Red blood cell therapy may promote immune tolerance in iTTP: Study
Potential treatment would teach body to stop attacking key protein
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Researchers are developing a potential treatment for immune-mediated thrombotic thrombocytopenic purpura (iTTP) that promotes immune tolerance rather than immunosuppression, according to a study.
The approach takes advantage of a naturally occurring process whereby red blood cells deliver small fragments of the ADAMTS13 protein to the immune system, teaching the body to stop attacking ADAMTS13 and restoring healthy immune balance.
“Based on our results, we propose [red blood cell]-mediated delivery of ADAMTS13-derived [fragments] as a potential strategy for promoting tolerance in patients with iTTP,” researchers wrote.
The study, “A red blood cell-based antigen delivery system to facilitate T cell epitope presentation to promote peripheral tolerance to ADAMTS13 in immune-mediated TTP,” was published in Research and Practice in Thrombosis and Haemostasis.
Up to half of treated patients experience relapses
Also called acquired TTP, iTTP is a life-threatening blood disorder in which the body’s immune system mistakenly attacks ADAMTS13, an enzyme that regulates blood clotting. Without enough of this enzyme, small blood clots form throughout the body, which can damage organs.
While current treatments have greatly improved survival in iTTP, up to half of patients experience relapses, “highlighting the need for therapies that ensure long-lasting recovery by restoring immune tolerance,” the researchers wrote.
Immune tolerance refers to a state in which the immune system doesn’t attack the body’s own cells and tissues. This tolerance is established by HLA genes, which encode for proteins found on the surface of immune cells that help the body distinguish self from non-self.
HLA proteins present antigens, which are small pieces of a self-protein from the body, or a non-self molecule from a virus, bacterium, or other substance that the immune system can recognize. HLA proteins bind to these antigens and present them on immune cell surfaces. They are then “inspected” by T-cells.
When HLA proteins present normal self-antigens from the body’s own tissues, T-cells are trained to recognize these as harmless, thus establishing immune tolerance. In contrast, if the antigens are non-self, T-cells are activated to mount an inflammatory response. When this tolerance fails, self-antigens are mistakenly attacked, leading to the development of autoimmune diseases.
Studies show that a self-antigen mistakenly targeted in iTTP is a fragment of the ADAMTS13 protein called FINVAPHAR. In people who carry the HLA-DRB1*11 gene, an iTTP genetic risk factor, some immune cells efficiently present FINVAPHAR to T-cells, increasing the likelihood of an autoimmune attack.
Normal bodily processes are naturally immune-tolerant
Normal bodily processes are naturally immune-tolerant, including the clearance of aging or damaged red blood cells from the bloodstream, called erythrophagocytosis. Here, immune macrophages identify damaged cells, engulf and digest them, and then present self-antigens on HLA molecules without eliciting an inflammatory response.
Researchers in the Netherlands wondered whether attaching FINVAPHAR to red blood cells during this natural clearance process could promote immune tolerance to ADAMTS13 and prevent harmful immune attacks in iTTP.
To find out, the team first connected FINVAPHAR to a TAT peptide, a molecule known for transporting cargo across cell membranes. Tests showed that TAT-FINVAPHAR bound efficiently and specifically to red blood cell surfaces, where it could be “seen” by the immune system during normal clearance. Control peptides without TAT showed minimal binding.
Next, the scientists studied what happens when macrophages naturally engulf TAT-FINVAPHAR-coated red blood cells. The experiments focused on macrophages from healthy donors carrying the HLA-DRB1*11 gene. They also included macrophages from donors with other HLA types to test whether the approach could work across different genetic backgrounds.
Our findings support the potential of [red blood cell]-mediated peptide delivery to promote antigen-specific tolerance in iTTP. We propose administering this therapy during remission, when the patient is clinically stable, ADAMTS13 activity is restored and systemic inflammation is no longer observed.
The researchers analyzed the antigens presented by HLA proteins on macrophage surfaces after they ingested TAT-FINVAPHAR-coated red blood cells. Results showed a structurally normal, biologically relevant FINVAPHAR presentation, confirming that the approach enabled proper immune recognition rather than random or nonspecific binding.
The analysis also showed that self fragments of hemoglobin, the oxygen-carrying protein in red blood cells, were abundantly present on macrophages, supporting erythrophagocytosis as a safe pathway for FINVAPHAR delivery.
The team noted that red blood cells have specific advantages as a delivery system. Billions of these cells are cleared from the bloodstream daily after a lifespan of about four months, thereby extending and strengthening the tolerance response. Also, as blood transfusions are a commonly performed medical procedure, red blood cells also serve as a safe and biocompatible delivery vehicle.
“Our findings support the potential of [red blood cell]-mediated peptide delivery to promote antigen-specific tolerance in iTTP,” the researchers concluded. “We propose administering this therapy during remission, when the patient is clinically stable, ADAMTS13 activity is restored, and systemic inflammation is no longer observed.”
