title: Immunomodulatory effects induced by cytotoxic T lymphocyte antigen 4 immunoglobulin with donor peripheral blood mononuclear cell infusion in canine major histocompatibility complex-haplo-identical non-myeloablative hematopoietic cell transplantation.
abstract: BACKGROUND AIMS. Previously, cytotoxic T lymphocyte antigen 4 (CTLA4) immunoglobulin (Ig) has been shown to allow sustained engraftment in dog leukocyte antigen (DLA)-identical hematopoietic cell transplant (HCT) after non-myeloablative conditioning with 100 cGy total body irradiation (TBI). In the current study, we investigated the efficacy of pre-transplant CTLA4-Ig in promoting engraftment across a DLA-mismatched barrier after non-myeloablative conditioning. METHODS. Eight dogs were treated with CTLA4-Ig and donor peripheral blood mononuclear cells (PBMC) prior to receiving 200 cGy TBI followed by transplantation of granulocyte-colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells from DLA haplo-identical littermates with post-grafting immunosuppression. A control group of six dogs was conditioned with 200 cGy only and transplanted with grafts from DLA haplo-identical littermates followed by post-grafting immunosuppression. RESULTS. In vitro and in vivo donor-specific hyporesponsiveness was demonstrated on day 0 before TBI in eight dogs that received CTLA4-Ig combined with donor PBMC infusions. Four of five dogs treated with increased doses of CTLA4-Ig achieved initial engraftment but eventually rejected, with a duration of mixed chimerism ranging from 12 to 22 weeks. CTLA4-Ig did not show any effect on host natural killer (NK) cell function in vitro or in vivo. No graft-versus-host disease (GvHD) was observed in dogs receiving CTLA4-Ig treatment. CONCLUSIONS. Non-myeloablative conditioning with 200 cGy TBI and CTLA4-Ig combined with donor PBMC infusion was able to overcome the T-cell barrier to achieve initial engraftment without GvHD in dogs receiving DLA haplo-identical grafts. However, rejection eventually occurred; we hypothesize because of the inability of CTLA4-Ig to abate natural killer cell function.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center ,  Seattle, Washington ,  USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Chen
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fukuda
authors.forename: Monica S
authors.initials: MS
authors.lastname: Thakar
authors.forename: Brian T
authors.initials: BT
authors.lastname: Kornblit
authors.forename: Barry E
authors.initials: BE
authors.lastname: Storer
authors.forename: Erlinda B
authors.initials: EB
authors.lastname: Santos
authors.forename: Rainer
authors.initials: R
authors.lastname: Storb
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Sandmaier
mesh_terms: D000069594:Abatacept; D000818:Animals; D046528:Chimerism / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006649:Histocompatibility Antigens / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000009:adverse effects; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000637:transplantation; D011300:Preoperative Care; D014019:Tissue Donors; D014916:Whole-Body Irradiation
chemical_list: D006649:Histocompatibility Antigens; D018796:Immunoconjugates; D000069594:Abatacept