Surreal illustration symbolizing the unlocking of immune tolerance through CD40/CD40L blockade.

Unlocking Tolerance: Can Blocking CD40/CD40L Revolutionize Chimerism-Based Therapies?

Nico Varela in Health & Wellness June 2025 • 4 min read.

"A deeper look into how targeting the CD40/CD40L pathway could transform transplant medicine and autoimmune disease treatments."

In the quest to improve long-term outcomes in transplant medicine, researchers are increasingly focusing on innovative strategies to induce tolerance—a state where the recipient's immune system accepts the new organ without rejection. One promising approach involves establishing hematopoietic chimerism, a condition where the recipient's bone marrow contains cells from both the recipient and the donor. This can lead to a more accepting immune environment.

Chimerism-based tolerance has shown encouraging results in clinical trials for kidney transplant recipients. However, the journey to full translational success is fraught with challenges, including the toxic effects of recipient conditioning and the limited applicability of current methods. As a result, there is a growing need for novel regimens that can overcome these limitations.

One such avenue of exploration is the use of costimulation blockers, particularly those targeting the CD40/CD40L pathway. This pathway plays a crucial role in immune cell activation and interaction, making it a key target for modulating immune responses. Recent research has focused on understanding whether blocking CD40/CD40L can enhance chimerism-based tolerance and improve transplant outcomes.

The Promise of CD40/CD40L Blockade: What the Research Shows

Surreal illustration symbolizing the unlocking of immune tolerance through CD40/CD40L blockade.

For over two decades, inhibiting the CD40/CD40L (CD154) pathway has yielded promising results in murine studies. In these preclinical models, anti-CD40L treatment—with or without additional CTLA4Ig—has allowed conditioning requirements to be substantially reduced, fostering chimerism-based tolerance. This approach has been shown to promote a unique interplay of deletional and regulatory mechanisms, solidifying anti-CD40L's position as a mainstay in experimental chimerism models.

Parallel to these findings, anti-CD40L monoclonal antibodies (mAbs) were developed as immunosuppressive drugs, capitalizing on their attractive immunomodulatory properties observed in preclinical studies. However, the development of conventional anti-CD40L mAbs was halted due to their propensity to cause thromboembolic adverse effects. This setback spurred the search for safer alternatives.

Monovalent anti-CD40L antibodies (domain antibodies or Fab fragments) have recently entered development, offering a potential solution to the thromboembolic risks.
Monoclonal antibodies specific for CD40—the receptor of CD40L—have emerged as a promising alternative, demonstrating freedom from thrombotic complications in preclinical and clinical studies.

In a recent issue of Transplantation, Oura and colleagues presented their experience with an anti-CD40 mAb in a nonhuman primate (NHP) model of chimerism-based tolerance. The researchers added anti-CD40 (clone 2C10R4) to a delayed bone marrow transplantation (BMT) regimen in kidney or kidney/islet recipients, who received immunosuppression (including anti-CD40) for four months.

The Future of Tolerance: Charting the Course Forward

The journey to unlock the full potential of chimerism-based tolerance and CD40/CD40L blockade is ongoing. Further research is needed to refine these strategies, mitigate risks, and expand their applicability. As scientists continue to unravel the complexities of immune regulation, the promise of transplant tolerance and effective treatments for autoimmune diseases moves closer to reality.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1097/tp.0000000000002418, Alternate LINK

Title: Blocking Cd40/Cd40L For Chimerism-Based Tolerance: Lost In Translation?

Subject: Transplantation

Journal: Transplantation

Publisher: Ovid Technologies (Wolters Kluwer Health)

Authors: Christoph Schwarz, Thomas Wekerle

Published: 2019-01-01

Everything You Need To Know

What is hematopoietic chimerism and why is it important in transplant medicine?

Hematopoietic chimerism is a condition where a recipient's bone marrow contains cells from both the recipient and a donor. It's significant because it can create an immune environment where the recipient's body is more accepting of a transplanted organ. The establishment of chimerism can lead to long-term tolerance, reducing or eliminating the need for continuous immunosuppression after transplantation. This could revolutionize transplant medicine by improving outcomes and reducing the side effects associated with long-term immunosuppressive drugs. The process to achieve it is complex.

What is the CD40/CD40L pathway and why is blocking it a potential strategy for improving transplant outcomes?

The CD40/CD40L pathway is a critical interaction in the activation of immune cells. CD40 is found on antigen-presenting cells and CD40L is found on T cells. Blocking this pathway can modulate immune responses. By inhibiting the CD40/CD40L interaction, researchers aim to prevent the activation of T cells that would otherwise reject a transplanted organ. This approach holds promise for enhancing chimerism-based tolerance and improving transplant outcomes by creating a more accepting immune environment.

Why were early anti-CD40L monoclonal antibodies halted in their development, and what alternatives are being explored?

Early anti-CD40L monoclonal antibodies were found to cause thromboembolic adverse effects. These are conditions where blood clots obstruct blood vessels. This led to a halt in their development. Researchers have been working on safer alternatives such as monovalent anti-CD40L antibodies (domain antibodies or Fab fragments) and monoclonal antibodies specific for CD40. The goal is to retain the immunomodulatory benefits of CD40/CD40L blockade without the dangerous side effects.

What did Oura and colleagues' study in nonhuman primates reveal about the use of anti-CD40 monoclonal antibodies in transplant?

Oura and colleagues tested an anti-CD40 monoclonal antibody (clone 2C10R4) in a nonhuman primate model involving kidney or kidney/islet transplant recipients. The anti-CD40 antibody was added to a delayed bone marrow transplantation regimen, along with four months of immunosuppression. This study is a step towards refining strategies for chimerism-based tolerance. It could help to expand their applicability by identifying optimal protocols and assessing long-term outcomes in a clinically relevant model.

What does the future hold for chimerism-based tolerance and CD40/CD40L blockade in transplant and autoimmune disease treatments?

The future of chimerism-based tolerance and CD40/CD40L blockade involves ongoing research to refine these strategies, mitigate risks, and expand their applicability. As scientists learn more about immune regulation, the goal is to achieve transplant tolerance and treatments for autoimmune diseases. This will involve identifying the optimal timing and duration of CD40/CD40L blockade, as well as combining it with other immunomodulatory agents to achieve synergistic effects.