The current standard of care for autoimmune disease is administration of immunosuppressive agents that require a lifetime of treatment and leave patients susceptible to opportunistic infections. Thus, there is a great need for therapies that induce lasting and antigen-specific tolerance, which would require fewer treatments and allow the immune system to fully respond to pathogens. A promising target for the induction of antigen-specific tolerance is the apoptotic pathway. Antigen-presenting cells create a tolerogenic milieu upon recognition of apoptotic debris, and antigen presentation by APCs to T cells in the absence of inflammatory cues typically leads to anergy and deletion. A large source of endogenous apoptotic cells is erythrocytes, or red blood cells. The purpose of this study is to discover antibody fragments (Fabs) that bind erythrocytes, and use these Fabs to deliver antigen to erythrocytes for processing via the apoptotic pathway and presentation to T cells for tolerance. Phage display on mouse erythrocytes yielded high affinity Fabs that lacked binding to peripheral blood mononuclear cells and induced no hematological changes. Erythrocyte-binding Fabs were recombinantly expressed with the model antigen ovalbumin and administered to mice. Targeting ovalbumin to erythrocytes led to robust abortive proliferation of antigen-specific T cells. Remaining cells appeared phenotypically exhausted, and had reduced capacity to produce inflammatory cytokines upon restimulation. Antigen presentation of erythrocyte-targeted antigen occurred in the spleen, because T cell exhaustion was completely reversed in splenectomized mice. Thus, targeting erythrocytes may induce lasting antigen-specific tolerance.
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