Review
New insights into chronic inflammation-induced immunosuppression

https://doi.org/10.1016/j.semcancer.2012.02.008Get rights and content

Abstract

Chronic inflammation is a common factor linking various pathologies that differ in their etiology and physiology such as cancer, autoimmune diseases, and infections. At a certain stage of each of these diseases, while the chronic inflammation proceeds, some key players of the immune system become immunosuppressed as natural killer (NK) cells and T cells. The suppressive environment induced during chronic inflammation is governed by a complex processes characterized by the accumulation and activation of immune suppressor cells, pro-inflammatory cytokines, chemokines, growth and angiogenic factors, and by the activation of several inflammatory signaling pathways mediated predominantly by NFκB and STAT3 transcription factors. A substantial body of evidence supports the notion that the development of a suppressive environment during chronic inflammation limits the success of immune-based and conventional therapies, skewing the balance in favor of a developing pathology. Thus, appropriate, well-designed and fine tuned immune interventions that could resolve inflammatory responses and associated immunosuppression could enhance disease regression and reinforce successful responses to a given therapy. This review describes the interrelationship between chronic inflammation and induced immunosuppression, and explains the current evidence linking inflammation and pathological processes, as found in cancer. We further highlight potential strategies, harnessing the immunosuppressive environment in treating autoimmune diseases and facilitating transplantation. In parallel, we emphasize the use of modalities to combat chronic inflammation-induced immunosuppression in cancer, to enhance the success of immune-based therapies leading to tumor regression. In both cases, the urgent necessity of identifying biomarkers for the evaluation of host immune status is discussed, with the goal of developing optimal personalized treatments.

Section snippets

Chronic inflammation and induced immunosuppression

An inflammatory process reflects the host's principal immune response aimed at eliminating foreign substances invading the body, or abnormally generated self-compounds produced during tissue injury. The response promotes the optimal restoration of tissue structure and function, but must also rapidly turned off in order to prevent over reaction that could result in irreversible damage [1], [2], [3]. In general, the innate immune response is initiated within minutes, and if necessary, it is

Clinical implications utilizing chronic immunosuppression for therapy

There is no doubt that chronic inflammation-induced immunosuppression drives serious complications and consequences in associated pathologies. However, there is another side of the coin in which the suppression of autoreactive cells and neutralization of the over-activated immune response could serve clinical goals, and even represent the only way to enable recovery. The suppressive function of MDSCs is the normal outcome of exacerbated inflammatory response [46]. These cells serve as key

Clinical implications in targeting immunosuppression

In most cases of chronic inflammation, the resulting milieu is deleterious to the host due to the array of pro-inflammatory cells and soluble factors that lead to immunosuppression, alongside susceptibility to cancer, opportunistic infections and the limited success of immune-based therapies. As opposed to the pathologies described in the previous section where inducing an immunosuppressive environment is suggested as a therapeutic strategy to inhibit autoimmune diseases or transplant

Biomarkers

Patients suffering from diseases characterized by chronic inflammation including autoimmune disorders, infections and cancer, tend to develop complications due to the sustained inflammation and associated immunosuppression, and in many cases, are subjected to a variety of treatments and drugs that differ in their impact on the immune system.

Currently, diagnostic tests that can distinguish between acute and chronic inflammation, and the ensuing immunosuppression are not available in the clinic,

Concluding remarks

The execution of an acute inflammatory response is critical to protect the body against tissue injury and pathogens, and is supported by structural and functional restoration processes, while unresolved chronic inflammation has harmful effects on the host's systems. In this review, we discussed the ramifications of chronic inflammatory responses shared by different types of chronic pathologies, predisposing the individuals to a developing immunosuppressive environment and accompanying disease

Conflict of interest statement

The authors, Julia Kanterman, Moshe Sade-Feldman and Michal Baniyash, submitting this manuscript declare that there are no conflicts of interest.

Acknowledgements

We gratefully acknowledge the support of the Society of Research Associates of the Lautenberg Center, the Concern Foundation of Los Angeles and the Harold B. Abramson Chair in Immunology. This study was supported by the US-Israel Binational Science Foundation, The Israel Academy of Sciences and Humanities, The Israeli Ministry of Health, The Israel Cancer Research Foundation (ICRF), The Joint German-Israeli Research Program (DKFZ), and by The Joseph and Matilda Melnick Funds.

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