Detection of a novel specificity (CTLA-4) in ATG/TMG globulins and sera from ATG-treated leukemic patients

• Published in: Transplantation Vol. 73; no. 8; p. 1295
• Main Authors: Pistillo, Maria Pia, Tazzari, Pier Luigi, Bonifazi, Francesca, Bandini, Giuseppe, Kato, Tomohiro, Matsui, Toshihiro, Nishioka, Kusuki, Conte, Roberto, Ferrara, Giovanni Battista
• Format: Journal Article
• Language: English
• Published: United States 27.04.2002
• Subjects: Abatacept; Animals; Antibody Specificity; Antigens, CD - immunology; Antigens, Differentiation - immunology; Antilymphocyte Serum - therapeutic use; B7-1 Antigen - immunology; B7-2 Antigen; CD28 Antigens - immunology; CTLA-4 Antigen; Hematologic Neoplasms - blood; Hematologic Neoplasms - immunology; Hematologic Neoplasms - therapy; Hematopoietic Stem Cell Transplantation; Humans; Immunoconjugates; Immunoglobulin Fc Fragments - immunology; Immunosuppressive Agents - immunology; Immunosuppressive Agents - therapeutic use; Membrane Glycoproteins - immunology; Mice; Multiple Myeloma - immunology; Recombinant Fusion Proteins - immunology; Recombinant Proteins - immunology; T-Lymphocytes - immunology; Thymus Gland - immunology; Tumor Cells, Cultured
• ISSN: 0041-1337; 1534-6080
• DOI: 10.1097/00007890-200204270-00019

T-cell costimulation has been shown to provide positive signals for T-cell activation and generation of effector activity. In this study, we analyzed the presence of antibodies (Abs) against the T-lymphocyte costimulatory molecules CD28, CTLA-4, CD80, and CD86 in anti-T-lymphocyte (ATG) and antithymocyte (TMG) globulin preparations to address their mechanism of action. We focused our attention on the role of CTLA-4-specific Abs in the immunosuppressive effect of ATG/TMG, because anti-CTLA-4 agonistic Abs may suppress T-cell proliferation and nonagonistic Abs may lead to T-cell depletion through an Ab-dependent cell cytotoxicity mechanism. ATG/TMG and patients' sera were tested for binding to recombinant human costimulatory molecules by ELISA techniques. CTLA-4 specificity was also analyzed by cytoplasmic immunofluorescence staining of a CTLA-4 transfectant by competitive inhibition immunofluorescence and by cell proliferation assay in allogeneic mixed lymphocyte reaction (MLR). Either ATG or TMG predominantly contained anti-CTLA-4 Abs, with higher reactivity in ATG followed by anti-CD86 and -CD28 Abs, whereas anti-CD80 Abs were found only in ATG. Anti-CTLA-4 Abs present in ATG/TMG recognized the native form of CTLA-4 molecule, and their removal reduced the effect of ATG in an allogeneic MLR. Kinetic studies indicated that such Abs were present in the sera of 12 ATG-treated leukemic patients up to 21 days after ATG administration. These data suggest that the novel anti-CTLA-4 Abs found in ATG may greatly contribute to its immunosuppressive effect, thus accounting for the absence of rejection and exceptionally low incidence of graft-versus-host disease in the group of patients analyzed.