Immune modulatory strategies: a playground with a swing and a seesaw

Immune modulation occurs as part of a normal immune process. Different tissues exert different restrictions on immune reactivity; for example, innate immunity in antigen-laden mucosal tissues has a higher threshold of activation than similar cells in lymph nodes or other peripheral organs. Immunity against antigen or vaccination is different in neonates and the elderly, caused by an immune modulation via an immature or senescent immune system. Pathogens display an array of immune modulator strategies which enhance their survival. Prior inflammatory events can modulate immunity to subsequent infections and host genetics and (in particular MHC haplotypes) can dictate whether or not the host survives. Even treatments for inflammatory diseases may modify aspects of innate or adaptive immunity [1,2]. This issue of Expert Review of Anti-infective Therapy contains reviews and debates detailing recent developments in immune modulation in all of these areas.

An effective immune response is necessary to clear pathogenic microorganisms, and malignant or damaged cells. An excessive immune response produces clinical symptoms that can be life threatening. This excess is evident by the persistence of the pathogen or autoantigen, and is prolonged if tissue integrity is not restored. Immunity is also required for normal tissue homeostasis by removing innocuous antigens/allergens and dead apoptotic or necrotic cells, which it usually achieves without untoward consequences. There is an ongoing dialogue between immune and more structural cell types (such as epithelial cells and fibroblasts) that helps to signify when tissue structural integrity has been compromised. Inflammation, therefore, only results in clinical manifestations in the presence of antigen and structural alterations. The immune system is continually active but held in check by a tissue-specific processes. Understanding correlates of immune-mediated pathology and how the immune system is contained in the absence of an antigen has revealed a vast array of immune-modulator strategies that may be harnessed to curtail inflammatory disease, or to overcome enhanced antivaccine immunity. The mucosal immune system provides a clear example of tissue-specific homeostasis (reviewed for the GI tract by Cieza, Cao, Cong and Torres [3]). In the lung (and most likely the gut), epithelial cells blunt macrophage and dendritic cell responses, via expression of the negative regulator CD200R and the production of IL-10 and TGF-β. Bacteria entering this system are cleared by innate immunity without overt inflammation. In a lung where the epithelium has been denuded (e.g., by influenza virus) tissue-specific suppression is lost and subsequent immunity is exaggerated. Immune modulation may, therefore, restore the ability to resolve inflammation, which in turn should allow a return of tissue integrity.

Equally suited to immune modulation is an inappropriate immune response. Inappropriate responses occur for a variety of reasons, and knowledge in this area has expanded exponentially in the last two decades. Host genetics (in particular MHC haplotype) influences the outcome to infection and it may now be possible to determine who is more at risk through genetic profiling (reviewed by Cunha and Carvalho for fungal diseases [4]). Similarly, the immature immune system in neonates [5], or the senescent immune system in the elderly, alters the ability to clear infectious disease and can predispose them to long-term consequences. The influence of the hosts age and genetic profile is further complicated by prior inflammatory events. In neonates, exposure to antigenic material can be protective of further inflammatory disease (the hygiene hypothesis) or increase the likelihood of excessive reactions to unrelated antigens such as the development of allergy following respiratory syncytial virus lung infection [5]. The longevity of this modulation is, in some cases, long lived (see [6]) and cannot be totally explained by alterations in immune cells themselves, but must also incorporate some form of stromal influence over incoming inflammatory cells.

Based on the expanding knowledge of what constitutes an appropriate or inappropriate immune response, a multitude of immune-modulator strategies are feasible. The strategies employed will depend on the site of inflammation and the inciting antigen. This special focus issue of Expert Review of Anti-infective Therapy contains provocative immune modulation possibilities for HIV infection [7], Prion disease [8], severe bacterial infection [9] and tuberculosis [10]. These strategies may constitute simple removal of an excessive immune factor (the classic example is TNF in rheumatoid arthritis patients), an attempt to skew immunity to a protective phenotype (e.g., a Th2 cytokine response to a Th1 during Leishmania infection) [11] or a decrease in T-cell activation to prevent early HIV viral load [7]. The identification of endogenous micro-inhibitory mRNA, that regulates mRNA through translational repression or degradation, has opened up an elegant area that may be amenable to therapeutic manipulation [12]. However, treating inflammatory disorders by immune modulation is not without its consequences. The prolonged neutralization of TNF in autoimmune conditions can cause vulnerability to a variety of infections and skew the Th2 to a Th1 cytokine profile thus, using IL-12 has toxic consequences. Endogenous inflammatory mediators are likely produced within a regulated environment and so the consequences of reducing or enhancing their levels must be considered. What we currently lack in the treatment of patients with inflammatory disorders are more selective modulators. It should be possible to target more restricted T-cell populations, macrophage subtypes and cells producing specific cytokines.

Finally, an area for immune modulation gaining considerable momentum are endogenous processes for resolving inflammatory disease. Regulatory T cells play a significant role in preventing the tissue damage associated with ongoing inflammation, but may also inadvertently cause persistence of infection [13]. Inflammation does not disappear once the antigen has been removed but must provide signals to cease activity. In most cases this involves a restoration of tissue integrity, which then provides the assurance that the danger has passed by expressing or secreting immune modulator proteins. Clearance of an inflammatory infiltrate is as important as recruiting it in the first place. This clearance needs to occur via apoptosis to avoid liberation of cell constituents that may activate pattern recognition receptors. Furthermore the phagocyte engulfing the apoptotic cell is provided with signals to reduce inflammatory responses to such self cells. Understanding how inflammation is resolved and the cells responsible [14] may help to curtail ongoing pathogenic inflammatory disease. In summary, identification of endogenous immune modulators is progressing at an exponential rate, and with the cooperation of scientists, clinicians and industry, some will have considerable potential in a multitude of clinical settings.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.