A CD28 based bi-directional molecular bridge that support plasma cell survival in the bone marrow. (46.16)

Abstract

Abstract Dendritic cells (DC) are essential for the long term survival of plasma cells (PC) in the bone marrow and for the maintenance of persistent antibody titers. But the molecular basis for these interactions is not very clear. Both normal and malignant PC (like myeloma) express the T-cell co-stimulatory molecule CD28. Our data show that CD28 expressed on PC play a major role in CD80/CD86 (B7) mediated DC induction of growth factors such as IL-6 and immunosuppressive enzyme indoleamine 2,3 dioxygenase (IDO) as well as in antibody or DC mediated protection of PC in vitro. While IL-6 protected PC in vitro, IDO induced the formation of regulatory T cells in culture. Use of myeloma drug lenalidomide to inhibit DC-B7 expression or anti-CD28(Fab)2 fragments to block CD28-B7 interactions reduced DC ability to protect MM cells or produce IL-6/IDO. Moreover, just like in T-cell models, CD28 activation in malignant PC triggers similar molecular events such as tyrosine phosphorylation and association of p85. We believe that downstream of CD28, while PI3K/Akt governs survival, the Vav1/SLP76 pathway regulate PC proliferation and these form the molecular basis for a bi-directional molecular bridge between the PC and bone marrow microenvironment. Targeting this bridge could form the basis for future therapeutic strategies. Our data suggests a role for CD28-B7 in plasma cell survival by modulating the bone marrow microenvironment.