Immunostasis is critical for the immune system to defend against infections and malignancy without causing autoimmune disorders. The programmed death-1 (PD-1) immune checkpoint is one mechanism that maintains immunostasis.<br/>In autoimmune diseases, the PD-1 immune checkpoint is overridden by immune stimulatory signals, and immunostasis is hence interrupted. Under this circumstance, PD-1 expression cells or PD-1-positive cells may be viewed a pathogenic cell population. Thus, depletion of PD-1-positive cells may be beneficial to suppress autoimmunity. To enable the depletion, we engineered an immunotoxin that has selective toxicity to PD-1-postive cells. The depletion of PD-1-positive cells ameliorated autoimmune diseases in two animal models, type-1 diabetes and experimental autoimmune encephalomyelitis (EAE). Interestingly, the depletion, although drastically inhibiting autoimmunity, did not compromise healthy adaptive immunity because the depletion did not affect naive lymphocytes which are PD-1-negative. Taken together, the depletion of PD-1-positive cells may become a therapeutic approach that selectively and specifically suppresses autoimmunity and restores the immunostasis.<br/>In cancer, some tumor cells hijack the PD-1 immune checkpoint to suppress anti-tumor immunity. Inhibitors of the PD-1 immune checkpoints have been developed to block the checkpoint and revive anti-tumor immunity. However, these inhibitors indiscriminately revive both tumor-reactive T cells and auto-reactive T cells and hence cause autoimmune toxicity. To fill this gap, we developed a protein-based nanoparticle carrier to specifically deliver the inhibitors to tumor-reactive T cells but not auto-reactive T cells. We also created a protein-based nanoparticle vaccine to amplify tumor-reactive T cells. The carrier and the vaccine potentially reduce the autoimmune toxicity of PD-1 immune checkpoint inhibitors while improve their efficacy.  <br/>In summary, protein engineering is a useful tool to modulate immunostases.

Protein engineering to modulate the immunostasis mediated by the PD-1 immune checkpoint

256th National Meeting (2018)

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