Contributions
Abstract: S447
Type: Oral Presentation
Presentation during EHA22: On Saturday, June 24, 2017 from 11:45 - 12:00
Location: Room N104
Background
Expression of HLA class II molecules is under non-inflammatory conditions predominantly restricted to hematopoietic cells. However, donor CD4 T cells directed against mismatched HLA-DP can cause Graft-versus-Host Disease (GVHD) after allogeneic stem cell transplantation (alloSCT) or donor lymphocyte infusions from HLA 10/10 matched but HLA-DP mismatched donors due to upregulation of HLA class II expression under inflammatory conditions. It is often assumed that allo-HLA-DP directed CD4 T cells recognize peptides encoded by household genes presented in foreign HLA-DP and that every cell that expresses the mismatched HLA-DP allele is a target for these T cells. However, in vitro experiments illustrated that allo-HLA-DP directed CD4 T cells were not always recognizing patient derived fibroblasts induced to express HLA-DP. We hypothesized that HLA-DP directed CD4 T cells can have tissue specificity if the presented peptides in HLA-DP are encoded by genes with tissue specific expression.
Aims
The aim of the study is to investigate whether donor CD4 T cells recognizing mismatched HLA-DP show tissue specific reactivities.
Methods
In a randomized clinical trial we treat patients 3 months after T cell depleted alloSCT from HLA 10/10 matched, HLA-DP mismatched, donors with 0.25-0.50 x 106/kg donor CD4 T cells to promote immune reconstitution. In 4 patients, Graft-versus-Leukemia reactivity and/or organ specific GVHD occurred after the infusion. To characterize the immune responses in these patients, in vivo activated T cells were clonally isolated and tested for reactivity against a panel of target cells, including patient and donor derived hematopoietic cells, third party hematopoietic cells as well as different GVHD target cells (patient skin fibroblasts, third party colon carcinoma cells, biliary epithelial cells and lung fibroblasts) expressing the mismatched, patient variant, HLA-DP molecule.
Results
Allo-HLA-DP directed CD4 T cells showing differential recognition of target cells were found in all 4 patients. A total of 33 HLA-DPB1*04:01 reactive CD4 T cell clones were isolated from patient 1 who suffered GVHD of skin and colon, but not liver. Within these 33 clones, 3 clones recognized only hematopoietic target cells, 9 clones recognized hematopoietic, skin and colon derived target cells and 5 clones recognized hematopoietic and colon derived cells only. None of the T cell clones recognized biliary epithelial cells. From patient 2 total of 230 HLA-DPB1*03:01 reactive CD4 T cell clones were isolated, of which 27 recognized only hematopoietic target cells and 96 clones also recognized GVHD target cells with differences in tissue specificity. 32 HLA-DPB1*03:01 reactive T cell clones were found from patient 3, of which 6 recognized only hematopoietic target cells, whereas other clones again showed various tissue specificities. From patient 4, 26 HLA-DPB1*01:01 reactive T cells could be isolated which all recognized biliary epithelial cells with or without co-recognition of other target cells. In addition, also 11 HLA-DPB1*03:01 reactive T cells were isolated, again with different tissue specificities.
Conclusion
These results illustrate that donor CD4 T cells directed against mismatched HLA-DP show differential recognition of target cells including restricted specificity for cells of hematopoietic origin. Donor CD4 T cells recognizing hematopoietic target antigens in the context of patient specific HLA-DP alleles can be used to mediate tumor specific immune responses after HLA 10/10 matched unrelated stem cell transplantation.
Session topic: 21. Stem cell transplantation - Experimental
Keyword(s): HLA mismatched, Graft-versus-tumor effect, Graft-versus-host disease (GVHD), CD4+ T cells
Abstract: S447
Type: Oral Presentation
Presentation during EHA22: On Saturday, June 24, 2017 from 11:45 - 12:00
Location: Room N104
Background
Expression of HLA class II molecules is under non-inflammatory conditions predominantly restricted to hematopoietic cells. However, donor CD4 T cells directed against mismatched HLA-DP can cause Graft-versus-Host Disease (GVHD) after allogeneic stem cell transplantation (alloSCT) or donor lymphocyte infusions from HLA 10/10 matched but HLA-DP mismatched donors due to upregulation of HLA class II expression under inflammatory conditions. It is often assumed that allo-HLA-DP directed CD4 T cells recognize peptides encoded by household genes presented in foreign HLA-DP and that every cell that expresses the mismatched HLA-DP allele is a target for these T cells. However, in vitro experiments illustrated that allo-HLA-DP directed CD4 T cells were not always recognizing patient derived fibroblasts induced to express HLA-DP. We hypothesized that HLA-DP directed CD4 T cells can have tissue specificity if the presented peptides in HLA-DP are encoded by genes with tissue specific expression.
Aims
The aim of the study is to investigate whether donor CD4 T cells recognizing mismatched HLA-DP show tissue specific reactivities.
Methods
In a randomized clinical trial we treat patients 3 months after T cell depleted alloSCT from HLA 10/10 matched, HLA-DP mismatched, donors with 0.25-0.50 x 106/kg donor CD4 T cells to promote immune reconstitution. In 4 patients, Graft-versus-Leukemia reactivity and/or organ specific GVHD occurred after the infusion. To characterize the immune responses in these patients, in vivo activated T cells were clonally isolated and tested for reactivity against a panel of target cells, including patient and donor derived hematopoietic cells, third party hematopoietic cells as well as different GVHD target cells (patient skin fibroblasts, third party colon carcinoma cells, biliary epithelial cells and lung fibroblasts) expressing the mismatched, patient variant, HLA-DP molecule.
Results
Allo-HLA-DP directed CD4 T cells showing differential recognition of target cells were found in all 4 patients. A total of 33 HLA-DPB1*04:01 reactive CD4 T cell clones were isolated from patient 1 who suffered GVHD of skin and colon, but not liver. Within these 33 clones, 3 clones recognized only hematopoietic target cells, 9 clones recognized hematopoietic, skin and colon derived target cells and 5 clones recognized hematopoietic and colon derived cells only. None of the T cell clones recognized biliary epithelial cells. From patient 2 total of 230 HLA-DPB1*03:01 reactive CD4 T cell clones were isolated, of which 27 recognized only hematopoietic target cells and 96 clones also recognized GVHD target cells with differences in tissue specificity. 32 HLA-DPB1*03:01 reactive T cell clones were found from patient 3, of which 6 recognized only hematopoietic target cells, whereas other clones again showed various tissue specificities. From patient 4, 26 HLA-DPB1*01:01 reactive T cells could be isolated which all recognized biliary epithelial cells with or without co-recognition of other target cells. In addition, also 11 HLA-DPB1*03:01 reactive T cells were isolated, again with different tissue specificities.
Conclusion
These results illustrate that donor CD4 T cells directed against mismatched HLA-DP show differential recognition of target cells including restricted specificity for cells of hematopoietic origin. Donor CD4 T cells recognizing hematopoietic target antigens in the context of patient specific HLA-DP alleles can be used to mediate tumor specific immune responses after HLA 10/10 matched unrelated stem cell transplantation.
Session topic: 21. Stem cell transplantation - Experimental
Keyword(s): HLA mismatched, Graft-versus-tumor effect, Graft-versus-host disease (GVHD), CD4+ T cells