title: Host T cells resist graft-versus-host disease mediated by donor leukocyte infusions.
abstract: Delayed lymphocyte infusions (DLIs) are used to treat relapse occurring post bone marrow transplantation (BMT) and to increase the donor chimerism in recipients receiving nonmyeloablative conditioning. As compared with donor lymphocytes given early post-BMT, DLIs are associated with a reduced risk of graft-vs-host disease (GVHD). The mechanism(s) responsible for such resistance have remained incompletely defined. We now have observed that host T cells present 3 wk after lethal total body irradiation, at the time of DLI, contribute to DLI-GVHD resistance. The infusion of donor splenocytes on day 0, a time when host bone marrow (BM)-derived T cells are absent, results in greater expansion than later post-BMT when host and donor BM-derived T cells coexist. Selective depletion of host T cells with anti-Thy1 allelic mAb increased the GVHD risk of DLI, indicating that a Thy1(+) host T cell regulated DLI-GVHD lethality. The conditions by which host T cells are required for optimal DLI resistance were determined. Recipients unable to express CD28 or 4-1BB were as susceptible to DLI-GVHD as anti-Thy1 allelic mAb-treated recipients, indicating that CD28 and 4-1BB are critical to DLI-GVHD resistance. Recipients deficient in both perforin and Fas ligand but not individually were highly susceptible to DLI-GVHD. Recipients that cannot produce IFN-gamma were more susceptible to DLI-GVHD, whereas those deficient in IL-12 or p55 TNFRI were not. Collectively, these data indicate that host T cells, which are capable of generating antidonor CTL effector cells, are responsible for the impaired ability of DLI to induce GVHD. These same mechanisms may limit the efficacy of DLI in cancer therapy under some conditions.
authors.affiliation: University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, Minneapolis, MN 55455, USA. blaza001@maroon.tc.umn.edu
authors.forename: B R
authors.initials: BR
authors.lastname: Blazar
authors.forename: C J
authors.initials: CJ
authors.lastname: Lees
authors.forename: P J
authors.initials: PJ
authors.lastname: Martin
authors.forename: R J
authors.initials: RJ
authors.lastname: Noelle
authors.forename: B
authors.initials: B
authors.lastname: Kwon
authors.forename: W
authors.initials: W
authors.lastname: Murphy
authors.forename: P A
authors.initials: PA
authors.lastname: Taylor
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D016026:Bone Marrow Transplantation / Q000276:immunology; D018106:CD28 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D053222:Fas Ligand Protein; D017353:Gene Deletion; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000502:physiology; D017708:Leukocyte Transfusion / Q000009:adverse effects; D008212:Lymphocyte Depletion; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011828:Radiation Chimera / Q000276:immunology; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
chemical_list: D015703:Antigens, CD; D018106:CD28 Antigens; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D054353:Perforin; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma