title: B-lymphocyte homeostasis and BLyS-directed immunotherapy in transplantation.
abstract: Current strategies for immunotherapy after transplantation are primarily T-lymphocyte directed and effectively abrogate acute rejection. However, the reality of chronic allograft rejection attests to the fact that transplantation tolerance remains an elusive goal. Donor-specific antibodies are considered the primary cause of chronic rejection. When naive, alloreactive B-cells encounter alloantigen and are activated, a resilient "sensitized" state, characterized by the presence of high-affinity antibody, is established. Here, we will delineate findings that support transient B-lymphocyte depletion therapy at the time of transplantation to preempt sensitization by eliminating alloreactive specificities from the recipient B-cell pool (ie, "repertoire remodeling"). Recent advances in our understanding of B-lymphocyte homeostasis provide novel targets for immunomodulation in transplantation. Specifically, the tumor necrosis factor-related cytokine BLyS is the dominant survival factor for "tolerance-susceptible" transitional and "preimmune" mature follicular B-cells. The transitional phenotype is the intermediate through which all newly formed B-cells pass before maturing into the follicular subset, which is responsible for mounting an alloantigen-specific antibody response. Systemic BLyS levels dictate the stringency of negative selection during peripheral B-cell repertoire development. Thus, targeting BLyS will likely provide an opportunity for repertoire-directed therapy to eliminate alloreactive B-cell specificities in transplant recipients, a requirement for the achievement of humoral tolerance and prevention of chronic rejection. In this review, the fundamentals of preimmune B-cell selection, homeostasis, and activation will be described. Furthermore, new and current B-lymphocyte-directed therapy for antibody-mediated rejection and the highly sensitized state will be discussed. Overall, our objective is to propose a rational approach for induction of humoral transplantation tolerance by remodeling the primary B-cell repertoire of the allograft recipient.
authors.affiliation: Harrison Department of Surgical Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Ronald F
authors.initials: RF
authors.lastname: Parsons
authors.forename: Kumar
authors.initials: K
authors.lastname: Vivek
authors.forename: Robert R
authors.initials: RR
authors.lastname: Redfield
authors.forename: Thi-Sau
authors.initials: TS
authors.lastname: Migone
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cancro
authors.forename: Ali
authors.initials: A
authors.lastname: Naji
authors.forename: Hooman
authors.initials: H
authors.lastname: Noorchashm
mesh_terms: D001324:Autoantigens / Q000276:immunology; D053264:B-Cell Activating Factor / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006706:Homeostasis; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D007518:Isoantibodies / Q000276:immunology; D007519:Isoantigens / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014181:Transplantation Immunology / Q000502:physiology*
chemical_list: D001324:Autoantigens; D053264:B-Cell Activating Factor; D007518:Isoantibodies; D007519:Isoantigens; C505719:TNFSF13B protein, human