טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentNaor Shulamit
SubjectB Cell Depletion Revives B Lymphopoiesis and Enhances
Immune Response in Aging
DepartmentDepartment of Medicine
Supervisor Professor Doron Melamed
Full Thesis textFull thesis text - English Version


Abstract

The immune system undergoes dramatic changes during aging. This is reflected by changes in the antibody repertoire, reduced responsiveness to vaccination as well as by increased autoimmunity. Studies have shown that B cell lymphopoiesis in the bone marrow is significantly reduced while long-lived memory B cells accumulate and pre-dominate the peripheral organs.

The mechanism underlining this alternation in the cellular compartment is unclear. There are two possible explanations for these changes: the long-lived peripheral B cells are selected as an adaptation to the poor B lymphopoiesis in the aged BM, or alternatively, B lymphopoiesis in the BM is depressed as an adaptation to the increase survival of peripheral B cells.

In the present study, we attempted to find whether a cross-talk mechanism exist between the progenitors B cells in the BM and the peripheral B cells and whether depletion of peripheral B cells reactive B lymphopoiesis in the BM and restored immune competence in aged mice.

In order to test whether B lymphopoiesis in aging is regulated by homeostatic demands that are set by B cells in the periphery we have used two different mouse models: BAFF-R Mx-cre and hCD20Tg mice. In both mouse models, immune-phenotyping of BM cells from aged treated mice (> 17 month) reveled reactivation of B lymphopoiesis compared to normal age-matched mice.

Importantly, analysis of BM hematopoietic progenitor reveled that B cell depletion expands CLP and MPP populations in old mice following treatment when compared to normal age-matched mice.

We next showed that B cell reconstitution after depletion originates from B lymphopoiesis in the BM and not from homeostatic proliferation of residual B cells.

Furthermore, our results indicated on a cross talk mechanism between the peripheral B cells and the progenitors B cells in the BM in which soluble factors within wild-type mice sera can repress lymphopoiesis in aged mice or stimulate lymphopoiesis in young mice.

More so, our results reveal that aged mice treated with anti-hCD20 antibodies developed a significantly increased antibody response to challenge with NP-CGG, compared to control non-treated age-matched mice. Furthermore, reconstituted B cells from treated aged mice had restored proliferation capacity, AID mRNA levels and the ability to secrete IgM and IgG antibodies in response to in-vitro stimulations.


Collectively, our results suggest that immune-senescence in the B lineage is reversible and that depletion of the long-lived peripheral B cells rejuvenates the B-lineage and enhances immune competence in aged mice.