B-lymphocyte homeostasis and BLyS-directed immunotherapy in transplantation

Ronald F. Parsons, Kumar Vivek, Robert R. Redfield, Thi Sau Migone, Michael P. Cancro, Ali Naji, Hooman Noorchashm

Research output: Contribution to journalReview article

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)207-221
Number of pages15
JournalTransplantation Reviews
Volume24
Issue number4
DOIs
StatePublished - Oct 1 2010
Externally publishedYes

ASJC Scopus subject areas

  • Transplantation

Fingerprint Dive into the research topics of 'B-lymphocyte homeostasis and BLyS-directed immunotherapy in transplantation'. Together they form a unique fingerprint.

  • Cite this

    Parsons, R. F., Vivek, K., Redfield, R. R., Migone, T. S., Cancro, M. P., Naji, A., & Noorchashm, H. (2010). B-lymphocyte homeostasis and BLyS-directed immunotherapy in transplantation. Transplantation Reviews, 24(4), 207-221. https://doi.org/10.1016/j.trre.2010.05.004