CD44 variant-specific antibodies trigger hemopoiesis by selective release of cytokines from bone marrow macrophages.

Hemopoiesis is regulated by the complex interplay between the bone marrow microenvironment and hemopoietic stem cells and progenitors. The local production of cytokines plays a critical role in this process. Using long-term bone marrow cultures, we show here that monoclonal antibodies directed against the CD44 v4 and CD44 v6 epitopes stimulate myelopoiesis (CD44 v4 and CD44 v6) and lymphopoiesis (CD44 v6). In the bone marrow cell population, CD44 v4 and CD44 v6 epitopes are found virtually exclusively on double-positive bone marrow macrophages. The anti-CD44 v4 and v6 antibodies act on bone marrow macrophages to stimulate granulocyte-macrophage colony-stimulating factor (GM-CSF) production (v4 and v6) and interleukin-6 (IL-6) production (v6). This profile of cytokine production explains the differential stimulation of hemopoiesis by the 2 antibodies. We suggest that the antibodies mimic ligand(s) that stimulate GM-CSF or IL-6 production by bone marrow-derived macrophages by binding to CD44 family members that bear CD44 v4 and CD44 v6 epitopes on these cells.