Clinical research has long focused on ways to harness the actions of the immune system. From vaccines to immunotherapies, researchers have used their knowledge of the immune system to develop therapies to treat or prevent diseases from influenza to autoimmune disease and cancer.
Now, researchers from Penn’s School of Dental Medicine and international collaborators have investigated the effects of training the innate immune system in experimental models of two chronic inflammatory diseases, periodontitis and arthritis. They found that this “trained” immunity, or TRIM, led to increased bone loss in these models. This study is published in Developmental Cell.
Previous approaches have largely focused on the adaptive immune system, that branch of the immune system that “remembers” previous threats and launches specific attacks when it encounters them again. The body also has an innate immunity branch, which, for a long time, was just considered the first-line, general attack arm of the immune system with no ability to remember prior assaults or respond differently when rechallenged.
“If you go and look at an immunology textbook—even today—it will likely tell you that innate immunity has no memory; its response doesn’t get improved the second time,” says George Hajishengallis, the Thomas W. Evans Centennial Professor in the Department of Basic & Translational Sciences at Penn Dental Medicine.
This belief, Hajishengallis notes, has been challenged over the past decade. Studies have shown that the innate immune system can respond more strongly when challenged again with the same or different stimulus—in other words, it can be “trained.”
And importantly, these studies have also shown that “training” the innate immune system has beneficial effects, such as anti-tumor activity and an increased response to fighting infections in certain experimental models.
But inflammation—the innate immune system’s natural response to harmful stimuli—can also exacerbate symptoms or even cause diseases, demonstrating the need to better understand the immune system when developing immune-based therapies. An increased response may not always be beneficial.
“Trained innate immunity (TRIM) has emerged as a major immunological principle that challenges the dogma that memory is restricted to adaptive immunity,” says Hajishengallis. “So, a better understanding of TRIM is imperative to appropriately harness it for therapeutic gain in human disease.”
The Hajishengallis team along with a collaborative lab led by Triantafyllos Chavakis at the Dresden University of Technology, induced TRIM using ß-glucan, a compound found in certain fungi, and measured the generation of osteoclasts, which resorb bone during growth and healing, in models of inflammatory periodontitis and arthritis.
“We found that this treatment primed osteoclast precursors to differentiate into osteoclasts more readily if presented with an inflammatory challenge like arthritis,” says Chavakis.
“So, although TRIM can have beneficial effects—protecting against infections and cancer—our results indicate that the memory of a previous infection may also contribute to inflammatory diseases and the comorbidity between inflammatory bone loss disorders,” adds Hajishengallis.
Their work, however, showed that ß-glucan only increases the opportunity for bone loss to occur—it does not cause actual bone loss. That only occurs if a second inflammatory stimulus, such as arthritis or periodontitis, is present.
“This requirement [for a secondary challenge] epitomizes the concept of trained immunity—the training stimulus causes a state of preparedness for future events,” says Hajishengallis.
Importantly, these results argue against the idea that it is the initial stimulus that is driving TRIM to be beneficial or maladaptive (harmful), as ß-glucan caused beneficial TRIM (for example, tumor growth inhibition) in previous studies by Hajishengallis and Chavakis.
“Our findings suggest that the context in which TRIM emerges dictates whether the functional outcome is protective or harmful,” says Chavakis.
“The double-edged sword nature of TRIM acquires special relevance when considering the preventive or therapeutic application of TRIM-inducing agents,” adds Hajishengallis.
George Hajishengallis is the Thomas W. Evans Centennial Professor in the Department of Basic & Translational Sciences in the School of Dental Medicine at the University of Pennsylvania.
Triantafyllos Chavakis is a professor and director of the Institute for Clinical Chemistry and Laboratory Medicine at the University Hospital Carl Gustav Carus, Technische Universität (TU) Dresden, Germany.
Other authors are Hui Wang of the School of Dental Medicine at the University of Pennsylvania and Sichuan University; Anisha U. Shah of the School of Dental Medicine at the University of Pennsylvania; Xiaofei Li of the School of Dental Medicine at the University of Pennsylvania and Shanghai Jiao Tong University; Jun Wang and Ling Ye of Sichuan University; Nora Haacke, Marko Barovic, Adelina Botezatu, Kyoung-Jin Chung, Bettina Gercken , Aikaterini Hatzioannou, Kosuke Nagai, Mangesh T. Jaykar, Martina Rauner, and Ben Wielockx of TU Dresden; Lydia Kalafati of TU Dresden and the Institute of Radiopharmaceutical Cancer Research; Giulia Trimaglio and Shu Yan of TU Dresden and the National Center for Tumor Diseases, Partner Site Dresden; and Mihai G. Netea of Radboud University Medical Center and the University of Bonn.
This work was supported by grants from the Stiftung für Pathobiochemie und Molekulare Diagnostik (to N.H.), the Deutsche Forschungsgemeinschaft (SFB-TRR369 to T.C., L.K., M.R., and B.W.) and the NIH (DE031206 and DE033643 to G.H.). T.C. is also supported by the European Research Council (LOSYSINCHRON), the Saxon State Ministry of Science, Culture and Tourism (SMWK), and the Deutsche Forschungsgemeinschaft (SFB-TRR332).
