Fas/FasL mediated apoptosis in GVHD and aplastic anemia

Johns Hopkins University, Baltimore MD

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Abstract

The ability to stably transduce lympho-hematopoietic stem-progenitor cells (HSCs) allows us to genetically engineer HSCs and their progeny to serve as improved cellular tools to treat disease and complications. In Specific Aim 1, we propose preclinical studies in mouse and human models to confirm the concept and elucidate the principal cellular and molecular mechanisms by which Fas ligand-transduced (FasL*) dendritic cells (DCs) or HSCs may selectively kill the T and NK cells that mediate GVHD. The results of Aim 1 will also provide modeling information on the application of transduced FasL+ cells to reduce immune attack against HSCs in severe aplastic anemia (SAA) (Specific Aim 3). Since it is expected that transduced FasL+ cells may be toxic in potential future translational in vivo applications, we will investigate technologies to limit potential FasL toxicity, eg by eliminating the transduced cells (or their FasL expression) after tolerance to HSCs has been generated. A novel transduced FasL+ cell therapy approach to reduce effector lymphocytes attacking host cells in GVHD (Aim 1) and SAA (Aim 3) may eventually be used in transplants for SAA, PNH and other diseases, and a potential clinical trial is outlined in Aim 1. In addition, our accompanying mechanistic studies on apoptotic pathways in alloimmune cells will increase information on the fundamentals of the Fas pathway in the effector cells mediating GVHD (and SAA), which in turn, should increase understanding of death pathways in the biology of (a) alloimmune responses, (b) hematologic malignancies that evade immune surveillance, and (c) transplanted organs (or pluripotent stem cells). In Specific Aim 2, Projects 1, 2 and 4 will cooperate to investigate the potential role of the Fas pathway in the pathophysiology of HSCs from SANPNH patients. Specific Aim 1: To engineer FasL+ host DCs or HSCs to selectively kill the cellular effectors of GVHD. Specific Aim 2: To investigate the role of the Fas pathway in the pathogenesis of SAA and PNH. Specific Aim 3: To investigate whether FasL+ HSCs selectively kill autologous anti-HSC CTLs in SAA.