NCI Funded Research Portfolio - Z01 BC 010525 Abstract

Z01 BC 010525 (Z01)
Title	Immune Reconstitution
Institution	NCI, Bethesda, MD
Principal Investigator	Gress, Ronald	NCI Program Director	N/A
Cancer Activity	N/A	Division	CCR
Funded Amount	$1,714,717	Project Dates	10/01/2003 - N/A
Fiscal Year	2007	Project Type	Intramural
Research Topics (SICs) w/ Percent Relevance		Cancer Types (Disease Sites) w/ Percent Relevance
Immunology (100.0%)		N/A
Common Scientific Outline
Application of Model Systems Systemic Therapies - Discovery and Development
Abstract	The biology of reconstitution of T cell populations following acute loss has, in the past, been extremely poorly characterized. Using murine models, we first identified two primary pathways of T cell immune reconstitution, the classic, thymic-dependent pathway, and a second, thymic-independent pathway. We then identified T cell surface markers which allowed identification, by phenotyping of reconstituted T cell populations, of the pathways which had given rise to them, and then applied this information to the characterization of T cell reconstitution in patients. Initial work established the applicability of this approach to the study of T cell population regeneration in humans. Current work has verified validity of the approach and has, for the first time, established the time course of T cell immune reconstitution in humans over time for each of the two primary pathways. This work has also shown an essential role for the thymus in regenerating CD4+ T cells quantitatively. CD8+ T cells depend more strongly on peripheral expansion for immune reconstitution. Both CD4+ and CD8+ T cells require thymic activity for maintenance or generation of repertoire diversity. These findings have led in turn to a research emphasis on understanding mechanisms which control thymic function, and new treatments, including vaccine strategies, to treat cancer in the setting of a regenerating immune system. Four models of thymic regulation have been developed. These models demonstrate one critical point of regulation, namely entry of early thymocyte progenitors, and also indicate that the extrathymic precursor pool may play a critical role in regulation of thymopoiesis. Studies are in progress to translate these findings into strategies to enhance immune reconstitution in humans. One such strategy is the use of IL-7, a primary T cell homeostatic cytokine, which we have now have introduced into initial clinical trials.