Between the late 1950s and the mid-1980s, several immunology laboratories started to use the new hybridoma technology to develop monoclonal antibodies (mAbs) and define receptors expressed at different stages of hematopoietic cell differentiation.

While doing these experiments, several mAbs were developed against a protein called CD40, a surface receptor of B cells that can be polyclonally activated by a binding ligand.

This receptor has been found to be essential in mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation.

[7] AT-hook transcription factor AKNA is reported to coordinately regulate the expression of this receptor and its ligand, which may be important for homotypic cell interactions.

The increase in activation results in the induction of potent microbicidal substances in the macrophage, including reactive oxygen species and nitric oxide, leading to the destruction of ingested microbe.

Early evidence for these effects were that in CD40 or CD40L deficient mice, there is little class switching or germinal centre formation,[9] and immune responses are severely inhibited.

[6] There are a number of completed and ongoing clinical trials using agonistic anti-CD40 monoclonal antibodies to elicit an anti-tumor T-cell response via dendritic cell activation.

Over the past 20 years, numerous human CD40 monoclonal antibodies have been developed and evaluated in clinical trials due to encouraging variability in cancer animal models.

[5] More recently, agonistic CD40 therapy has been shown to decrease T cell cytotoxicity in preclinical glioma models, and in fact affect the efficacy of immune checkpoint blockade.

This is likely due to the high mutational burden most of these models display, which causes them to respond better to immune checkpoint blockade than human glioma, but is nonetheless relevant information for research in immunomodulatory therapies.

CD40 is involved in the development of hyper-IgM syndrome in that it serves as a co-stimulatory molecule in the activation differentiation of B cells, which play a key role in producing immunoglobulins.

For example, drugs that block CD40 signaling have shown promise in treating autoimmune diseases, such as rheumatoid arthritis, by suppressing the overactive immune response.