Tissue specific HLA-DPB1 reactive T cells in allogeneic hematopoietic stem cell transplantation

点击翻译按钮获取中文摘要

Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the standard of care treatment for chemorefractory or relapsed acute myeloid leukemia (AML) patients. The curative effect of HSCT is based on an immune reaction of the donor immune system, especially of donor T cells. Donor T cells recognize patients AML blasts through histocompatibility antigens and are the main mediators of this graft-versus-leukemia (GvL) effect. However, donor T cells can also recognize non-hematopoietic cells of patient origin thereby mediating the sometimes life-threatening graft-versus-host disease (GvHD). One major aim of HSCT research is to specifically redirect donor T cells against AML cells and strengthen the GvL effect without inducing GvHD. Therefore, the identification of T-cell defined antigens which are exclusively expressed on AML cells would be desirable. A potential target antigen is HLA-DP, which belongs to HLA class II molecules and is under steady state conditions selectively expressed on hematopoietic cells. Currently, only HLA-A, -B, -C, -DR, and -DQ is taken into account for donor search. Because of low genetic linkage disequilibrium of HLA-DP and the other HLA class II loci, 80 % of unrelated donor HSC transplantations are mismatched in at least one HLA-DPB1 allele. Therefore, it appears reasonable to generate HLA-DPB1 mismatch reactive donor T cells selectively recognizing patient hematopoietic cells. In previous xenotransplantation studies, we were able to show that in vitro generated allo-HLA-DPB1 reactive human T cells eradicate primary HLA-DPB1+ AML blasts engrafted in immunodeficient mice. However, under inflammatory conditions HLA-DPB1 shows upregulated expression on non-hematopoietic cells and therefore allo-HLA-DPB1 reactive T cells might also trigger GvHD. In the proposed project, I would like to identify allo-HLA-DPB1 reactive CD4+ T cells exclusively recognizing hematopoietic cells. First of all, I will characterize peptides binding to HLA-DPB1 on different hematopoietic and non-hematopoietic cells by mass spectrometry sequence analysis. The identification of peptide epitopes restricted to hematopoietic cells would allow me to generate allo-HLA-DPB1 reactive CD4+ T cells which should mediate a selective GvL effect in the absence of GvHD. In the second part, I will clone the T cell receptor (TCR) from those allo-HLA-DPB1 reactive T cell clones. TCR gene transfer will be used for the rapid generation of allo-HLA-DPB1 reactive T cells from different donors, which should pave the way for future clinical application of this approach in the context of adoptive T-cell immunotherapy after allogeneic HSCT.