Immunobiology and experimental transplantation: dendritic cells; co-stimulatory pathways; intracellular signalingThe role of CD154 (CD40-ligand) in costimulation☆
Section snippets
Anti-CD154 mAbS in transplantation graft acceptance
The CD154 protein was discovered by generating a murine mAb antibody 5c8 that inhibited the contact-dependent helper function of a T-cell line by binding to a novel 30-kD surface protein.1 Studies with 5c8 mAb revealed that CD154 was transiently expressed by activated CD4+ T cells1 (Fig 1). Although these discoveries stimulated a profound interest in identifying the counterreceptor for CD154 and exploring the role of CD154 in mediating help for non-B cells, the appreciation that anti-CD154
Biology of CD154 and its counterreceptor CD40
In parallel with the development of mAb anti-CD154 therapeutics has been substantial progress in understanding the structure and function of CD154 (the 5c8 Ag18, 19, 20) and its counterreceptor, CD40. Among the many new and important advances in this field, perhaps two general areas are the most significant for transplantation: first, how closely CD154 expression is regulated and how the transience of CD154 expression relates to “monogamy;” second, how broadly CD40 is expressed and how CD40
Role of TRAF-3 in CD40 signaling
The understanding of CD40 signaling is another area of considerable interest that has the potential to yield fundamentally new modalities to facilitate graft acceptance. TRAF-3 was identified as a cytoplasmic signaling molecule that interacts with the cytoplasmic tails of CD40 and certain other tumor necrosis factor receptor (TNF-R) family members.34, 35, 36, 37 Although understanding of the role of TRAF-3 in signaling is still evolving, TRAF-3 gene products are known to participate in
Conclusion
Progress in the evaluation of anti-CD154 mAbs as therapeutics for graft acceptance has validated the CD154/CD40 pathway as a target for therapeutic intervention. Refinements in therapeutics could derive from understanding the ordered sequence by which CD4+ T helper cells activate appropriate APC to express costimulatory factors which result in T-cell clonal expansion and differentiation into effector cells. The CD40 signaling pathway provides additional avenues for rational therapeutic
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This work was supported by grants from the National Cancer Institute, NIH, and from Biogen Corporation, Cambridge, MA.