返回Google圖書搜尋

Genetically Engineered Antigen-specific Treg Cells in Immunotherapy: Opportunities and Challenges

出版	Universität, 2016
URL	http://books.google.com.hk/books?id=RyfEswEACAAJ&hl=&source=gbs_api

註釋Abstract: The success of a transplantation is restricted by the immune response of the recipient directed against the donor's graft (graft rejection) or the other way around; immune response of the donor against the recipient (GvHD). Promoting a state of immunological tolerance instead of long-term immunosuppression would address these issues. Adoptive immunotherapy with regulatory T cells (TREG) provides such an opportunity, as they own the potential to suppress a broad spectrum of immune cells. Since TREG cell activation via the T cell receptor (TCR) is essential for their suppressive ability, TCR specificity of TREG cells is important for their performance during clinical application. Therefore, antigen-specific TREG cells with the specificity for alloantigens, referred to as (allo)antigen-specific TREG cells, are favoured over polyclonal TREG cells for tolerance induction. The major aim of this PhD-thesis was to study the potential of receptor engineered (allo)antigen-specific TREG cells in models of skin transplantation and GvHD. One way to achieve (allo)antigen-specificity was the genetic modification of ex vivo expanded TREG cells of CBA/JRj mice (haplotype H2k), using (allo)antigen-specific TCR gene transfer. Alternatively, we transferred (allo)antigen-specific chimeric antigen receptors (CARs) into ex vivo expanded TREG cells. The later approach gave us the opportunity to generate (allo)antigen-specific TREG cells, independent of MHC restriction. Altogether, we were able to establish a long-term TREG cell line from CBA/JRj mice, referred to as ex vivo generated CBA TREG line. This cell line remained stable with respect to a variety of markers (surface and intracellular) and continued to express FoxP3 in vitro as well in vivo. In agreement with the herein described phenotype, the cell line was hyporesponsive and highly suppressive in vitro and in vivo. However, the long-term cultivated ex vivo generated CBA TREG line differed in several details from naïve TREG cells, e.g. sub-phenotype, chemokine receptor and adhesion molecule expression and TCR repertoire. Further, we could effectively generate (allo)antigen-specific TREG cells using TCR-gene transfer (OT II TCR). These cells displayed sufficient (allo)antigen-specific activation, expansion and in vitro suppression. Additionally, we here describe the engineering of (allo)antigen-specific CARs ([alpha]H-2Kb CAR and [alpha]SIINFEKL-H-2Kb CAR) and their use in the generation of (allo)antigen-specific CBA TRE ...