Immunosuppressive platelets open new therapeutic avenues for treating immune disorders

Platelets play an integral protective role in our blood. These small cells are key components in our body’s innate and adaptive immune systems.  Their importance in the promotion of inflammation, our body’s initial response to injuries or infections, and in increasing immune response has been widely documented. The pro-inflammation and pro-immunity property that platelets express can also be harmful, evidenced in autoimmune diseases such as multiple sclerosis, and in allioimmune disorders, where the body’s immune response is out of proportion to the threat, such as allergies.

Recently, a University of Toronto team was investigating the role that a specific type of platelet  – called a desialylated platelet because it is missing a sialic residue on its surface –   might play in increasing immune responses when they found that these platelets did the opposite of what they expected.

“This discovery shifts the prevailing view that platelets are pro-inflammatory and pro-immunity. Our study demonstrated, surprisingly, that desialylated platelets can systematically inhibit inflammation and immune response,’ said Heyu Ni, professor at the University of Toronto's Departments of Laboratory Medicine and Pathobiology and lead author on the paper.

This unexpected result could lead to new treatment options for many disorders. “Desialylated platelets may provide daily protective mechanisms preventing autoimmune and alloimmune diseases,” Ni said.

The researchers published their results on Oct. 5 in Research.

They found that it was not the presence of the platelets themselves that lowered inflammation and supressed immune responses. but the process of removing these platelets from circulation that caused the reduction.

Platelets are cleared from circulation for several reasons. They may have already been activated, been damaged by disease, or simply due to old age. There are several mechanisms that allow the body to recognize which platelets need to be removed. One of these mechanisms is desialylation. Desialylated platelets generally lose the sialic residue on their cell surfaces as they age, and this marks them for removal.

Most platelets are cleared in the spleen. However, these researchers showed that desialylated platelets are cleared by the Kupffer cells in our livers. They also demonstrated that it is the clearance of the desialylated platelets by the Kupffer cells that stimulates an immunosuppressive response. To measure the effectiveness of this response they introduced non-native cells and found that fewer antibodies than expected were produced. This means that the introduction of these platelets can cause an immunosuppressive response strong enough to reduce the creation of antibodies.

To test this in a clinical model where the body’s immune response was problematic, they looked to Hemophilia A. Hemophilia A is a disorder caused by a defect in the gene that codes for Factor VIII, an integral blood clotting protein. Individuals lacking this protein cannot properly clot and if injured, bleed excessively. The standard treatment for Hemophilia A is a transfusion of FVIII, called the anti-hemophilic factor. Unfortunately, many patients exhibit a strong immune response to the transfused clotting factor and their bodies create antibodies to it, reducing or removing any benefit from the transfusion.

The University of Toronto team found that mice that had the Hemophilia A deficiency of FVIII and were exposed to desialylated platelets prior to transfusion of the FVIII clotting factor had significantly reduced production of anti-FVIII antibodies, compared to mice that were given FVIII transfusions without exposure to the platelets. These results show the platelets’ immense promise in limiting damaging immune responses.

Desialylated platelets are also easily obtained, which increases their utility in therapeutic interventions.

“Platelet desialylation can naturally occur every day in aged platelets or occur following platelet activation in our blood circulation. It can also occur in blood bank, and/or engineered platelets,” Ni said.

In the future they plan “to apply this discovery and test whether transfusion of desialylated platelets can treat autoimmune diseases such as multiple sclerosis, arthritis, lupus and Type 1 diabetes, and alloimmune diseases such as allergies and over-reactive infection diseases, and prevent failures of organ transplants and blood transfusions,” Ni said.

Contributors include June Li, Danielle Karakas, Sonya A MacParland, John W. Semple, and John Freedman from the Department of Laboratory Medicine and Pathobiology, University of Toronto; Guangheng Zhu from the Toronto Platelet Immunobiology Group; Yeni H. Yucel and Haibo Zhang from the Keenan Research Centre for Biomedical Science of St. Michael’s Hospital; Feng Xue, Yingyu Chen and Qizhen Shi from the Departments of Pediatrics, Medical College of Wisconsin, and the Blood Research Institute. Quizhen Shi is also affiliated with the Children’s Research Institute and the Midwest Athletes Against Childhood Cancer Fund Research Center.

This work was supported in part by Canadian Institutes of Health Research Foundation grant, Canadian Institutes of Health Research, CIHR-Canadian Blood Services Partnership, Canadian Blood Services Intramural Grant, the Canadian Foundation for Innovation, the National Institutes of Health, National Heart, Lung, and Blood Institute grant, and Midwest Athletes Against Childhood Cancer (MACC) Fund. J.L. is a recipient of Graduate Fellowship from Canadian Blood Services Centre for Innovation, D.K. is a recipient of a St. Michael's Hospital Research Training Centre (RTC) Scholarship, and Queen Elizabeth II (QE-II) Graduate Scholarship.