Depletion of B cells rejuvenates the peripheral B-cell compartment but is insufficient to restore immune competence in aging

Irit Avivi, Simona Zisman-Rozen, Shulamit Naor, Isabelle Dai, David Benhamou, Gitit Shahaf, Hilla Tabibian-Keissar, Noemie Rosenthal, Aviya Rakovsky, Ammuri Hanna, Arik Shechter, Eli Peled, Noam Benyamini, Ekaterina Dmitrukha, Iris Barshack, Ramit Mehr, Doron Melamed

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Aging is associated with increasing prevalence and severity of infections caused by a decline in bone marrow (BM) lymphopoiesis and reduced B-cell repertoire diversity. The current study proposes a strategy to enhance immune responsiveness in aged mice and humans, through rejuvenation of the B lineage upon B-cell depletion. We used hCD20Tg mice to deplete peripheral B cells in old and young mice, analyzing B-cell subsets, repertoire and cellular functions in vitro, and immune responsiveness in vivo. Additionally, elderly patients, previously treated with rituximab healthy elderly and young individuals, were vaccinated against hepatitis B (HBV) after undergoing a detailed analysis for B-cell compartments. B-cell depletion in old mice resulted in rejuvenated B-cell population that was derived from de novo synthesis in the bone marrow. The rejuvenated B cells exhibited a "young"-like repertoire and cellular responsiveness to immune stimuli in vitro. Yet, mice treated with B-cell depletion did not mount enhanced antibody responses to immunization in vivo, nor did they survive longer than control mice in "dirty" environment. Consistent with these results, peripheral B cells from elderly depleted patients showed a "young"-like repertoire, population dynamics, and cellular responsiveness to stimulus. Nevertheless, the response rate to HBV vaccination was similar between elderly depleted and nondepleted subjects, although antibody titers were higher in depleted patients. This study proposes a proof of principle to rejuvenate the peripheral B-cell compartment in aging, through B-cell depletion. Further studies are warranted in order to apply this approach for enhancing humoral immune responsiveness among the elderly population.

Original languageEnglish
Article numbere12959
JournalAging Cell
Volume18
Issue number4
Early online date6 May 2019
DOIs
StatePublished - Aug 2019

Bibliographical note

Publisher Copyright:
© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Funding

Foundation—FIRST program (grant no 1362/11), Wolens Gerontology Research Fund, the WEISZ FUND FOR GERONTOLOGY RESEARCH and the Colleck Research Fund (to DM); and a grant from the BIU‐Sheba joint research fund (to RM and IB). Dr. Gitit Lavy‐Shahaf was supported by a FLARE‐2 (Future Leaders in Aging Research in Europe) Postdoctoral Fellowship. Noemie Rosenthal's work was supported by a Grant from the Myers‐JDC‐Brookdale Institute of Gerontology and Human Development, and Eshel—The Israel Science Foundation ‐ FIRST program, Grant/Award Number: 1362/11; Wolens Gerontology Research Fund; WEISZ FUND FOR GERONTOLOGY RESEARCH; Colleck Research Fund; BIU‐Sheba joint research fund; FLARE‐2 Post‐doctoral Fellowship; Myers‐JDC‐Brookdale Institute This work was supported by grants from the Israel Science This work was supported by grants from the Israel Science Foundation—FIRST program (grant no 1362/11), Wolens Gerontology Research Fund, the WEISZ FUND FOR GERONTOLOGY RESEARCH and the Colleck Research Fund (to DM); and a grant from the BIU-Sheba joint research fund (to RM and IB). Dr. Gitit Lavy-Shahaf was supported by a FLARE-2 (Future Leaders in Aging Research in Europe) Postdoctoral Fellowship. Noemie Rosenthal's work was supported by a Grant from the Myers-JDC-Brookdale Institute of Gerontology and Human Development, and Eshel—The Association for the Planning and Development of Services for the Aged in Israel.

FundersFunder number
Colleck Research fund
Israel Science
Israel Science Foundation ‐ FIRST1362/11
Myers‐JDC‐Brookdale Institute of Gerontology and Human Development
Wolens Gerontology Research Fund
Myers-JDC-Brookdale Institute
Israel Science Foundation

    Keywords

    • B cell depletion
    • B cell rejuvenation
    • B cell repertoire
    • aging
    • immunity and severity
    • infections prevalence

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