Immunomodulatory effect of mesenchymal stem cell study

Abstract

Allogeneic hematopoietic stem cell transplantation has been used for hematological diseases and other pathologies treatment over 40 years. Very often this is the only available treatment that leads patients to healing. The effect known as graft versus leukemia (GVL) or graft versus tumor (GVT) is able to eliminate residual disease in several hematological pathologies. Around 25.000 procedures are performed annually. Besides the development of new strategies related to allogeneic transplants such as leukocyte infusions, non myeloablatives conditioning regimens and umbilical cord blood transplant, the development of acute and systemic graft versus host disease (GVHD) occurs in 40% of the receptors. The associated GVHD mortality and morbidity remains an obstacle for that procedure. GVHD is a Public Health Problem in Brazil, once it causes longer hospitalization periods after transplants and it is the main reason of re-hospitalization as referred in the Portaria nº 1317/GM.Previous study with mouse was able to describe an important participation of Th17 in the development of GVHD. The Th17 cells differentiated from naïve T cells, injected in mice, were able to cause acute and lethal GVHD with severe damage on skin and lungs. The conventional treatment for acute GVHD is corticosteroid, however not all the patients are able to respond to this treatment. Nowadays, there is huge interest on new treatments that can block intracellular signalization; an example is the Bortezomib, an inhibitor of proteassome. Other treatment that has been used with good results is the mesenchymal stem cell (MSC) derived from bone marrow infusions, but little is known about these cells on GVHD and it seems to be an immunomodulatory effect that is able to regulate lymphocytes responses via CCR2/CCL2. On the other hand, some authors demonstrated that after interferon gamma stimulation, the MSC can act as antigen presenting cells interacting with the T cell antigenic receptor (TCR).The TCR it is an octameric receptor with 2 chains, , ±² or ³´, which can bind specifically to peptides presented by the major complex of histocompatibility (MHC). Those chains are associated in a non covalent way to the CD3 subunits subunits ³µ and ´µ and the heterodim ¶ which mediates the signal transduction. The binding of the antigenic receptors to others ligands induce tyrosine phosphorilation of several proteins that lead to functional responses. Then our hypothesis is the existence of interconnections between T lymphocytes induced immunetolerance and the expression of transcription factor, genes and activativation of signaling pathways are also related to Th17. This knowledge can help in the development and selection of new targets for GVHD therapies. (AU)