Immunological Senescence and Thymic Function in Transplantation Ricardo Pujol-Borrell, 1,2,3 Maria Jose Herrero-Mata, 1 Eduard Palou, 1 and Maria Pilar Armengol 1,2 In the field of organ transplantation, the state of thymic function has not been a major concern but data from bone marrow transplantation studies have unravel the persistence of some thymopoiesis in the adult and, more importantly, the possibility of reinducing it. Given the central role of the thymus in tolerance, these facts have stimulated the interest in the biology of the thymus in humans. Contemporarily, basic research has provided new tools, if imperfect, to monitor thymic function, that is, T-cell receptor excision circles, markers for lymphocytes recently emigrated from the thymus and new imaging techniques. The deployment of these new tools is already changing some paradigms and has now established that re-enactment of thymic activity in the course of bone marrow transplantation or in patients with human immunodeficiency virus on highly active anti-retroviral therapy is beneficial and that can be achieved in the adult. Clinical trials using thymopoiesis-stimulating factors are underway. On the other hand, the discovery that the thymus contains a broad representation of self-antigens and that this depends on the expression of the product of the gene AIRE by the medullary thymic epithelial cells opens the possibility of manipulating central tolerance. Current protocols induc- ing microchimerism to generate tolerance to solid organ grafts suggest that this could be a feasible therapeutic goal. Therefore, there are many signs indicating that a period of translational research applying the principles of thymic biology and central tolerance to transplantation has already started. Keywords: Tolerance, Thymus, Transplantation, Chimerism, DiGeorge syndrome. (Transplantation 2009;88: S8–S13) T ackling the biological basis of the main immunologic problems in transplantation, that is rejection and graft- versus-host disease (GVHD), requires understanding one of the most central functions of the immune system, discerning self from non-self. Up to 10 years ago, the responsibility of such process was ascribed to the adaptive immune system, but now, we know that the innate immune system is also capable of a remarkable degree of discrimination even though it classifies the antigens as nondangerous and dangerous, than in self and non-self. There is growing evidence that the rec- ognition of a graft as dangerous by detecting stress proteins, or necrotic components, may accelerate or even trigger rejec- tion and this way the innate response plays a crucial role in rejection. In the coming years, a lot more will be known of the role of natural immunity, but most immunologists still accept that the rejection is ultimately determined by the lack of tol- erance to the graft by the repertoire of T cells generated in the thymus. NEW PARADIGMS IN TOLERANCE AND THYMIC FUNCTION RELEVANT TO TRANSPLANTATION Current Knowledge of the Role of Thymus in the Shaping T-Cell Repertoire The crucial role of the thymus in the generation of T cells was recognized by Miller in the 1960s of the last century, and from then on every promotion of medical and biological science graduates have been indoctrinated with a schematic view of its function (1, 2). This simplified vision can be sum- marized as follows: T lymphocytes are generated in the thy- mus through a process that includes the proliferation and differentiation of T lymphocytes running in parallel with a subtle but drastic selection process designated as thymic ed- ucation. This selection includes a positive step that is only overcome by T cells bearing a T-cell receptor (TCR) capable of binding self-major histocompatibility complex proteins ir- respective of the peptide loaded into them and a negative step in which T cells bearing a TCR that binds major his- tocompatibility complex plus self-peptide with high affinity are triggered to enter apoptosis. These positive and negative se- lection processes are now believed to be consecutive: the first step occurs mainly in the thymic cortex and the second one in the medulla (3). The experimental evidence that supports this scheme is large, from the initial observation of the small proportion of thymocytes that eventually leave the thymus (3%–5%) to the demonstration of negative selection by superantigen and large number of experiments using TCR transgenic mice (4). From this general model and the observations of the biology of thymus in the mouse, several extrapolations and unsupported inferences were uncritically accepted. Some have important implications for understanding rejection and tolerance to solid organ and, more specially, to hematopoietic stem-cell transplantation (HSCT): (1) the repertoire is purged in the thymus from T lymphocytes that recognize ubiquitous but Supported in part by grant 03/1601 of Fondo de Investigaciones Sanitarias, In- stituto de Salud Carlos III, Ministry of Health, Spain; and by grant SAF 2005-1060 from the Ministry of Education; and by the Consortium Euro- thymaide of the 6th Framework program of the EU, and by the Research Directorate (DGR) of the Department of Research and Universities (DURSI) of the Generalitat de Catalunya 2004 –2008. 1 Laboratory of Immunobiology for Research and Application to Diagnosis (LIRAD), Banc de Sang i Teixits (Blood and Tissue Bank), Institut d’Investigacio ´ en Cie `ncies de la Salut Germans Trias i Pujol, Badalona, Barcelona, Catalonia, Spain. 2 Department of Cell Biology, Physiology and Immunology, Faculty of Med- icine, Badalona Unit, Universitat Auto ` noma de Barcelona, Badalona, Spain. 3 Address correspondence to: R. Pujol-Borrell, M.D., Ph.D., LIRAD-BST, Institut d’Investigacio ´ en Cie `ncies de la Salut Germans Trias i Pujol, Carretera de Can Ruti, Camí de les Escoles, 08916 Badalona, Barcelona, Spain. E-mail: rpujolb@servet.uab.es Copyright © 2009 by Lippincott Williams & Wilkins ISSN 0041-1337/09/8803S-8 DOI: 10.1097/TP.0b013e3181af653c S8 | www.transplantjournal.com Transplantation • Volume 88, Number 3S, August 15, 2009