Study of the expression of FasL, TNF-alpha and TRAIL in haematological malignancies

Abstract

The activation of naive T lymphocytes occurs through the presentation of peptides by APCs in secondary lymphoid organs and is characterized by a differential gene expression, proliferation and differentiation of these cells into effector and memory cells, are responsible for increasing the reactive capacity of the immune system with each successive exposure to the antigen. The process of activation of T lymphocytes is essential for host defense. However, mechanisms controlling this process are essential to eliminate self-reactive cells (central tolerance) and control the number of repeatedly activated T lymphocytes in the periphery. This latter mechanism for maintaining the immunological balance involves a process called cell death induced by activation (activation-induced cell death - AICD). In recent years, the identification and characterization of molecules and pathways that are involved in the regulation and execution of cell death in leukemia cells and lymphoma, has led to major advances in the development of new diagnostic tools and molecular approaches. Our research group showed for the first time that PGE2, released by dendritic cells and macrophages in response to agonists of TLRs, can have a negative effect on the induction of CD95L that occurs after stimulation via the complex TcR/CD3 (Weinlich et al., 2008). This result implies that in the absence of expression of CD95L, the CD4 T lymphocytes (TH) remain AICD and are not able to induce cell death in the APC sensitive to stimulation of apoptosis via CD95. Considering that a variety of regulatory molecules of apoptosis are promising targets for therapeutic intervention, the application of basic knowledge on apoptosis pathways in clinical practice should result in the production of new biomarkers and therapies for the treatment of hematologic malignancies. This study aims to investigate the expression of death receptors and their ligands in hematologic malignancies (leukemias and lymphomas), in order to elucidate the involvement of these molecules in disease progression. Moreover, we find the possible effect of PGE2 on the expression of CD95L, TNF-alfa and TRAIL in subpopulations T cells (Th1, Th2, Th17, Th22 and Treg) in patients with leukemias (LMA and LLA) and lymphomas, multiple myeloma and myelodysplasia. This doctoral project will count with the colaboration of Dr. Nelson Hamerschlak (Hospital Israelita Albert Einstein, SP) which will contribute mainly with samples and clinical data of patients.