Figure 4. Immunotherapy of sepsis.

There are several immunotherapeutic agents that have shown promise in reversing the immunosuppressive phase of sepsis including recombinant interleukin-7 (IL-7), programmed cell death 1 (PD1)- or PDL1-specific antibodies, recombinant interferon-γ (IFNγ) and recombinant granulocyte/macrophage colony-stimulating factor (GM-CSF). GM-CSF and IFNγ act primarily on monocytes and macrophages to increase HLA-DR expression and induce activation. IL-7 and PD1-specific antibodies have the advantage of targeting CD4⁺ and CD8⁺ T cells to restore the function of adaptive immune system. By reengaging CD4⁺ T cells, both recombinant IL-7 and PD1-specific antibodies will have effects not only on adaptive immune cells but indirectly on monocytes and macrophages. PD1—and PDL1-specific antibodies will prevent and/or reverse T cell exhaustion. Thus, the net effects of these antibodies will be to prevent decreased interferon-γ (IFNγ) production, T cell apoptosis and decreased CD8⁺ T cell cytotoxicity. IL-7 will block T cell apoptosis, induce T cell proliferation, increase IFNγ production by T cells, increase T cell receptor (TCR) diversity, and increase T cell trafficking by increasing the expression of cell integrins such as lymphocyte function-associated antigen 1 (LFA1). The application of immunotherapeutic agents will depend on the use of various biomarkers or tests of immune function to document that patients have entered the immunosuppressive phase of sepsis.