title: Reversing endogenous alloreactive B cell GC responses with anti-CD154 or CTLA-4Ig.
abstract: Alloantibodies mediate acute antibody-mediated rejection as well as chronic allograft rejection in clinical transplantation. To better understand the cellular dynamics driving antibody production, we focused on the activation and differentiation of alloreactive B cells in the draining lymph nodes and spleen following sensitization to allogeneic cells or hearts. We used a modified staining approach with a single MHC Class I tetramer (K(d)) bound to two different fluorochromes to discriminate between the Class I-binding and fluorochrome-streptavidin-binding B cells with a high degree of specificity and binding efficiency. By Day 7-8 postsensitization, there was a 1.5- to 3.2-fold increase in the total numbers of K(d) -binding B cells. Within this K(d) -binding B cell population, approximately half were IgD(low) , MHC Class II(high) and CD86(+), 30-45% expressed a germinal center (Fas(+) GL7(+)) phenotype and 3-12% were IRF4(hi) plasma cells. Remarkably, blockade with anti-CD40 or CTLA-4Ig, starting on Day 7 postimmunization for 1 or 4 weeks, completely dissolved established GCs and halted further development of the alloantibody response. Thus MHC Class I tetramers can specifically track the in vivo fate of endogenous, Class I-specific B cells and was used to demonstrate the ability of delayed treatment with anti-CD154 or CTLA-4Ig to halt established allo-B cell responses.
authors.affiliation: Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: H
authors.initials: H
authors.lastname: Yin
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.forename: K L
authors.initials: KL
authors.lastname: Edelblum
authors.forename: R
authors.initials: R
authors.lastname: Sciammas
authors.forename: A S
authors.initials: AS
authors.lastname: Chong
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000276:immunology*; D018858:Germinal Center / Q000276:immunology*; D016027:Heart Transplantation; D007136:Immunoglobulins / Q000494:pharmacology; D007518:Isoantibodies / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D014184:Transplantation, Homologous
chemical_list: D060908:CTLA-4 Antigen; D007136:Immunoglobulins; D007518:Isoantibodies; D023201:CD40 Ligand
keywords: Allograft rejection; CTLA-4Ig; GC; MHC Class I tetramers; PCs; alloreactive B cells; anti-CD154