title: Immune reconstitution in recipients of photodepleted HLA-identical sibling donor stem cell transplantations: T cell subset frequencies predict outcome.
abstract: We evaluated an ex vivo photodepletion (PD) technique to selectively deplete graft-versus-host disease (GVHD) alloreacting T cells given to 24 human leukocyte antigen (HLA)-identical sibling stem cell transplantation (SCT) recipients. Donor lymphocytes were activated by 72-hour exposure to irradiated in vitro expanded recipient T lymphocytes and pulsed with a TH9402 photosensitizer. Alloactivated T cells preferentially retaining the photosensitizer were eliminated by light exposure. The PD product showed an inverted CD4(+)/CD8(+) ratio with greatest depletion occurring in the CD4(+) naive and central memory populations. In contrast, the CD8(+) naive and effector cells were relatively conserved, reflecting the differential extrusion of TH9402 by T cell subsets. Cytomegalovirus reactive T cells were reduced in the PD product and in recipient blood 100 days after SCT when compared with contemporaneous HLA-identical sibling donor T cell-depleted SCT recipients. Although PD SCT recipients experienced similar absolute lymphocyte counts during the first 100 days after SCT, they achieved 100% donor T cell chimerism more rapidly and had higher CD8(+) naive T cell counts early after SCT. SCT recipients of PD products with the lowest CD4 central memory content had the highest risk of developing chronic GVHD (cGVHD) (P = .04) and a poorer survival (P = .03). Although the persistence of CD8(+) naive T cells may have contributed to important antileukemia responses resulting in a relatively low relapse rate, our findings emphasize the role of donor memory T cells and CD4 cells in establishing immune competence post-SCT. Although PD is associated with excellent outcomes in the haploidentical setting, the low frequency of alloactivations in HLA-matched pairs makes the PD approach used by our group for allodepletion in HLA-matched sibling transplantations an inefficient technique.
authors.affiliation: Allotransplantation Section, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. mciverza@nhlbi.nih.gov
authors.forename: Zachariah A
authors.initials: ZA
authors.lastname: McIver
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Melenhorst
authors.forename: Andrew
authors.initials: A
authors.lastname: Grim
authors.forename: Nicholas
authors.initials: N
authors.lastname: Naguib
authors.forename: Gerrit
authors.initials: G
authors.lastname: Weber
authors.forename: Vicki
authors.initials: V
authors.lastname: Fellowes
authors.forename: Hahn
authors.initials: H
authors.lastname: Khuu
authors.forename: David S
authors.initials: DS
authors.lastname: Stroncek
authors.forename: Susan F
authors.initials: SF
authors.lastname: Leitman
authors.forename: Minoo
authors.initials: M
authors.lastname: Battiwalla
authors.forename: A John
authors.initials: AJ
authors.lastname: Barrett
mesh_terms: D016516:CD4-CD8 Ratio; D005260:Female; D006680:HLA Antigens / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D008212:Lymphocyte Depletion / Q000379:methods*; D008297:Male; D017319:Photosensitizing Agents / Q000627:therapeutic use*; D012235:Rhodamines / Q000627:therapeutic use*; D035781:Siblings; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014019:Tissue Donors; D016896:Treatment Outcome
chemical_list: D006680:HLA Antigens; D017319:Photosensitizing Agents; D012235:Rhodamines; C121365:4,5-dibromorhodamine 123