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Dec 06, 2012
 |  BC Innovations  |  Tools & Techniques

Micromanaging tolerance

Researchers at Northwestern University and the Myelin Repair Foundation have simplified an autologous cell-based strategy for promoting antigen-specific tolerance by replacing splenic leukocytes with synthetic microparticles as the antigen carrier.1 The groups are planning to first develop the therapy and establish clinical proof of concept in autoimmune indications for which the key antigen is known before moving forward in multiple sclerosis.

Apoptotic splenic leukocytes coupled to peptide antigens induce antigen-specific immune tolerance in T cell-mediated autoimmune diseases such as MS.2-4 Indeed, in a Phase I trial in patients with new-onset relapsing-remitting MS (RRMS), researchers showed that infusion of such cells induced tolerance against the coupled myelin peptide antigens and did not cause significant adverse effects.

The trial was sponsored by the Myelin Repair Foundation (MRF) and the German government.

Despite the positive initial results, the MRF and Northwestern researchers wanted to simplify the approach and make it more amenable for commercialization as an off-the-shelf therapy. The cell therapy involves isolating patient leukocytes via leukapheresis, coupling the cells to peptide autoantigens via ethylene carbodiimide chemistry, rendering the cells apoptotic and then infusing the cells back into the patient.

"In the clinical trial, we found that we could infuse patients with up to three billion such cells without causing significant adverse effects and promote tolerance toward multiple myelin-associated antigens," said Stephen Miller, a professor and director of the Interdepartmental Immunobiology Center at Northwestern. "However, producing these cells is a very complex and expensive process."

Thus, the team sought to develop an alternative synthetic vehicle that could mimic the antigen-carrying role of the apoptotic splenic leukocytes...

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