VIP

This review consolidates two decades of laboratory work on VIP as an endogenous immunoregulatory peptide. The authors summarize evidence that VIP is produced not only by neurons but also by activated T cells and other immune cells, and that it binds two class B G-protein-coupled receptors — VPAC1 (constitutively expressed on resting lymphocytes and macrophages) and VPAC2 (induced upon immune activation). Downstream, VIP signaling raises intracellular cAMP and modulates transcription factors including CREB, NF-κB, and AP-1. In cultured macrophages and dendritic cells, VIP exposure was associated with reduced production of pro-inflammatory mediators (TNF-α, IL-6, IL-12) and increased anti-inflammatory IL-10 output. In CD4 T cell cultures, VIP shifted differentiation away from Th1/Th17 phenotypes and favored induction of regulatory T cells via tolerogenic dendritic cells. The authors place these findings in the broader context of in vivo rodent models of autoimmune and chronic inflammatory disease.

This paper pulls together years of research showing that VIP is not just a gut and nerve peptide — it is also made by immune cells and acts as a brake on inflammation. The authors describe how VIP attaches to two receptors (VPAC1 and VPAC2) on immune cells and changes which signals those cells send out. In laboratory studies, VIP reduced the alarm signals immune cells release during inflammation and increased calming signals instead. It also pushed certain T cells toward a "regulatory" state, which is a normal mechanism the body uses to keep immune responses from running unchecked.

This open-label phase II clinical investigation enrolled 20 adults with biopsy-confirmed pulmonary sarcoidosis. Participants received nebulized VIP (100 μg, four times daily) for four weeks. The primary readouts were bronchoalveolar lavage (BAL) cytokine profiles and T cell subset composition before and after the inhalation period. The authors reported a reduction in TNF-α release from BAL cells and an increase in the proportion of CD4+CD25+FoxP3+ regulatory T cells in BAL fluid post-treatment. No serious adverse events were reported during the inhalation period. The authors interpret the findings as the first in-human demonstration that inhaled VIP exerts immunoregulatory effects on the pulmonary compartment, consistent with prior animal model literature, and call for larger controlled trials.

Researchers in Germany tested whether inhaled VIP could change the immune signaling inside the lungs of people with sarcoidosis, a condition where the immune system forms small clumps of cells (granulomas) in the lungs. Twenty participants inhaled VIP four times a day for four weeks. Afterwards, the inflammatory signal TNF-α from lung-fluid samples was lower, and the proportion of "regulatory" T cells (the calming kind) was higher. The participants tolerated the inhalation. This was the first study showing that VIP, delivered straight to the lungs, produces measurable immune-system changes in humans — a finding that motivated further investigation.