A Rationale for Age-Adapted Immunosuppression in Organ Transplantation

Abstract

Demographic changes are associated with a steady increase of older patients with end-stage organ failure in need for transplantation. As a result, the majority of transplant recipients are currently older >50 years and organs from elderly donors are more frequently utilized. Nevertheless, the benefit of transplantation in older patients is well recognized whereas the most frequent causes of death among older recipients are potentially linked to side effects of their immunosuppressants. Immunosenescence is a physiological part of aging linked to higher rates of diabetes, bacterial infections and malignancies representing the major causes of death in older patients. These age-related changes impact older transplant candidates and may have significant implications for an age-adapted immunosuppression. For instance, immunosenescence is linked to lower rates of acute rejections in older recipients while the engraftment of older organs has been associated with higher rejection rates. Moreover, new-onset diabetes mellitus following transplantation is more frequent in the elderly, potentially related to corticosteroids, calcineurin inhibitors and mTOR inhibitors. This review presents current knowledge for an age-adapted immunosuppression based on both, experimental and clinical studies in and beyond transplantation. Recommendations of maintenance and induction therapy may help to improve graft function and to design future clinical trials in the elderly.

Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus

“…Moreover, we and others have reported that immunosenescence impacts alloimmune responses following organ transplantation. (29,30) Although rejection rates are less frequent in older patients (13), little is known about age-specific aspects of established immunosuppressants. Yet, age-specific concepts of immunosuppression are of clinical significance as the majority of renal transplant recipients are older than 50 years.…”

“…To the best of our knowledge, this is a novel finding in the debate on age-specific immunosuppression. (29)…”

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

“…There is some clinical evidence that the ageing process is associated with enhanced immunosuppression. For instance, (i) the risk for cancers is enhanced in elderly people, (ii) the efficiency of immunotherapy declines with aging, (iii) transplantation tolerance increases during the aging process, (iv) elderly people are vulnerable to infections, and (v) vaccination efficacy decreases during the aging process [153][154][155]. All these phenomena are associated with increased immunosuppression.…”

Acute Thymic Involution and Mechanisms for Recovery

“…ATI is a common and well-known feature in various fungal Mendes-Giannini et al 2008;Souto et al 2003), viral (Duan et al 2015;Falkenberg et al 2014;Gao et al 2015) and bacterial infectious diseases (LeyvaRangel et al 2015;Ross et al 2012;Savino 2006). ATI can also be caused by immune suppression (Billard et al 2011;Zhou et al 2016), hunger (Gavia-García et al 2015;Savino et al 2007), chemotherapy, radiography (DeBo et al 2015;Lynch et al 2009), pregnancy (Ekin et al 2016;Jacques et al 2014Jacques et al , 2015, transplant rejection (Gracia-Ahufinger et al 2015;Krenzien et al 2015) and other severe disease conditions (Wang et al 2016). ATI in certain physiological conditions (e.g., during malnutrition and pregnancy) is usually mediated by the neuroendocrine system, and the transient thymic regression is characterized by increased thymocyte death, with the capability to recuperate after the removal of the insult (Gruver and Sempowski 2008;Shanley et al 2009).…”