100th Anniversary of Nagoya J Med Sci: Comments to the Highly Cited Articles
Nagoya J. Med. Sci. 85. 21–22, 2023
doi:10.18999/nagjms.85.1.21

The fruits of CD40 research in basic and clinical medicine
will soon be harvested
Tsutomu Kawabe
Division of Host Defense Sciences, Omics Health Sciences, Department of Integrated Health Sciences,
Nagoya University Graduate School of Medicine, Nagoya, Japan

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Kawabe T, Matsushima M, Hashimoto N, Imaizumi K, Hasegawa Y. CD40/CD40 ligand interactions in immune responses and pulmonary immunity. Nagoya J Med Sci. 2011;73(3–4):
69–78.
The CD40 ligand/CD40 pathway is widely recognized for its prominent role in immune
regulation and homeostasis. CD40, a member of the tumor necrosis factor receptor family, isexpressed by antigen-presenting cells, as well as non-immune cells and tumors. The engagement of the CD40 and CD40 ligands, which are transiently expressed on T cells and othernon-immune cells under inflammatory conditions, regulates a wide spectrum of molecular andcellular processes, including the initiation and progression of cellular and humoral adaptiveimmunity. Based on recent research findings, the engagement of the CD40 with a deregulated
amount of CD40 ligand has been implicated in a number of inflammatory diseases. We will
discuss the involvement of the CD40 ligand/CD40 interaction in the pathophysiology ofinflammatory diseases, including autoimmune diseases, atherothrombosis, cancer, and respiratory diseases.
Keywords: CD40, Immunity, B cells, Alveolar macrophages
It is a great honor to have an opportunity to write my article for the centenary issue of theNagoya J Med Sci. I also appreciate everyone who nominated me, especially Prof Toyokuni,
Editor-in-Chief. When I began my CD40 research in 1992 as a graduate student, my theme wasto establish CD40-deficient mice. Since the CD40 knock-out mouse has many unique phenotypes,
we published our first report in Immunity,1 which has been cited around 1,000 times. When I wasinvited to write a review article in the Nagoya J Med Sci in 2011,2 I wrote a manuscript basedon the latest information, including the findings of our several published papers. I prospected thefuture of CD40 research at the end of that review, concluding that a blockade of the CD40LCD40 interaction should provide promising and novel therapeutic methods.
Received: October 11, 2022; accepted: November 17, 2022
Corresponding Author: Tsutomu Kawabe, MD, PhD
Division of Host Defense Sciences, Omics Health Sciences, Department of Integrated Health Sciences,Nagoya University Graduate School of Medicine, 1-1-20 Daiko-minami, Higashi-ku, Nagoya 461-8673, Japan
E-mail: kawabe@met.nagoya-u.ac.jp
21Tsutomu Kawabe

I supposed at least two intriguing issues for investigating CD40 function. One is to elucidate
the mechanism for promoting somatic hypermutation of the immunoglobulin by CD40 signaling
to enhance affinity for antigen. Based on the findings from the intensive research in this field,
the in vitro system will be established for fine-tuning on antigen specificity of an antibody
produced from hybridoma cell lines. Another is a clinical application to activate or inactivate
the immune system by agonists or antagonists of the CD40L/CD40 pathway, respectively, underdisease conditions such as transplantation, autoimmune disorders, and cancer. Unfortunately, there
is still no clinically available therapy, although it has been 11 years since my review article waspublished. However, over 100 clinical trials were observed by searching with the word “CD40”
on the clinical trial registration webpage (https://clinicaltrials.gov/) run by the United States
National Library of Medicine. While all clinical trials using an anti-CD40L monoclonal antibody(mAb) in conditions ranging from transplantation to lupus nephritis and immune thrombocytopenic
purpura were halted because of severe thromboembolic side effects,3 therapeutic approach targeting
CD40 rather than CD40L has been developed as a safer and promising alternative to allow aninterruption of the CD40/CD40L interaction.
Ongoing clinical trials using an anti-CD40 mAb bleselumab have shown its acceptable efficacy
and safety in preventing acute rejection in kidney transplantation.3,4 Moreover, interruption of theCD40/CD40L interaction inhibits the proliferation and activation of B cells in autoimmune disorders.
Subsequently, autoantibody production is down-regulated, achieving a therapeutic effect. Clinical trials
using an anti-CD40 mAb and an anti-CD40L antibody lacking a functional Fc region, dapirolizumab,
are ongoing. Dapirolizumab inhibits CD40L-dependent immune responses without thromboticcomplications and improves the clinical response in patients with systemic lupus erythematosus.
While most cancer immunotherapy has focused on blockage of immune checkpoints, including
the treatment with anti-CTLA4 and/or anti-PD1 mAbs, immune stimulation is considered analternative approach that involves activation of anti-tumor immune pathways such as promotion of the T-cell priming against tumor antigens by an agonist of a stimulatory receptor on
antigen-presenting cells, such as an anti-CD40 antibody. Immune potentiating of the CD40L/
CD40 pathway using agonist anti-CD40 mAbs alone has demonstrated moderate clinical activity,
providing opportunities to use in synergistic combination with other cancer therapy, such as
vaccines, chemotherapy, and treatment with immune checkpoint inhibitors.5 Due to the recently
developed antibody-based technologies, bispecific antibodies, including anti-CD40 or anti-CD40L
mAbs, offer new treatment potential for cancer therapy. Therefore, we will see novel therapies
targeting the CD40L/CD40 pathway in the near future.

REFERENCES
1Kawabe T, Naka T, Yoshida K, et al. The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity. 1994;1(3):167–178. doi:10.1016/10747613(94)90095-7.
2 Kawabe T, Matsushima M, Hashimoto N, Imaizumi K, Hasegawa Y. CD40/CD40 ligand interactions in
immune responses and pulmonary immunity. Nagoya J Med Sci. 2011;73(3–4):69–78.
3 Koritzinsky EH, Tsuda H, Fairchild RL. Endogenous memory T cells with donor-reactivity: Early posttransplant mediators of acute graft injury in unsensitized recipients. Transpl Int. 2021;34(8):1360–1373.
doi:10.1111/tri.13900.
4 Louis K, Macedo C, Lefaucheur C, Metes D. Adaptive immune cell responses as therapeutic targets inantibody-mediated organ rejection. Trends Mol Med. 2022;28(3):237–250. doi:10.1016/j.molmed.2022.01.002.
5 Smith KE, Deronic A, Hägerbrand K, Norlén P, Ellmark P. Rationale and clinical development of CD40
agonistic antibodies for cancer immunotherapy. Expert Opin Biol Ther. 2021;21(12):1635–1646. doi:10.10
80/14712598.2021.1934446.
References EndNagoya J. Med. Sci. 85. 21–22, 2023

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doi:10.18999/nagjms.85.1.21