title: Complete blockade of B7 family-mediated costimulation is necessary to induce human alloantigen-specific anergy: a method to ameliorate graft-versus-host disease and extend the donor pool.
abstract: Graft-versus-host disease (GVHD) is initiated by adoptively transferred donor T cells that recognize host alloantigens. Whereas the absence of donor T-cell proliferation to host alloantigens in a mixed-leukocyte reaction does not predict freedom from GVHD, the frequency of alloreactive precursor helper T lymphocytes (pHTL) is predictive. Complete blockade of 87 family-mediated costimulation, but not of major histocompatibility complex recognition or adhesion, induces host alloantigenic-specific energy by reducing cytokine production below threshold levels necessary for common gamma chain signaling. The associated reduction of alloreactive pHTL frequency below that predictive for GVHD, without depletion of either nonallospecific T cells or hematopoietic progenitors, has led us to embark upon human clinical trials of haplomismatched allogeneic bone marrow transplantation.
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Gribben
authors.forename: E C
authors.initials: EC
authors.lastname: Guinan
authors.forename: V A
authors.initials: VA
authors.lastname: Boussiotis
authors.forename: X Y
authors.initials: XY
authors.lastname: Ke
authors.forename: L
authors.initials: L
authors.lastname: Linsley
authors.forename: C
authors.initials: C
authors.lastname: Sieff
authors.forename: G S
authors.initials: GS
authors.lastname: Gray
authors.forename: G J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: L M
authors.initials: LM
authors.lastname: Nadler
mesh_terms: D000069594:Abatacept; D017951:Antigen Presentation / Q000187:drug effects*; D015703:Antigens, CD / Q000502:physiology*; D000943:Antigens, Differentiation / Q000276:immunology; D018122:B7-1 Antigen / Q000502:physiology*; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000502:physiology*; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000187:drug effects / Q000502:physiology*; D006086:Graft vs Host Disease / Q000276:immunology / Q000628:therapy*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D018796:Immunoconjugates; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014019:Tissue Donors; D009927:Tissue and Organ Procurement
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007376:Interleukin-2; D007519:Isoantigens; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D015847:Interleukin-4; D000069594:Abatacept