Mechanisms and potential therapeutic targets in allergic inflammation: recent insights

Abstract

Deeper insight into pathogenetic pathways and into the biological effects of immunomodulatory agents will help to optimize or adopt therapeutic strategies for atopic disorders. In this article, we highlight selected findings of potential therapeutic relevance that emerged from recent mechanistic studies with focus on molecular and cellular aspects of allergic inflammation. Furthermore, the often complex mechanisms of action of pleiotropic immunomodulatory agents, such as glucocorticoids, vitamin D, or intravenous immunoglobulin (IVIG), are discussed, as their dissection might reveal targets for novel therapeutics or lead to a more rational use of these compounds. Besides reporting novel evidence, this article points to areas of current debate or uncertainty and aims at stimulating scientific discussion and experimental work.Clinicians and scientists working in the field of allergy experience a rapidly growing body of original articles on specific aspects of allergic disease. Here, we highlight recent mechanistic insights that reveal potential targets for therapy or may lead to a more rational use of distinct therapeutic agents. Novel therapeutic strategies for atopic diseases may be derived not only from the analysis of molecular and cellular processes in allergic inflammation, but also from a better understanding of the mode of action of therapeutic compounds used in daily practice or tested in clinical trials. While pleiotropic agents, such as glucocorticoids, vitamin D, or intravenous immunoglobulin (IVIG), act in manifold and often complex ways, careful dissection of their molecular mechanisms of action may lead to the identification of potential drug targets or reveal pathogenetic differences between specific patient subgroups (e.g., genetic polymorphisms). For more comprehensive and in-depth information on specific topics, we refer to the abundant body of timely and excellent review articles in the field. In the present article, areas of scientific uncertainty or debate are also discussed, as the identification of today's gaps of knowledge and the awareness of methodological limitations are mandatory for goal-directed research and the improvement in therapeutic strategies for atopic disorders.

Recent Advances in Experimental Allergy

“…Clues from cellular biology to the pharmacodynamics of traditional or alternative therapeutics may pave the way. Recently, we highlighted the potential of pleiotropic agents, such as glucocorticoids [70], vitamin D, or polyclonal intravenous immunoglobulin that target multiple molecular processes in inflammatory and allergic disorders [15]. Exploring the underlying mechanisms of pleiotropic agents may further lead to the identification of druggable pathways, for instance effects of specific antibodies within polyclonal [71] and pluripotent intravenous immunoglobulin [72], which may target eosinophils [73] or other relevant cells in allergic conditions.…”

“…Depending on the dose and duration of use, corticosteroids can result in mild to severe side effects. In recent years, alternative therapies have come under the spotlight [15]. …”

IVIG regulates the survival of human but not mouse neutrophils

“…In contrast, IVIG even exacerbated EAE symptoms if applied 7 days after disease induction 39 . Responses to IVIG in a mouse model of ITP was dependent on strain differences 19 . As pointed out by Mestas and Hughes, it is imperative to understand the potential limitations of extrapolating data from mice to humans, especially where complex multicomponent processes differ 59, 64 .…”

“…As pointed out by Mestas and Hughes, it is imperative to understand the potential limitations of extrapolating data from mice to humans, especially where complex multicomponent processes differ 59, 64 . Inherent challenges working with IVIG are imposed by its pleiotropic pharmacodynamics actions 17, 19 and its xenogeneicity in mice that is associated with gain- or loss-of-function effects 7 . A better understanding of the limitations of current models for IVIG will lead to more caution in interpreting preclinical data obtained in mice 17, 39, 60–63 , and to an improved study design of in vivo studies, e.g.…”

“…Other studies suggest that sialylation of both the Fc and Fab regions of IgG may contribute to the anti-inflammatory effects of IVIG 11–13 ; yet, conflicting evidence in models of immune thrombocytopenia (ITP) and rheumatoid arthritis (RA) indicates the need for further investigations 3, 14–16 , in which potential experimental limitations related to the disease model or to intrinsic characteristics of IVIG are given special attention in terms of study design and data interpretation 17, 18 . The pharmacological complexity of IVIG is determined by its pluripotency 6, 17, 19 , polyclonality, and origin from different individuals. Notably, these complex human preparations might have xenogeneic effects at least on certain immunological players in animals, eventually leading to loss-of-function or gain-of-function effects 7 .…”