This application was received in response to RFA AI 93-11 entitled """"""""Causes and Consequences of Thymus Involution"""""""". The goal of this project is to determine the consequences of thymic involution on T cell development and to investigate procedures to rejuvenate the involuted thymus.
Specific Aim 1 will investigate the effects on thymic involution of T cell subpopulations by quantifying the frequency and absolute number of CD4-CD8- double negative and CD4 and CD8 single positive thymocytes in the involuted thymus. In order to determine how the proliferative and differentiative potential of thymocytes from the involuted thymus compares to cells from the neonate, thymocytes will be analyzed in a novel long-term thymocyte culture system developed in this applicant's laboratory.
Specific Aim 2 will investigate whether decreased cell numbers in the involuted thymus are due to failure of normal cytokine production by thymic stromal cells or inability of the thymocytes to respond. Particular focus will be placed on evaluating the role of various endocrine hormones on Dymic function in mice of various ages. Finally, Aim 3 will build upon preliminary data indicating that administration of insulin-like growth factor (IGF-1) to mice results in a reversal of thymic involution. Experiments will be performed to investigate if the increase in thymocyte numbers following IGF-1 treatment is selective for one thymus population or affects all subsets comparably. Numbers and functional activity of T cells that appear in secondary lymphoid organs also will be examined. It is hoped that the results obtained will further elucidate a basic biological process and will provide insights into preventing declines in thymopoiesis that result from disease or therapeutically induced stress.
