Tolerogenic synthetic nanoparticles for the prevention of murine acute graft-versus-host disease

Abstract

We have shown that treatment with biodegradable tolerogenic nanoparticles carrying rapamycin (synthetic vaccine particles, SVP) and antigen (inside the particles or admixed) induces durable, antigen-specific immune tolerance even in the presence of potent Toll-like receptor agonists. Treatment with SVP and antigen results in durable B cell tolerance, the differentiation of T and B regulatory cells, the inhibition of T and B cell activation, inhibition of hypersensitivity reactions, and the treatment of relapsing experimental autoimmune encephalomyelitis and celiac disease. Here we describe the use of SVP to promote graft tolerance and prevent acute Graft-versus-host disease (GvHD). GvHD occurs when donor T cells contained in bone marrow transplants become activated against host cells and subsequently destroy them. Current mitigation strategies involve chronic immune suppression regimens. However, prolonged immunosuppression has many side effects, including susceptibility to opportunistic infections. A favorable strategy would be to tolerize the graft to the host. To evaluate SVP we utilized two mouse models of acute GvHD: (1) B6-to-F1 and (2) B6-to-Balb/c. A single SVP administration provided at the time of the graft improved disease score, blunted inflammatory cytokines and controlled the activation of donor cells. Importantly, this resulted in a significant increase in survival compared to mock treated animals. SVP therapy represents a novel approach for the induction of immunological tolerance and the prevention of acute GvHD.