) within the niche. Previous preclinical studies have pointed out this role showing that HPCs can be mobilized by in vivo administration of a blocking anti-VLA-4 antibody (Ab) (Papayannopoulou et al, 1993). Very recently, two papers (Bonig et al, 2008; Zohren et al, 2008) have shown that such Ab exhibits a similar effect in humans for one month after treatment by natalizumab. In the present study, we have investigated long-term hematopoietic effects (up to 23 months) of repeated infusions of natalizumab in patients treated for multiple sclerosis (n=22). Seven patients have been explored sequentially (every month for one year) and 15 have been studied punctually (6 before and 9 after one year of treatment). We found that peripheral blood leukocytosis was consistently increased for one year in relation to lymphocytes, particularly to B lineage (by 3-fold). In parallel, an increase of circulating HPCs (CD34+ cells and total CFU) was observed and appeared more pronounced with levels above baseline values in all the patients studied (by 6-fold) while no increase of circulating mesenchymal stromal cells (CFU-F) was found. The increase was noted for both lymphoid (T and B lineages) and myeloid (granulo-monocyte, erythroid, and megakaryocyte) committed progenitor cells but also for primitive HPC (CD34+CD38- cells and CAFC). This effect was still found at long-term (up to two years of treatment) for both committed and primitive HPC. In conclusion, the HPC mobilizing effect of chronic administration of anti-VLA-4 Ab in humans involves all types of HPCs (lymphoid and myeloid, committed and primitive ones) and is not exhausted with time.