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

• Published in: Blood Vol. 87; no. 11; pp. 4887 - 4893
• Main Authors: Gribben, John G., Guinan, Eva C., Boussiotis, Vassiliki A., Ke, Xiao-Yan, Linsley, Letitia, Sieff, Colin, Gray, Gary S., Freeman, Gordon J., Nadler, Lee M.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.06.1996; The Americain Society of Hematology
• Subjects: Abatacept; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Antigen Presentation - drug effects; Antigens, CD - physiology; Antigens, Differentiation - immunology; B7-1 Antigen - physiology; B7-2 Antigen; Biological and medical sciences; Bone marrow, stem cells transplantation. Graft versus host reaction; CD28 Antigens - physiology; Cells, Cultured; Clonal Anergy - drug effects; Clonal Anergy - physiology; CTLA-4 Antigen; Graft vs Host Disease - immunology; Graft vs Host Disease - therapy; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Humans; Immunoconjugates; Interleukin-2 - biosynthesis; Interleukin-2 - genetics; Interleukin-4 - biosynthesis; Interleukin-4 - genetics; Isoantigens - immunology; Lymphocyte Activation - drug effects; Lymphocyte Culture Test, Mixed; Medical sciences; Membrane Glycoproteins - physiology; RNA, Messenger - biosynthesis; T-Lymphocytes, Cytotoxic - immunology; Tissue and Organ Procurement; Tissue Donors; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Human; Immunopathology; Anergy; Ex vivo; T-Lymphocyte; Bone marrow; Helper cell; Graft; Graft versus host reaction; Cellular immunity; Pretreatment
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V87.11.4887.bloodjournal87114887

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 B7 family-mediated costimulation, but not of major histocompatibility complex recognition or adhesion, induces host alloantigen-specific anergy by reducing cytokine production below threshold levels necessary for common γ-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.