Interleukin 12 in COVID-19 Prophylactics
Interleukin 12 is a cytokine with wide-reaching effects in the innate and adaptive immune system. Of considerable interest for intervention purposes is the ability of IL-12 to link innate resistance and adaptive immunity. Recently, IL-12’s unique ability to influence the production of interferon-γ and cause differentiation to Th1 cells has been harnessed to create a vaccine against COVID-19, the novel coronavirus pandemic caused by the SARS-CoV-2 virus.
IL-12 in the Innate and Adaptive Immune System
IL-12 expression regulates the innate immune response during infection and is ultimately responsible for determining the length and type of the following adaptive immune response. Similarly, IL-12 promotes differentiation in naive CD4+ helper T cells into the Th1 phenotype. Th1 T cells then go on to produce IFN-γ and facilitate cell-mediated immunity.
IL-12 can drive interferon-γ (IFN-γ) production in dendritic cells (DCs), NK cells, macrophages, and T cells. The production of IL-12 is induced by microbial peptides, and its role in shaping the adaptive immune response means that it is a key player in coordinating both innate and adaptive immunity. This fascinating cytokine sits at the intersection of two major immune functions, and thus has become a target for therapeutic intervention.
Fig 1. IL-12 crystal structure
Structure and Function of Interleukin 12
IL-12 is a heterodimeric cytokine which is encoded by two genes: IL-12A (also called p35) and IL-12B (p40). Following protein synthesis, the active heterodimer— termed ‘p70’— and homodimer p40 are assembled. IL-12 is comprised of four alpha helices, as seen in the figure above. IL-12 and IL-23 both contain a p40 subunit.
Once IL-12 binds to its receptor, the signal is transduced via the JAK/STAT pathway. Ultimately, the binding of IL-12 triggers the up-regulation of BOLA2, PSME2, MTAP, CA1, GSTA2, RALA, CNN2, CFL1, TCP1, HNRNPDL, MIF, AIP, SOD1, PPIA and PDCD4 in helper T cells.
IL-12 as a Therapeutic Target
Ustekinumab is a human monoclonal antibody which targets the p40 subunit found in both IL-12 and IL-23. It is primarily used in the treatment of psoriasis and ulcerative colitis. Both of these diseases are autoimmune in nature, and blocking p40 is thought to dampen the immune response to autoantigens.
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IL-12 in COVID-19 Vaccines
An IL-12 plasmid vaccine for COVID-19 has been developed and is currently awaiting FDA approval. The prophylactic, developed by OncoSec, utilizes a modified SARS-CoV-2 S glycoprotein (also called the spike protein) to activate an innate immune response. The benefit of IL-12 comes in strengthening the innate immune response, and skewing it to a Type-1 immune response. The Type-1 response favours cytotoxic functions for effector cells and cytokines. Thus, the IL-12 present in the microenvironment ameliorates the functions of immune cells and allows for an augmented response to the SARS-CoV-2 S antigen.
The TAVO™ technology that the vaccine is based on has shown promising results in cancer, where it has been able to induce a renewed immune response to tumours which were previously able to suppress effector immune cell functions.