CD40 ligand in CLL pathogenesis and therapy

Advances in immunology during the past three decades have facilitated our understanding of the biology of specific lymphoid neoplasms including chronic lymphocytic leukemia (CLL). Investigations in our laboratory have focused on CD40, a critical regulator of B cell survival and differentiation, and its ligand, CD154 (CD40L). We have established that in some cases of CLL the malignant cells express both CD40 and CD154, and on the basis of those observations, proposed a model for CLL tumor growth due to CD40-CD154 interactions within and among the malignant cells, and for the occurrence of autoimmune syndromes in some cases of CLL. Here, we include an update on our studies regarding CD154 expression in CLL, a review of the data regarding the consequences of CD40 engagement in CLL B cells, and a discussion of these findings in the context of the complex and potentially opposite outcomes that have been reported for CD40-mediated signals in CLL. The implications for therapy, such as by impedance to CD154-CD40 interaction using antibody to CD154, or by selective inhibitors of NF-kappa B, are considered.