Why Blocking CD40 Alone May Not Be Enough to Stop Type 1 Diabetes

Scientists have long known that the immune system's response to Type 1 diabetes involves both B cells and T cells working together to attack the pancreas. Researchers thought that blocking a molecular interaction called CD40-CD40L might be an effective way to dial down this immune response. Iscalimab, a therapeutic antibody, was designed to do exactly that—by blocking CD40, it was expected to reduce the activation signals that antigen-presenting cells send to immune cells.

The approach made biological sense and showed promise in laboratory studies. However, when iscalimab was tested in clinical trials for autoimmune diseases and transplant rejection, it delivered only modest benefits. A new study set out to understand why.

Researchers at a European institution tested a biosimilar version of iscalimab in a controlled laboratory setting to measure its effects on different immune cell populations. The results were clear-cut: the antibody worked very well at what it was designed to do. It successfully bound to B cells and dendritic cells, and it completely blocked B cell proliferation.

But when the team tested iscalimab against the T cells that actually drive Type 1 diabetes—specifically, autoreactive CD4 T cells that target beta cells—the antibody showed little to no inhibitory effect. The CD40 blockade also failed to prevent dendritic cells from activating naive T cells, another critical step in the autoimmune cascade.

This disconnect between B cell and T cell suppression was striking. While iscalimab could shut down B cell responses, it left the T cell attack on beta cells largely untouched.

The findings suggest an important limitation: blocking CD40 alone is insufficient to halt the T cell–mediated attack that characterizes Type 1 diabetes. Because T cells appear to be the primary drivers of beta cell destruction, a therapy that doesn't effectively suppress them is unlikely to provide durable benefit.

The researchers propose that CD40 blockade may work better as part of a broader, multi-targeted strategy—one that directly addresses T cell activation in addition to controlling B cell responses. Other approaches, such as therapies that target T cell costimulation more directly, may be more effective for Type 1 diabetes.

This laboratory work adds to a growing body of evidence that the immune system's role in Type 1 diabetes is complex and may require interventions designed specifically to interrupt T cell responses, not just B cell activity.

This in vitro study does not close the door on CD40-targeted therapies for Type 1 diabetes—laboratory findings don't always predict real-world outcomes. However, it does suggest that researchers should think carefully about which immune pathways are most important to target and whether single-antibody approaches are likely to succeed.

Future therapies may need to combine multiple mechanisms to address both the T cell and B cell arms of Type 1 diabetes autoimmunity, or to focus exclusively on the T cell responses that appear most critical to disease progression.

Source: PloS one. Evidence type: PubMed indexed literature. Type1Cure is an information and intelligence hub, not a medical advice service. This article summarizes published research and does not provide diagnosis, treatment, or personal medical guidance. Always talk to your own care team before changing anything about your Type 1 diabetes management.