CLINICAL AND TRANSLATIONAL RELEVANCE OF UNDERSTANDING THE THYMIC MICROENVIRONMENT

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Thymic output is quantitatively and qualitatively correlated with peripheral immune function. Loss of thymic output occurs during aging, as well as due to a wide variety of conditions including genetic disorders, AIDS, and cancer therapies such as irradiation and chemotherapy. The reduced output of naïve T cells after age-related thymus involution in humans severely impairs the ability to respond to newly encountered antigens. Older people are less likely to develop protective immunity after vaccination and therefore are more susceptible to new infectious diseases such as West Nile virus (126). Diminished thymus function is a particular problem for patients who have undergone therapeutic bone marrow transplantation (BMT) (127, 128). The cytoablative treatment used to prepare patients for BMT damages the thymus microenvironment. This poses a serious risk even to young patients, who would otherwise sustain robust T cell output from a functional thymus. T cell deficiency resulting from treatment-induced thymus damage renders these patients susceptible to infection for months after transplantation. Restoration of thymus function would thus be extremely efficacious in reducing post-transplant morbidity and mortality. Patients with T cell-based immunodeficiency from AIDS are also vulnerable. Overall, the identification of mechanisms to prevent or revert thymus involution would benefit a large patient population.

Important proof of concept studies in infants presenting with full DiGeorge Syndrome have demonstrated that transplantation of neonatal human thymus tissue leads to generation of a functional adaptive immune system (129-131). In these studies, in vitro cultured neonatal thymus fragments were transplanted into the quadriceps muscle of full DiGeorge syndrome patients presenting with no circulating T cells, aged between 51 and 127 days on the date of grafting. In the initial study, five children were transplanted. Three died of complications arising from DiGeorge Syndrome but unrelated to the thymus transplant. However, the two surviving patients developed host T cells which exhibited a normal TCRbV repertoire, showed robust responses to mitogen and developed appropriate B cell responses to tetanus and pneumococcus vaccinations. Interestingly, one of these grafts was completely unmatched at HLA. TRECS were detected in both patients after but not before grafting (129). This study has now been enlarged and followed up for more than 12 years (130-137), and recently the same approach has been successfully extended to treating human nude patients (138). These studies provide proof of principle that cell replacement approaches in general can work for increasing thymus function, and that thymus grafting into an ectopic location, at least of neonatal tissue, can be successful in reconstituting a functional T cell population.

Aging-associated immunodeficiency represents a key component of the pathophysiological effects of aging and has multiple well-documented effects on the quality of life and health. Hallmarks of aging with respect to immune function include enhanced susceptibility to infection, poor responses to vaccination, and increased autoimmunity, all of which are factors that increase morbidity and mortality in the elderly. Even in middle-aged people, reduced thymic function is a contributing factor in the ability to combat infectious diseases such as influenza. Immune deficiency is exacerbated by diseases including cancer and AIDS, and is a major side effect of chemotherapy, radiation, and adult bone marrow transplantation, all of which are compounded by the effects of aging-related immunosenescence. A major component of immunosenescence is the loss of T cell production from the thymus as a result of aging-associated involution. Age-related T cell abnormalities that contribute to reduced immune system function include a decline in the frequency and function of naïve peripheral T cells as well as a decline in the expansion of memory T cells leading to a restricted T cell repertoire. The diminished capacity of peripheral T cells to proliferate and produce cytokines in older individuals is thought to result from defects accumulated after prolonged T cell residence in the periphery (139). As the reduced number (and repertoire) of naïve T cells in the peripheral pool is due to diminished output from the aged thymus (140), many of the age-associated changes in peripheral T cells are directly or indirectly related to reduced thymic output. The incidence of autoimmune diseases also increases with age and may be mechanistically linked to thymic involution. Regenerating thymic output of naïve T cells thus has the potential to substantially improve immune status for a wide variety of patients and the elderly, while prevention or amelioration of thymic involution could reduce the incidence of autoimmunity. Due to the high demand and clinical need for therapies to ameliorate immunodeficiency caused by aging, disease, or disease treatment, some preclinical and clinical studies to enhance thymus function are already in progress or on the horizon (reviewed in (141, 142)). A better understanding of the biology underlying involution should lead to the development of more specific and effective strategies for reversing or even preventing age-related involution, thus improving overall immune function in the aged and aging population.

Understanding the development and function of the thymic microenvironment is critical for any efforts to reverse or prevent its degeneration from aging or disease. Knowledge of the mechanisms by which cells in the thymus differentially translate extracellular signals to achieve homeostasis could lead to the development of strategies that manipulate thymic output in patients and normal individuals during aging.