New Insights into Immunotherapy for Allergic Disorders
Effects of Allergen Immunotherapy and Omalizumab on Molecular and Cellular Mechanisms of Inflammation
Thomas B. Casale, MD FAAAAI
Creighton University School of Medicine
Omaha, NE USA
A number of mechanisms for the clinical effects of allergen-specific immunotherapy (SIT) and the monoclonal anti-IgE antibody, omalizumab, have been proposed. The effects of allergen-SIT include changes in both inflammatory mediators and cells. Mast cell and eosinophil numbers and mediator release decrease. Decreased levels of IL-4 and IL-5, potent drivers of the Th2 response, have been observed in both tissue and peripheral blood. Corresponding increases in IFNγ, a Th1-profile cytokine, have also been observed in skin and nasal tissue after pollen SIT, although not in peripheral blood. Perhaps one of the most important changes involves the generation of Treg cells and the secretion of IL-10 and TGF-β. These cytokines promote increased levels of serum-specific IgA and IgG4, and an eventual decline in serum-specific IgE. SIT appears to act, at least in part, through cytokine deviation by modulating the balance of Th1/Th2 cells towards a more Th1-like response.
The primary effects of omalizumab include a rapid decrease in free IgE levels in serum and the decreased expression of the high affinity IgE receptor. These effects lead to decreased mediator release and inflammation.
In a recent clinical trial where anti-IgE (omalizumab) was shown to increase the safety profile for ragweed allergen immunotherapy, we sought to further elucidate the mechanisms by which allergen-SIT modulates the immune response by collecting blood from all 4 treatment groups (omalizumab alone, omalizumab preceding and co-administered with SIT, SIT alone and placebo). The studies were part of a randomized, placebo-controlled clinical trial, where rush immunotherapy (RIT) was administered and followed by high-dose subcutaneous immunotherapy (SCIT) for 12 weeks. We assessed longitudinal gene expression changes induced in peripheral blood cells.
We found that all treatments were associated with significant changes in gene transcripts. For example, 457 transcripts were differentially expressed between omalizumab plus immunotherapy vs. placebo plus immunotherapy at study week 13. In addition, seasonal exposure to ragweed in the placebo treated group also resulted in a number of gene transcript changes.
Our studies indicate that immunotherapy results in gene expression changes representative of a diminished inflammatory response and a program of B and T cell differentiation towards a memory Th1-like response. A subset of genes related to the Th2 program was identified and appears to be regulated by seasonal exposure to allergen, and are unaffected by SIT.
The data provide an in depth view of a systemic allergic response triggered by inhaled allergens and show how immunotherapy works to counteract this response. These data show that the major effect of immunotherapy involves modulation of the inflammatory response and the differentiation of B and T cells to a memory phenotype. In addition to providing a better understanding of the nature of the allergic response, the immunotherapy and seasonally regulated genes discovered present opportunities for new targets of therapy. Finally this study provides evidence that biomarkers of peripheral blood immune responses are valuable tools for assessing disease onset, progression, and therapeutic efficacy.
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