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B-lymphocyte homeostasis and BLyS-directed immunotherapy in transplantation Parsons RF; Vivek K; Redfield RR 3rd; Migone TS; Cancro MP; Naji A; Noorchashm HTransplant Rev (Orlando) 2010[Oct]; 24 (4): 207-21Current 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.|Autoantigens/immunology[MESH]|B-Cell Activating Factor/*therapeutic use[MESH]|B-Lymphocytes/*immunology[MESH]|Graft Rejection/immunology/prevention & control[MESH]|Homeostasis[MESH]|Humans[MESH]|Immune Tolerance/immunology[MESH]|Immunotherapy/*methods[MESH]|Isoantibodies/immunology[MESH]|Isoantigens/immunology[MESH]|T-Lymphocytes/immunology[MESH]|Transplantation Immunology/*physiology[MESH] |
