title: Strategies to inhibit alloantibody production in alloprimed murine recipients of hematopoietic stem cell grafts.
abstract: Alloantibody, not primed T cells, is the major barrier to bone marrow (BM) engraftment in allosensitized mice. We have shown that a single intravenous injection of donor splenocytes, to mimic a blood transfusion, results in high, sustained levels of serum alloantibody sufficient to eliminate donor BM within 3 h, resulting in uniform mortality in lethally irradiated allogeneic recipients. Current studies focused preventing and treating allopriming. Blockade of B cell survival signals with mTACI-Ig pre- and postpriming was ineffective, as was the B cell but not plasma cell depleting anti-CD20 mAb. Germinal center formation inhibition by lymphotoxin-beta receptor-Ig (LβR-Ig) diminished allosensitization, although conditional Prmd1 (Blimp-1) deletion in CD19+ cells was highly effective. By combining anti-CD20 mAb to reduce B cells and LTβR-Ig to diminish the frequency of B cells that could form germinal centers pre- and postpriming, allosensitization was precluded, permitting long-term survival in T- and NK-depleted, irradiated allogeneic recipients, whereas combined therapy postpriming alone was ineffective. As evidence of the critical role of B cells, the proteosomal inhibitor, bortezomib, given unencapsulated or encapsulated, proved ineffective in influencing allosensitization. These data extend our understanding of allopriming and provide a potential therapy for patients at risk for allosensitization and BM graft rejection.
authors.affiliation: Division of Blood and Marrow Transplantation, University of MN, Masonic Cancer, Center and Department of Pediatrics, Minneapolis, MN.
authors.forename: B R
authors.initials: BR
authors.lastname: Blazar
authors.forename: R
authors.initials: R
authors.lastname: Flynn
authors.forename: R
authors.initials: R
authors.lastname: Lee
authors.forename: G
authors.initials: G
authors.lastname: Marcucci
authors.forename: M A
authors.initials: MA
authors.lastname: Caliguiri
authors.forename: P S
authors.initials: PS
authors.lastname: Heeger
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D018941:Antigens, CD19 / Q000276:immunology; D018951:Antigens, CD20 / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D007074:Immunoglobulin G / Q000276:immunology; D007518:Isoantibodies / Q000096:biosynthesis*; D053259:Lymphotoxin beta Receptor / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D000074462:Positive Regulatory Domain I-Binding Factor 1; D014157:Transcription Factors / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D018951:Antigens, CD20; D007074:Immunoglobulin G; D007518:Isoantibodies; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; C513258:Prdm1 protein, mouse; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1
keywords: B cell biology; alloantibody; basic (laboratory) research / science; bone marrow / hematopoietic stem cell transplantation; donor-specific transfusion / antigen delivery; fusion proteins and monoclonal antibodies; immunosuppressant; immunosuppression / immune modulation; rejection: antibody-mediated (ABMR); translational research / science