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Injury-Induced Allograft Rejection: a Rendezvous with Evolution Walter Gottlieb Land

Injury-Induced Allograft Rejection: a Rendezvous with Evolution Walter Gottlieb Land. Professeur Conventionné , LabEx Transplantex Faculty of Medicine, University of Strasbourg, France Honorary President, German Academy of Transplantation Medicine, Munich, Germany.

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Injury-Induced Allograft Rejection: a Rendezvous with Evolution Walter Gottlieb Land

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  1. Injury-Induced Allograft Rejection: a Rendezvous with Evolution Walter Gottlieb Land ProfesseurConventionné, LabExTransplantex Faculty of Medicine, University of Strasbourg, France Honorary President, German Academy of Transplantation Medicine, Munich, Germany

  2. The 3 major paradigms in immunology

  3. Land et al. Transplantation 1994, Matzinger,1994 discovery and description of the phenomenon: “Injury induces Immunity”

  4. Danger/injury model of (allo)immunity: largely accepted in 2012/2013 →oxidative injury → allograft rejection Selected References: Matzinger P. Annu Rev Immunol.1994;12:991, Land et al., Transplantation. 1994; 57: 211, Oppenheim et al. AdvExp Med Biol 2007;601:185, Bianchi ME. J LeukocBiol 2007; 81:1, Beutler B. Immunol Rev 2007;220: 113, Lotze et al. Immunol Rev 2007;220:60, Klune et al. Mol Med 2008;14:476, Zhang and Mosser. J Pathol 2008;214:161, Manfredi et al. Crit Rev Immunol 2009;29:69, Martinon et al. Annu Rev Immunol 2009;27:229, Rock et al. Annu Rev Immunol 2010;28:321, Latz E. CurrOpinImmunol 2010;22:28, Rock et al. Immunol Rev 2011;243: 191, Benichouet al. Front Immunol. 2012;3:73, Gallo and Gallucci. Front Immunol 2013; 4:138, Richmond et al. CurrOpinImmunol 2013;25: 676, Lartigue and Faustin. Int J Biochem Cell Biol 2013; 45: 2052, Spahn et al. CurrOpin Organ Transplant. 2013, in press.

  5. In regard to the existence of microbiotas→the immune system appears to be more a “bouncer” rather than a defensive army posted to guard the body against other hostile organisms. harmless non-self: harmful non-self: discrimination DAMPs control control Selected References: Goodman WA, Pizarro TT. Regulatory cell populations in the intestinal mucosa. CurrOpinGastroenterol. 2013; 29:614, Han D, et al. Dendritic cell expression of the signaling molecule TRAF6 is critical for gut microbiota-dependent immune tolerance. Immunity. 2013;38:1211, KamdarK et al. Toll-like receptor signaling and regulation of intestinal immunity. Virulence. 2013; 4: 207, KamadaN et al. Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol. 2013;13: 321, Owen JL,.. Microbial activation of gut dendritic cells and the control of mucosal immunity. J Interferon Cytokine Res. 2013;33: 619-31, Bollrath J, Powrie FM. Controlling the frontier: Regulatory T-cells and intestinal homeostasis. SeminImmunol. 2013; 25: 352. Immunity is not directed against foreign antigens - provided there is no injury -

  6. The innate immune system has evolved in all phyla across the tree of life (plants → lower and higher invertebrates → lower and higher vertebrates) damage –associated molecular patterns DAMPs microbe –associated molecular patterns MAMPs innate immune system in: PRRs Ag presentation by APCs (DCs) Ag adaptive immune system in: plants innate immune cell invertebrates vertebrates TCR vertebrates naïve T cell PRRs- controlled immunity, resistance tolerance protection defense response protective response

  7. DAMPs-elicited (indirect) immune defense of plants via emission of “volatiles” plant injury-induced, DAMPs: “volatiles” (VOCs) Selected References: Holopainen JK, Blande JD. Wehre do herbivore-induced plant volatiles go? Front Plant Sci 2013; 4: 185, Kim et al. Priming of antiherbivore defensive responses in plants. Insect Sci. 2013; 20: 273, Karban et al. Volatile communication between plants that affects herbivory: a meta-analysis. EcolLett. 2014;17: 44, Bricchi et al.. Robotic mechanical wounding (MecWorm) versus herbivore-induced responses: early signaling and volatile emission in Lima bean (Phaseoluslunatus L.). Planta. 2010; 232: 719.

  8. Immune defense is primarily directed against life-threatening injuries: an evolution-driven immunological phenomenon (probably) found in all phyla. Plant Physiol. 2005 Mar;137(3):1160-8. “VOCs” - operating as - DAMPs robotic device → mechanical “sterile” wounding

  9. the danger/injury model inherently rules out: non-self per se induces immunity” confirmed by tolerance to microbiota, - the more confirmed as microbiotas have evolved, under the control of innate immunity, across the tree of life.

  10. Evolution tells us why the overall existence of microbiotas really makes sense: It is the formation of the “holobiont”, a metaorganism, that is, the host(self) plus all of its associated microorganisms (non-self) that - in terms of a strong unit of selection in evolution - provides that kind of fitness to all species on earth to successfully live, survive and reproduce. - (according to Zilber-Rosenberg and Rosenberg, FEMS Microbiol Rev 32 (2008) 723: “the hologenome concept of evolution”). holobiont’s fitness = development, growth, adaptation, reproduction, survival Shelter to symbiota, Nutrients provision to symbiota. host (genome) symbiota (genome) → “We all evolve, develop, grow, and function as multi-genomic ecosystems, armed with an immune system directed against sterile and infectious injuries” “hologenome”

  11. Example of an active immunological protection of (“beneficial”) non-self: • pregnancy in placental mammals - emerged ~ 400 MYA. • → reflecting an evolution-driven phenomenon on the basis of innate immunity-controlled tolerance induction to semi-allogeneic “non-self” → aiming to ensure reproduction! *) Samstein et al. Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell 2012; 150: 29, Chen T et al. Self-specific memory regulatory T cells protect embryos at implantation in mice. J Immunol 2013; 191: 2273, Teles A et al. Control of uterine microenvironment by foxp3(+) cells facilitates embryo implantation. Front Immunol 2013; 4: 158.

  12. In the interest of evolution → reproduction by successful parturition: • disruption of fetal tolerance via a DAMPs-induced uterine innate immune response • leading to ”innate” allograft rejection *) + ROS *) Review: Kobayashi H. The entry of fetal and amniotic fluid components into the uterine vessel circulation leads to sterile inflammatory processes during parturition. Front Immunol2012 Oct 23; 3: 321.

  13. Lesson learnt from evolution to avoid allograft rejection: prevent allograft injury to induce allotolerance → formation of “transplant holobiont”. the “transplant holobiont” innate immunity-controlled , tolDC-induced, Tregs-mediated tolerance to allogeneic non-self the microbial holobiont innate immunity-controlled, tolDC-induced, Tregs-mediated tolerance to microbial “non-self” innate immunity-controlled, tolDC-induced, Tregs-mediated tolerance to semiallogeneic non-self fetus non-self transplant Thank you very much, Paul ! Evolution-driven paradigm in immunology: tolerance to non-injuring/non-injured non-self

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