Transplantation Therapy

The primary goals of the Transplantation Therapy Section are to generate new understandings in transplantation biology and to develop new transplantation therapies based on those basic science investigations. The section concentrates on efforts in four complementary areas:

• In the area of cellular hematopoiesis, investigations are carried out to characterize negative regulation; the clinical aim is to generate strategies for establishing effective hematopoiesis of progenitor cells manipulated in vivo or in vitro (including purging). These studies have delineated the regulatory role of IGF-II in CD34+ cell proliferation and have begun to characterize the role of chemokines as negative regulators of hematopoiesis.
   
• In the area of T cell regeneration, the goal of our studies is to characterize mechanisms of T cell reconstitution; clinically, the aim is to maximize T cell regeneration for therapeutic gain. We have found that efficient T cell regeneration is dependent on thymic activity, which varies inversely with age so that compromise exists even in young adults. In older adults, expansion of postthymic T cells accounts for the majority of CD4+ T cell reconstitution, but such T cell populations then tend to diminish with time. This latter observation has prompted our work to identify mechanisms by which expanded T cell populations are lost.
   
• Currently, we are studying the role of the SPATIAL gene in thymus function using mouse knockout model systems combined with cellular and molecular techniques. SPATIAL is specifically expressed in thymic subcapsular cells and our data suggests it negatively regulates thymic input of precursor cells. Our studies are focused on the following: regulation of SPATIAL function, the impact of SPATIAL on cell cycle control mechanisms, regulation of ubiquitination, stem cell migration into the thymus, intrathymic precursor cell proliferation, post bone marrow transplant T cell reconstitution, and differential gene expression in stromal cells. We plan to build on these experiments to develop new drugs to enhance thymus function and T cell reconstitution to improve human health following a period of immune deficiency.

• Current and planned clinical studies follow themes developed within the preceding projects with emphasis on the augmentation of T cell regeneration/responses. Current clinical studies focus on treatment of residual disease in patients with breast cancer and exploit the understanding that post-chemotherapy T cell regeneration in adults involves primarily extrathymic expansion, requires mature T cell progenitors, is antigen driven, is prone to skewing, and is cytokine regulated. Such studies also seek to characterize further the regeneration of T cells (especially CD8+ cells) in patients with cancer.