title: Targeted pretransplant host lymphocyte depletion prior to T-cell depleted reduced-intensity allogeneic stem cell transplantation.
abstract: Mixed chimaerism and graft rejection are higher after reduced-intensity allogeneic stem cell transplantation (RIST) with T-cell depleted (TCD) allografts. As host immune status before RIST affects engraftment, we hypothesized that targeted depletion of host lymphocytes prior to RIST would abrogate graft rejection and promote donor chimaerism. Lymphocyte-depleting chemotherapy was administered at conventional doses to subjects prior to RIST with the intent of decreasing CD4(+) counts to <0.05 x 10(9)cells/l. Subjects (n = 18) then received reduced-intensity conditioning followed by ex vivo TCD human leucocyte antigen-matched sibling allografts. All evaluable patients (n = 17) were engrafted; there were no late graft failures. At day +28 post-RIST, 12 patients showed complete donor chimaerism. Mixed chimaerism in the remaining five patients was associated with higher numbers of circulating host CD3(+) cells (P = 0.0032) after lymphocyte-depleting chemotherapy and was preferentially observed in T lymphoid rather than myeloid cells. Full donor chimaerism was achieved in all patients after planned donor lymphocyte infusions. These data reflect the importance of host immune status prior to RIST and suggest that targeted host lymphocyte depletion facilitates the engraftment of TCD allografts. Targeted lymphocyte depletion may permit an individualized approach to conditioning based on host immune status prior to RIST.
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. mbishop@mail.nih.gov
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bishop
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Gress
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Hardy
authors.forename: Donna
authors.initials: D
authors.lastname: Marchigiani
authors.forename: Claude
authors.initials: C
authors.lastname: Kasten-Sportes
authors.forename: Robert
authors.initials: R
authors.lastname: Dean
authors.forename: Steven Z
authors.initials: SZ
authors.lastname: Pavletic
authors.forename: Juan
authors.initials: J
authors.lastname: Gea-Banacloche
authors.forename: Kathleen
authors.initials: K
authors.lastname: Castro
authors.forename: Fran
authors.initials: F
authors.lastname: Hakim
authors.forename: Michael
authors.initials: M
authors.lastname: Krumlauf
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Read
authors.forename: Charles
authors.initials: C
authors.lastname: Carter
authors.forename: Susan F
authors.initials: SF
authors.lastname: Leitman
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Fowler
mesh_terms: D000328:Adult; D018952:Antigens, CD34 / Q000032:analysis; D001943:Breast Neoplasms / Q000628:therapy*; D018791:CD4 Lymphocyte Count; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000517:prevention & control; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D008212:Lymphocyte Depletion / Q000379:methods*; D017710:Lymphocyte Transfusion; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology*; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods
chemical_list: D018952:Antigens, CD34