Ageing Dev. from the immune system (immune senescence) is a significant barrier to immune tolerance, but this barrier can be overcome by targeting sex steroid production with commonly used clinical therapeutics. INTRODUCTION A healthy and normally functioning immune system has many important attributes, including the ability to respond rapidly to pathogenic agents while maintaining robust self-tolerance. Many fields of medicine seek to alter this balance either to obtain a stronger immune response (for example, Tonabersat (SB-220453) to defend against infection) or to curtail the response to quell autoimmunity or support transplantation tolerance. In most clinical scenarios, these two aims are at odds with one another, and fostering one is nearly always at the expense of the other. In the case of immune senescence, there is a clear decrement in the ability to respond protectively to novel antigens (1C5). However, in these same older individuals, there is also evidence of increasing failure in immune tolerance mechanisms and a greater propensity to autoimmunity (6, 7). Although several research strategies are aimed at augmenting immune responsiveness in older individuals to protect against infection, it is not yet well defined whether these same strategies may support restoration of immune tolerance. The senescent immune response has been best characterized in terms of the response to vaccination and infectious agents. Although the peripheral immune system in aged individuals contains a high number of memory cells formed against agents encountered earlier in their lifetimes (8C10), response to novel antigens, particularly in terms of B cellCderived antibody production, can be sparse (11C13). In addition, generation of new T cells is compromised because of thymic involution (14C17). These processes combine to leave a number of holes within the peripheral repertoire and result in the inability of the immune system PPARG to see novel Tonabersat (SB-220453) antigens. This decreased immune reactivity may seem like an ideal scenario in which to obtain nonresponsiveness to novel antigens, which is the goal of transplantation tolerance. However, tolerance induction is not simply a process of nonresponsiveness, but an active immune program requiring a specific response (regulation) against the transplant antigens. Murine models of transplantation depend on critical, active responses from both the B lymphocyte repertoire and the thymus (18C20). The inability of Tonabersat (SB-220453) the senescent immune Tonabersat (SB-220453) system to respond appropriately to novel antigens at the thymic and peripheral levels represents a daunting challenge for the attainment of peripheral tolerance. In addition, understanding this problem is central to the advancement of clinical transplant protocols because most of the clinical research protocols are performed in Tonabersat (SB-220453) aged individuals in whom there has been significant thymic involution and other signs of immune senescence. Herein, we describe a clinically applicable approach to reverse immune senescence, restore thymic mass, and rejuvenate the capacity of the immune system to respond to tolerogenic stimuli. Overall, we identify immune senescence as a reversible barrier to transplantation tolerance. RESULTS Tolerance-inducing therapy fails in mice that are more than 1 year old Because the induction of immune tolerance is an active process requiring antigen recognition and regulatory cell activation and differentiation, we hypothesized that this process would be diminished in aged mice. For the purposes of this investigation, we studied tolerance to cardiac allografts induced by monoclonal antibody (mAb) therapy targeting the CD45RB molecule using a standard short-term course of therapy. As previously published, we found robust tolerance induction in young mice (2 months), in which more than 50% of treated mice demonstrated long-term allograft survival. All untreated mice demonstrated rapid graft rejection by day 11 [median survival time (MST) = 9 days] (Fig. 1A). Mice at age 6 and 9months were similarly susceptible to tolerance induction. However, by 1 year of age, no treated mouse showed long-term tolerance, although there was a modest prolongation in MST of 43 days (treated) versus 10 days (untreated) (Figs. 1B and ?and2).2). By 14 months of age, the MST (33 days) was further decreased, and again, no treated animal showed long-term tolerance (Fig. 1B). Open in a separate window Fig. 1 Aging eliminated the tolerance-inducing effect of anti-CD45RB on cardiac allografts. Hearts from C3H mice were transplanted into the abdominal cavity of B6 mice at different ages and.