Esma Yolcu, Ph.D. Research Interests
The major interest of Dr. Yolcu's laboratory is to employ a novel technology designated as ProtEx™ to generate a library of recombinant proteins with immunoregulatory functions and display these proteins on the surface of bone marrow cells for immunomodulation. In collaboration with Dr. Shirwan, she pioneered the ProtEx™ technology as a practical, safe, and effective alternative to gene therapy for cell and tissue engineering.
ProtEx™ involves the generation of chimeric molecules consisting of core streptavidin and extracellular portions of immunological ligands, and the display of these molecules on the surface of cells, tissues, and/or organs of interest that have been biotinylated under physiological conditions. Chimeric molecules exist as stable tetramers and higher structures owing to the tetramer-forming properties of streptavidin. Inasmuch as receptor/ligand coaggregation on the cell surface is critical to the transduction of effective immunological signals, chimeric molecules as tetramers and higher structures possess improved functions when compared with their native counterparts. Proof-of-principle for the application of ProtEx™ technology to effective immunomodulation has recently been obtained in transplantation and cancer immunotherapeutic settings in preclinical models and human ex vivo studies.
GRAFT-VERSUS-HOST AND HOST-VERSUS-GRAFT REACTIONS
Bone marrow transplantation (BMT) as a source of hematopoietic stem cells (HSC) is potentially a curative therapy for a series of inherited and acquired hematological disorders. BMT can also be used as a cell-based immunomodulatory approach to induce tolerance to foreign and auto-antigens for the prevention/treatment of foreign graft rejection and autoimmune disorders. The routine application of allogeneic BMT in the clinic, however, is complicated by two different types of immunological reactions; host-versus-graft (HVG) and graft-versus-host (GVH). HVG is responsible for the rejection of foreign BMC whereas GVH incites graft–versus–host disease (GVHD). T cells play a critical role as main initiators/effectors of both types of reactions by responding to host or donor alloantigens. Although, elimination of T cells from the donor BM or the graft recipient can curtail both types of reactions, lack of engraftment and immunoincompetence are the observed complications. Therefore, the development of approaches that specifically target the physical/functional elimination of alloreactive T cells, without compromising the function of those with unrelated antigenic specificities, is critical to the routine, efficient, and safe application of BMT to the clinic as a therapeutic intervention.
This project focuses on the engineering of BMC to display on their surface various immunoregulatory proteins, such as FasL, using the ProtEx™ technology and the use of the engineered cells to induce tolerance to both donor and recipient alloantigens for the prevention of HVG and GVH reactions.
MIXED ALLOGENEIC HEMATOPOIETIC CHIMERISM AS A MEANS OF INDUCING TOLERANCE TO AUTOREACTIVE LYMPHOCYTES IN TYPE 1 DIABETES
Type 1 diabetes (T1D) is a chronic autoimmune disease that targets the insulin-producing β cells in pancreatic islets of Langerhans for destruction, leading to insulin deficiency and hyperglycemia. The immunology of T1D is characterized by a spontaneous loss of immunological tolerance to unique pancreatic β cell antigens manifested by the appearance of autoantibodies and T cells reactive to specific islet antigens. Failure to regulate immunological responses to self-antigens results in the infiltration of islets with mononuclear cells (insulitis) which, in time, completely destroy the insulin-producing cells, leading to diabetes.
Durable hematopoietic mixed chimerism has recently emerged as an effective therapeutic strategy for the prevention and treatment of T1D. Mixed chimeras are tolerant to both donor and host antigens since i) stem cells in the donor bone marrow give rise to immune cells, such as lymphocytes, that are “educated” in the host immune environment for nonresponsiveness to host antigens and ii) macrophages and dendritic cells arising from the donor bone marrow serve as antigen-presenting cells (APC) in the thymus to eliminate donor reactive host lymphocytes. In addition to this “central tolerance”, other peripheral immunoregulatory mechanisms, such as clonal anergy and immune suppression, appear to contribute to the overall tolerance observed in mixed hematopoietic chimeras. Establishment of hematopoietic mixed chimerism, however, requires prevention of GVH and HVG reactions mediated by mature donor and host T cells, respectively, and partial depletion of host hematopoietic stem cells to open “space” for the engraftment of donor cells.
The focus of this project is to overcome these obstacles by using BMC engineered to display on their surface various immunological proteins for immunomodulation under clinically applicable conditions to establish mixed chimerism.