title: Antiviral immunity and T-regulatory cell function are retained after selective alloreactive T-cell depletion in both the HLA-identical and HLA-mismatched settings.
abstract: Nonselective T-cell depletion reduces the incidence of severe graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, but the cost is delayed and disordered antigen-specific immune reconstitution and increased infection. We use a method of selective depletion of alloreactive T cells expressing the activation marker CD69 after coculture with stimulator cells in a modified or standard mixed lymphocyte reaction. The technique has been shown to reduce alloreactivity while retaining third-party responses in vitro and, in a mismatched murine model, led to donor T-cell engraftment with a virtual absence of graft-versus-host disease and increased survival. We show in a human HLA-mismatched and unrelated HLA-identical setting that this technique retains >80% of specific cellular antiviral activity by cytomegalovirus-tetramer analysis and cytomegalovirus/Epstein-Barr virus peptide-stimulated interferon-gamma ELISpot assay. Furthermore, CD4(+) CD25(+) T-regulatory cells are not removed by this method of selective allodepletion and retain their function in suppressing allogeneic proliferative responses. Preservation of antiviral cytotoxic T lymphocytes in selectively allodepleted stem cell grafts would lead to improved antiviral immunity after transplantation. The retention of immunosuppressive CD4(+) CD25(+) T-regulatory cells could lead to more ordered immune reconstitution and further suppress alloreactive responses after transplantation.
authors.affiliation: Department of Haematology, Royal Free & University College Medical School, London, United Kingdom, UK. j.davies@rfc.ucl.ac.uk
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Davies
authors.forename: Mickey B c
authors.initials: MB
authors.lastname: Koh
authors.forename: Mark W
authors.initials: MW
authors.lastname: Lowdell
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D018920:Coculture Techniques; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000517:prevention & control; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D006680:HLA Antigens / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D004854:Herpesvirus 4, Human; D006650:Histocompatibility Testing; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology*; D014764:Viral Proteins / Q000276:immunology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000956:Antigens, Viral; D006680:HLA Antigens; D007371:Interferon-gamma; D037181:Lectins, C-Type; D014764:Viral Proteins; D000099192:CD69 Antigens