Kitasato Symposium 2011 : Translational prospects for cytokines in 2011

not submitted at time of publication O2 Inducing a tolerogenic microenvironment within tissues Stephen P Cobbold Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK E-mail: [email protected] Arthritis Research & Therapy 2011, 13(Suppl 2):O2 The maintenance of tolerance to both self tissues foreign organ grafts depends on the activity of foxp3 regulatory T cells (Treg). We have used MHC-matched skin grafts as a model system to study how such Treg can be induced therapeutically and the mechanisms by which they act. Using Arthritis Research & Therapy 2011, Volume 13 Suppl 2 http://arthritis-research.com/supplements/13/S2 © 2011 BioMed Central Ltd. All articles published in this supplement are distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. monospecific TCR transgenic mice we have shown that a short treatment with monoclonal antibodies that block full T cell activation in vivo allows the targeted tissue to itself induce de novo, antigen specific, foxp3 Treg (iTreg) [1]. We also show that these iTreg are not only concentrated within the target tissue, but are continuously required to suppress the activity of primed effector cells also present within the tissue [2]. When taken together with previous findings of linked suppression and infectious tolerance [3], the evidence suggests that tolerance maintained by iTreg is dependent on a local, tolerogenic microenviroment within the tissue. One component of this microenvironment is the induction, by both innate inflammation and iTreg, of multiple enzymes that consume essential amino acids, including tryptophan, arginine and valine. Local amino acid depletion can be sensed by naïve and effector T cells, via the mammalian target of the immunosuppressive drug rapamycin (mTOR) pathway, which can synergise with TGFb for the further induction of foxp3 iTreg [4]. TGFb is also able to up-regulate the ectoenzymes CD39 and CD73 both on T cells and antigen presenting cells to catabolise inflammatory ATP to anti-inflammatory adenosine [5]. Microarray analysis of tolerated and control skin grafts for patterns of gene expression associated with the tolerogenic microenvironment confirms that these mechanisms are preferentially active locally within the tolerated tissues rather than throughout the systemic lymphoid system. Of particular interest, these same mechanisms seem to be active in grafted syngeneic tissues [6], suggesting that iTreg maintained microenvironments are important for maintaining self tolerance in the face of an inflammatory insult. The challenge now is how we can exploit appropriate combinations of T cell blockade, mTOR inhibition and TGFb activation for translation to the clinic. References 1. Cobbold SP, Castejon R, Adams E, Zelenika D, Graca L, Humm S, Waldmann H: Induction of foxp3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants. J Immunol 2004, 172:6003-6010. 2. Kendal AR, Chen Y, Regateiro F, Ma J, Adams E, Cobbold SP, Hori S, Waldmann H: Sustained vigilance of Foxp3+ T cells is vital for infectious tolerance in vivo. J Exp Med 2011 in press. 3. Cobbold SP, Adams E, Nolan KF, Regateiro FS, Waldmann H: Connecting the mechanisms of T cell regulation: dendritic cells as the missing link. Immunological Reviews 2010, 236:203-218. 4. Cobbold SP, Adams E, Farquhar CA, Nolan KF, Howie D, Lui KO, Fairchild PJ, Mellor AL, Ron D, Waldmann H: Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc Natl Acad Sci USA 2009, 106(29):12055-60. 5. Regateiro FS, Howie D, Agorogiannis EI, Greaves DR, Cobbold SP, Waldmann H: CD73 expression and adenosine generation are controlled by TGF-b and modulated by inflammatory cytokines. Eur J Immunol 2011 in press. 6. Cobbold SP, Adams E, Waldmann H: Biomarkers of transplantation tolerance: more hopeful than helpful? Front Immun 2011, 2:9, p. 1-8. doi:10.3389/fimmu.2011.00009. O3 Peptides reloaded new strategies for tolerogenic vaccination Alf Hamann, Jennifer Pfeil, Elisabeth Kenngott, Tony Pernthaner, Susanne Hartmann, Ute Hoffmann Experimental Rheumatology, Charite Universitätsmedizin and Deutsches Rheuma-Forschungszentrum Berlin, Germany; AgResearch, Hopkirk Research Institute, Massey University, Palmerston North, New Zealand; Inst. Parasitology, Humboldt University Berlin, Germany Arthritis Research & Therapy 2011, 13(Suppl 2):O3 Uncontrolled immune reactions, e.g. in autoimmunity, chronic inflammation or allergy are a major cause of chronic and partially life-threatening diseases. Current treatments including those involving biologics largely rely on unspecific suppression of the effector cells and rarely are able to cure the disease. The native mechanisms of tolerance, notably those of active suppression by regulatory cells, have therefore fascinated immunologists from the beginning on as they promise modulation of the immune system in an antigen-specific way. However, early attempts to achieve tolerance by oral immunization or peptide vaccination worked in mouse models, but hardly were successful in humans. This might have two reasons: a), the modes of tolerogenic vaccination might not be very efficient, and b), the abundance of inflammatory effector/memory cells in adult humans might prevent induction and functioning of regulatory cells. Our group is presently focusing on the first point and designing novel modifications of peptide-based vaccines able to induce regulatory cells. Conjugation of peptides to carrier molecules is one way to improve their in vivo efficacy in inducing Foxp3+ Tregs. In an EAE model, an improved protective efficacy can be demonstrated. A second approach is aiming to target the antigen to the gastrointestinal route which is usually associated with tolerization rather than effector response. Use of signal molecules targeting the peptides to epithelial transport mechanisms is presently explored to improve the efficacy of intestinal vaccination. Finally, we investigate immunomodulatory substances produced by parasites for a potential use as tolerogenic adjuvants. While these approaches might help to improve feasibility of peptide vaccination to induce tolerance, we assume that treatment of existing autoimmune disease will require a combination therapy which incorporates elimination of inflammatory effector cells or suppression of their activity. O4 Regulatory T cells in transplantation from preclinical models to clinical study Kathryn Wood Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford OX3