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The potential (therapeutic) role of BAFF, FLT3L and IL-2 in immune disorders

Kreuzaler, Matthias. The potential (therapeutic) role of BAFF, FLT3L and IL-2 in immune disorders. 2013, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10512

Abstract

The TNF family member protein BAFF/BLyS is essential for B cell survival. In humans, increased
concentrations of soluble BAFF are found during different pathological conditions, which may be as
diverse as autoimmune diseases, B cell malignancies, and primary Ab deficiencies (PAD). We have
developed a sensitive ELISA for soluble human BAFF, which allows us to study some parameters that
might determine the level of soluble BAFF in circulation. We show that, patients suffering from PAD
including severe functional B cell defects, such as BTK‐, BAFF‐R‐, or TACI‐deficiencies, were all found
to have higher BAFF levels in their blood than asplenic individuals, patients having undergone anti‐
CD20 B cell depletion, chronic lymphocytic leukemia patients, or healthy blood donors. In a
comparable manner, transgenic mice constitutively expressing soluble human BAFF were found to
have higher concentrations of circulating human BAFF in the absence of B cells. Therefore, our data
strongly suggest that the steady‐state concentration of BAFF mainly depends on the number of B
cells present as well as on the expression of BAFF‐binding receptors. Because most patients with PAD
have high levels of circulating BAFF, the increase in BAFF concentrations cannot compensate for the
defects in B cell development and function.
In a second study, we showed that treatment of mice with the fms‐like tyrosine kinase ligand (FLT3L)
as well as with an IL‐2/αIL‐2 mAb complex (JES6‐1A12, S4B6) led to an expansion of the Treg
compartment. We show that this increased number of NTregs is due to proliferation of pre‐existing
NTregs, likely due to favored interactions with the increased number of DCs. The increase of NTregs
in the IL‐2/αIL‐2 complex treated mice is due to a direct effect of IL‐2 signaling. Thus the lifespan and
availability of the IL‐2 molecules is prolonged due to the complex with the mAb and therefore
stronger/longer signals via the IL‐2R can be achieved. We investigated the potential of FLT3L and IL‐
2/αIL‐2 pretreatment of mice and could show that administration of FLT3L could prevent death
induced by an acute GvHD in BDF1 mice. However, when we used a different mouse strain,
(BM1xBM12)F1, no protection could be observed, even though the Treg cells increase in these mice
was similar to the one in BDF1 mice. By depleting the NK cell compartment of acute GvHD mice, we
could show that NTregs themselves are not protective in this system.
In a third study, the potential use of FLT3L and IL‐2/αIL‐2 complex (JES6‐1A12) pre‐treated recipients
of solid allografts were investigated. To test whether Flt3L treatment was effective in prolonging
allograft survival we used the transplant model where the tail skin from a BM12 mouse was
transferred to the trunk of B6 mice. An IL‐2/αIL‐2 complex pre‐treatment, previously shown to be
highly effective in a pancreatic islet allograft transplant model, was used as a control. All PBS treated
B6 mice rejected the graft within 12 days, the IL‐2/αIL‐2 treated mice kept their allografts for a
maximum of 70 days +/‐ 5 days. In the FLT3L treated group, 12,5% of the mice rejected the graft with
similar kinetics as the PBS treated mice. 62,5% of the mice showed a delayed rejection of the graft by
4‐14 days. Only 25% of recipient mice had a graft survival similar to the IL‐2/αIL‐2 treated mice.
Reducing the numbers of Tregs in FLT3L treated mice by a αCD25 mAb injection resulted in a graft
survival time similar to that observed in PBS treated mice suggesting that the FLT3L induced
prolonged graft survival was due to increased numbers of Tregs.
Taken together these findings indicate that FLT3L treatment could be a possible prophylactic therapy
for preventing solid organ rejection.
Advisors:Rolink, Antonius G.
Committee Members:Palmer, Ed
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Further Research Groups at DBM > Developmental and Molecular Immunology (Rolink)
Item Type:Thesis
Thesis no:10512
Bibsysno:Link to catalogue
Number of Pages:134 Bl.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:53
Deposited On:16 Oct 2013 15:23

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