Targeting the CD40-CD154 Signaling Pathway for Treatment of Autoimmune Arthritis

Abstract

Full activation of T lymphocytes requires signals from both T cell receptors and costimulatory molecules. In addition to CD28, several T cell molecules could deliver costimulatory signals, including CD154, which primarily interacts with CD40 on B-cells. CD40 is a critical molecule regulating several B-cell functions, such as antibody production, germinal center formation and cellular proliferation. Upregulated expression of CD40 and CD154 occurs in immune effector cells and non-immune cells in different autoimmune diseases. In addition, therapeutic benefits have been observed by blocking the CD40-CD154 interaction in animals with collagen-induced arthritis. Given the therapeutic success of the biologics abatacept, which blocks CD28 costimulation, and rituximab, which deletes B cells in the treatment of autoimmune arthritis, the inhibition of the CD40-CD154 axis has two advantages, namely, attenuating CD154-mediated T cell costimulation and suppressing CD40-mediated B-cell stimulation. Furthermore, blockade of the CD40-CD154 interaction drives the conversion of CD4+ T cells to regulatory T cells that mediate immunosuppression. Currently, several biological products targeting the CD40-CD154 axis have been developed and are undergoing early phase clinical trials with encouraging success in several autoimmune disorders, including autoimmune arthritis. This review addresses the roles of the CD40-CD154 axis in the pathogenesis of autoimmune arthritis and its potential as a therapeutic target.

B cell depletion therapies in autoimmune disease: advances and mechanistic insights

“…Although the first anti-CD40L drug (ruplizumab; BG9588) was not viable because it caused thrombotic side effects 266 , new and safer variants are being tested. Given the importance of CD40-dependent T cell-B cell interactions in the GC as provided by T FH cells, we optimistically await the results of testing new forms of anti-CD40 or anti-CD40L therapies in autoimmune disease settings 267,268 .…”

Percentages of CD4+CD8+ double-positive T lymphocytes in the peripheral blood of adults from a blood bank in Bogotá, Colombia

“…Remarkably, this DPT subpopulation has an effector memory phenotype [9,10]. CD154 is the ligand of CD40, and this axis has been found to be of particular interest in the therapy of autoimmune diseases [29]. It would be very important to elucidate the functional role of CD154 in DPTs.…”

Dendritic cell biology and its role in tumor immunotherapy

“…These T cells also stimulate and govern B cells to produce antibodies. The interaction of CD40 on DCs in addition to CD40L on T cells leads to DC activation, enabling DCs to prime T cells and induce the upregulation of co-stimulatory molecules, adhesion molecules, and the Th1-polarizing cytokine IL-12 in both mouse and human DCs [81]. Notably, the IL-12 produced after the interaction of CD40 with CD40L plays a decisive role in determining the type of CD4 + T cell immunity [69].…”