Mechanism Overview

The central role of CD40/CD40L signaling in generating pro-inflammatory responses makes it an attractive candidate for therapeutic intervention in autoimmune disease, induction and maintenance of transplant tolerance, and neuroinflammation. Blocking the activation of the CD40L (also called CD154) pathway ameliorates disease progression and pathology in preclinical models of autoimmunity and prevents acute and long-term allograft transplant rejection in multiple animal species.

Interaction of CD40 with CD40L on immune cells mediates the activation of the co-stimulatory immune pathway, controlling “cross talk” between the adaptive and innate immune systems. The engagement of these receptors plays a pivotal role in immune system activation by mediating both antibody and cellular immune responses through modulation of germinal cell function and B cell responses, as well as polarization of pro-inflammatory T cells.

The initiation of a robust immune response is mitigated by costimulatory signaling when CD40L binds costimulatory receptors, such as CD40, on antigen presenting cells. These antigen presenting cells are simultaneously presenting foreign peptides on their major histocompatibility complex (MHC) receptors to the T cell receptor on lymphocytes. The interaction of CD40L and CD40 results in clonal expansion, antibody production, and secretion of pro-inflammatory cytokines that amplify an immune response.

Importantly, blocking CD40L is not associated with the lymphopenia seen in many immunosuppressive drugs.