Beneficial and unfavourable immune cells in fracture healing
Final Report Abstract
Bone is a complex organ with the capacity to regenerate. Even with this healing potential healing results in fractured bone are unsatisfactory in a considerable patient cohort even with a good treatment regime. These delayed healing cases encourage further research into possible new treatment approaches. The recently developed field of osteoimmunology addressing the tight interconnectivity of the skeletal system and the immune system could be a promising opportunity in this regard. The early phase of bone healing is crucial for the long term healing outcome, since the inflammatory phase initiates the healing cascade. Results from earlier sheep and human analyses suggest that during this stage regulatory T cells are beneficial for fracture healing whereas cytotoxic T cells might impair the process. Based on these findings, we hypothesized that a specific balance of cytotoxic and regulatory T cells in the local immunological environment is a prerequisite for successful bone healing. Therefore, we addressed the beneficial/unfavorable effect of distinct immune cell subpopulations on fracture healing taking into account the influence of the fracture surrounding tissues. In a consecutive experimental-therapeutical approach, immune cell subsets were selectively targeted in order to enhance fracture healing. Cytotoxic CD8 positive T cells were shown to impair bone healing. This was demonstrated in a mouse model were CD8 T cells were depleted and healing improved in comparison with untreated controls. This effect was simultaneously shown in a patient cohort in a related study. These findings were honoured with the Grundlagenforschungspreis of the GKOU. In consequence a biomarker is in development to stratify patients with a high risk of delayed fracture healing and a patent has evolved. The possibilities of immune modulatory interventions to enhance bone healing have been further analysed with respect to the influence of the adaptive immune system. The sterile housing conditions in conventional animal housing leads to a minimal experienced immune system. Rehousing the animals in semi-sterile conditions for at least 4 weeks delays the regenerative bone healing process. At the same time the effector T cell pool increases. This led to a change in our animal studies. Now, animals that were used in immune modulatory experiments are housed semi-sterile to enable effector cell formation and to more closely mimic the patient situation. Regulatory T cells and macrophages were successfully addressed to enhance bone healing though immune modulation. During this project the topic of immune cells in bone healing has become more and more important with a higher number of publications in this field. But immune modulatory strategies to enhance bone healing are still at the beginning. However, with the demographic shift towards an older population the meaning of this topic is still increasing, as it becomes apparent, that the immune system changes during aging and that these changes could be essential in understanding and targeting the specific needs of regeneration in aged.
Publications
- Terminally differentiated CD8⁺ T cells negatively affect bone regeneration in humans. Sci Transl Med. 2013 Mar 20;5(177):177ra36. Erratum in: Sci Transl Med. 2013 May 29;5(187):187er4
Reinke S, Geissler S, Taylor WR, Schmidt-Bleek K, Juelke K, Schwachmeyer V, Dahne M, Hartwig T, Akyüz L, Meisel C, Unterwalder N, Singh NB, Reinke P, Haas NP, Volk HD, Duda GN
(See online at https://doi.org/10.1126/scitranslmed.3004754) - Initiation and early control of tissue regeneration - bone healing as a model system for tissue regeneration. Expert Opin Biol Ther. 2014 Feb;14(2):247-59
Schmidt-Bleek K, Petersen A, Dienelt A, Schwarz C, Duda GN
(See online at https://doi.org/10.1517/14712598.2014.857653) - T and B cells participate in bone repair by infiltrating the fracture callus in a two-wave fashion. Bone. 2014 Jul;64:155-65
Könnecke I, Serra A, El Khassawna T, Schlundt C, Schell H, Hauser A, Ellinghaus A, Volk HD, Radbruch A, Duda GN, Schmidt-Bleek K
(See online at https://doi.org/10.1016/j.bone.2014.03.052) - Boon and Bane of Inflammation in Bone Tissue Regeneration and Its Link with Angiogenesis. Tissue Eng Part B Rev. 2015 Aug;21(4):354-64
Schmidt-Bleek K, Kwee BJ, Mooney DJ, Duda GN
(See online at https://doi.org/10.1089/ten.teb.2014.0677) - Immune modulation as a therapeutic strategy in bone regeneration. J Exp Orthop. 2015 Dec; 2
Schlundt C, Schell H, Goodman SB, Vunjak-Novakovic G, Duda GN, Schmidt-Bleek K
(See online at https://doi.org/10.1186/s40634-014-0017-6) - Macrophages in bone fracture healing: Their essential role in endochondral ossification. Bone. 2015 Oct 31
Schlundt C, El Khassawna T, Serra A, Dienelt A, Wendler S, Schell H, van Rooijen N, Radbruch A, Lucius R, Hartmann S, Duda GN, Schmidt-Bleek K
(See online at https://doi.org/10.1016/j.bone.2015.10.019)
