Monoclonal antibodies to Pgp-1/CD44 block lympho-hemopoiesis in long-term bone marrow cultures.

Abstract

A new panel of mAbs was prepared to a stromal cell line known to support lymphocytes in Whitlock-Witte type long-term bone marrow cultures. These antibodies were then screened with a cell adhesion assay and four were selected that inhibited the binding of B lineage cells to stromal cell monolayers. Immunofluorescent and biochemical analyses revealed that these new antibodies detected epitopes of the previously described Pgp-1/CD44 antigen complex. Addition of Pgp-1/CD44 antibodies to Dexter-type long-term bone marrow cultures completely prevented emergence of myeloid cells and they also blocked lymphocyte growth in Whitlock-Witte type cultures. mAbs MEL-14, LFA-1, and CD45R did not inhibit under the same conditions and there was no apparent relationship to Ig isotype. Adherent layers in treated cultures were not unusual in terms of morphology and the antibodies did not affect factor-dependent replication of lymphoid or myeloid progenitor cells. Therefore, the mechanism of inhibition may not involve direct toxicity to precursors or microenvironmental elements. Previous studies in humans and mice have implicated Pgp-1/CD44-related glycoproteins in the migration of peripheral lymphoid cells, as well as interactions of cells with the extracellular matrix. These findings suggest that they may also be critical for formation of lymphoid and myeloid cells within bone marrow.

Chemotherapy-induced mesenchymal stem cell damage in patients with hematological malignancy

“…It is known that CD44 influences the production of progenitor cells and bears and influences myeloid differentiation [31,36]. Anti-CD44 mAbs significantly affect both the formation of cobblestone areas within the adherent layer of long-term bone marrow cultures and the production of mature cells [37,38] and also completely prevented emergence of myeloid cells, and they also blocked lymphocyte growth in Dexter-type long-term bone marrow cultures [38]. In addition, it has shown that CD44 present on stromal cells is critical for the adhesion and development of NK cells in culture [39].…”

MUC18, a member of the immunoglobulin superfamily, is expressed on bone marrow fibroblasts and a subset of hematological malignancies

“…8 Studies involving physical separation of hemopoietic progenitors from stromal layers or the addition of monoclonal antibodies to adhesion molecules such as CD44 suggest that contact is important. 7,9 It therefore follows that molecules expressed on the cell surface of bone marrow stromal cells are likely to play an important role in the maintenance and regulation of hemopoiesis. Bone marrow fibroblasts (BMF) are a major constituent of these cultures, and under certain culture conditions can be grown as a virtually homogenous population.…”

Antibodies to CD44 enhance adhesion of normal CD34+ cells and acute myeloblastic but not lymphoblastic leukaemia cells to bone marrow stroma

“…However, these mechanisms do not account for all the adhesion observed. In the murine system CD44 is known to play a major role in progenitor/stromal adhesion (Miyake et al, 1990a). In humans, CD44 mediates adhesion of committed progenitors to fibronectin via co-operation with VLA-4 (Verfaillie et al, 1994).…”