Esma Shirwan Yolcu, Ph.D.

Esma Shirwan Yolcu, Ph.D.

Research Interests

PROGRAM SUMMARY

The major interest of Dr. Yolcu's laboratory is to employ a novel technology designated asProtEx™ to generate a library of recombinant proteins with immunoinhibitory functions and deliver these molecules to the surface of various cells of the immune system for immunotherapy. In collaboration with Dr. Shirwan, she recently developed the ProtEx™ technology as a practical and effective alternative to gene therapy for immunomodulation.

The ProtEx™ technology allows for i) the generation of novel molecules having potent immunoregulatory functions and ii) their rapid, durable, and efficient display at the protein level on cellular membranes for immunomodulation. 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 ofProtEx™ technology to effective immunomodulation has recently been obtained in transplantation and cancer immunotherapeutic settings in preclinical models and human ex vivo studies.

Projects

GRAFT-VERSUS-HOST AND HOST-VERSUS-GRAFT REACTIONS

BM 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.

T his project focuses on the engineering of BMC to express various immunoinhibitory molecules using the ProtEx™ technology and the use of these engineered cells to induce tolerance to both donor and recipient alloantigens during transplantation, thereby preventing HVG and GVH reactions.

MIXED ALLOGENEIC HEMATOPOIETIC CHIMERISM AS A MEANS OF INDUCING TOLERANCE TO AUTOREACTIVE LYMPHOCYTES IN TYPE 1 DIABETES

T1D is a chronic autoimmune disease that targets the insulin-producing b 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 b 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 b cells, leading to diabetes. Advances in our understanding of the molecular and cellular basis of T1D have led to the development of various immunotherapeutic approaches targeting the regulation of autoreactive lymphocytes to treat type I diabetes in experimental and clinical models. Despite significant improvement, none of these approaches can adequately control autoreactive lymphocytes and abrogate the autoimmune destruction of islets of Langerhans.

Durable hematopoietic 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 graft-versus-host and host-versus-graft 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 use mixed allogeneic hematopoietic chimerism as a means of inducing tolerance to auto- and allo-antigens for the prevention/treatment of T1D under clinically applicable conditions. Towards this end, v arious immunoinhibitory proteins will be used in conjunction with minimally myeloablative regimens to open space and prevent GVH and HVG reactions for the establishment of durable mixed chimerism. This approach will be tested both in chemically, as well as spontaneously- induced diabetes rodent models, for immunotherapy before its translation to large animal models.

Selected Publications

Schabowsky RH, Madireddi S, Sharma R, Yolcu ES, Shirwan H.Targeting CD4+CD25+FoxP3+ regulatory T-cells for the augmentation of cancer immunotherapy.  Curr Opin Investig Drugs. 2007 Dec;8(12):1002-8. http://www.ncbi.nlm.nih.gov/sites/entrez/18058571

Elpek KG, Yolcu ES, Franke DD, Lacelle C, Schabowsky RH, Shirwan H.Ex vivo expansion of CD4+CD25+FoxP3+ T regulatory cells based on synergy between IL-2 and 4-1BB signaling.  J Immunol. 2007 Dec 1;179(11):7295-304. http://www.ncbi.nlm.nih.gov/sites/entrez/18025172

Pearl-Yafe M, Yolcu ES, Stein J, Kaplan O, Shirwan H, Yaniv I, Askenasy N.Expression of Fas and Fas-ligand in donor hematopoietic stem and progenitor cells is dissociated from the sensitivity to apoptosis.  Exp Hematol. 2007 Oct;35(10):1601-12. ttp://www.ncbi.nlm.nih.gov/sites/entrez/17889725

Pearl-Yafe M, Stein J, Yolcu ES, Farkas DL, Shirwan H, Yaniv I, Askenasy N.Fas transduces dual apoptotic and trophic signals in hematopoietic progenitors.  Stem Cells. 2007 Dec;25(12):3194-203. Epub 2007 Sep 13.  http://www.ncbi.nlm.nih.gov/sites/entrez/17872500

Elpek KG, Lacelle C, Singh NP, Yolcu ES, Shirwan H.CD4+CD25+ T regulatory cells dominate multiple immune evasion mechanisms in early but not late phases of tumor development in a B cell lymphoma model.  J Immunol. 2007 Jun 1;178(11):6840-8.  http://www.ncbi.nlm.nih.gov/sites/entrez/17513732