HLA-DPB1 mismatch alleles represent powerful leukemia rejection antigens in CD4 T-cell immunotherapy after allogeneic stem-cell transplantation.

Abstract

Refractory or relapsed acute myeloid leukemia (AML) represents a frequent complication after allogeneic hematopoietic stem-cell transplantation (HSCT). We show herein that primary in vitro stimulation of CD45RA-selected CD4 T cells of stem-cell donors with 10/10 HLA-matched AML blasts results in expansion of cytolytic T-lymphocytes (CTL) that almost all recognize HLA-DPB1 mismatch alleles, which clinically occur in up to 80% of donor-patient pairs. Primary AML blasts were found to strongly express HLA-DPB1, whereas fibroblasts and keratinocytes used as surrogate target cells for graft-versus-host disease did express HLA-DPB1 only upon IFN-γ pre-treatment. Since patients' AML blasts are rarely available in clinical routine, we developed a protocol based on stimulation of donor-derived CD45RA-selected CD4 T cells with autologous dendritic cells electroporated with RNA encoding patients' HLA-DPB1 mismatch alleles. Short-term stimulated T cell-lines specifically lysed HLA-DPB1 mismatch-expressing AML blasts, but not fibroblasts and keratinocytes without IFN-γ pre-treatment. Notably, these CD4 CTL efficiently eliminated AML blasts upon adoptive transfer into leukemia-engrafted NSG mice. In conclusion, we show strong immunogenicity of HLA-DPB1 mismatch alleles in CD45RA-selected CD4 T cells of stem-cell donors and introduce a novel strategy to reliably generate HLA-DPB1-specific CD4 CTL that might be powerful cellular therapeutics in relapsed or refractory AML after HSCT.

• Authors: W Herr, Y Eichinger, J Beshay, A Bloetz, S Vatter, C Mirbeth, E Distler, U F Hartwig, S Thomas
• Journal: Leukemia (Leukemia) Vol. 31 Issue 2 Pg. 434-445 (02 2017) ISSN: 1476-5551 [Electronic] England
• PMID: 27479183 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HLA-DP beta-Chains
• HLA-DPB1 antigen

Topics

• Alleles
• Animals
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• Cytotoxicity, Immunologic (genetics, immunology)
• Female
• Genotype
• HLA-DP beta-Chains (genetics, immunology, metabolism)
• Hematopoietic Stem Cell Transplantation
• Humans
• Immunotherapy
• Immunotherapy, Adoptive
• Leukemia (genetics, immunology, therapy)
• Leukemia, Myeloid, Acute (genetics, immunology, metabolism, pathology)
• Lymphocyte Activation (genetics, immunology)
• Mice
• Tissue Donors
• Transplantation, Homologous