Schmied, Laurent. Killer cell immunoglobulin-like receptors (KIR), licensing and ectosomes in the regulation of natural killer cell function : clinical implications and perspectives. 2016, PhD Thesis, University of Basel, Faculty of Science.
Restricted to Repository staff only until 30 January 2018.
Official URL: http://edoc.unibas.ch/diss/DissB_12008
A unique opportunity to study NK cell licensing is provided during the first months after hematopoietic stem cell transplantation when the NK cell repertoire is rebuilt. Previous studies found that leukemia patients receiving hematopoietic stem cell transplantation (HSCT) from a haploidentical donor, benefit from a survival advantage if KIR ligands are mismatched and NK cell tolerance is irreversibly broken. Recent studies reported controversial findings concerning a survival advantage and NK cell mediated graft versus leukemia effect (GVL) as a consequence of disturbed NK cell licensing early after HSCT, when NK cells are unselectively equipped with functional capacity. Differences in allogeneic HSCT protocols were discussed as possible reason for the opposing results. We investigated reconstitution of NK cell function and NK cell licensing in 56 patients receiving allogeneic (33) or autologous (23) HSCT during the first six months after transplantation. We found that NK cell licensing was maintained after both kinds of transplantation. However licensing effects were less distinct after allogenic compared to autologous HSCT. Additionally, we identified GvHD and pre-transplant ATG administration as variables associated with less prominent licensing in recipients of allogeneic grafts.
Whereas research on inhibitory KIR and NK cell licensing has already influenced treatment modalities of HSCT, much less is known about activating KIR receptors. Ligands to many activating KIR remain unidentified and little is known in which diseases activating KIR may play a role. Recent studies in our lab and elsewhere described associations between KIR genotypes and relative protection from cytomegalovirus (CMV) replication after solid organ transplantation (SOT) and HSCT. We prospectively followed a cohort of 649 patients after SOT, assessed the KIR genotype and recorded common opportunistic viral infections. Subsequent analyses of our data revealed an association of KIR B haplotypes, which encompass many activating KIR, and relative protection from varicella zoster virus (VZV) and a tendency for relative protection from Epstein-Barr virus (EBV) replication. In subsequent analyses we found that centromeric rather than telomeric activating KIR protect from VZV. In contrast, we detected no association between activating KIR genotype and BK polyomavirus (BKPyV) or Herpes simplex (HSV) replication.
Besides intrinsic factors such as licensing or expression of activating KIR, extrinsic factors determine antitumor and antiviral activity of NK cells. Early after HSCT when NK cell driven GVL is assumed most effective, prophylactic immunosuppression is given and cellular products are administered including erythrocytes (ERY) and platelets (PLT). During storage, blood products release ectosomes. PLT ectosomes can reduce monocyte and dendritic cell function. Furthermore, they favour differentiation of naïve T-cells into T-regulatory cells. However, little is known about their interaction with NK cells. We assessed phenotypical and functional changes on NK cells after co-incubation with PLT ectosomes in vitro, and found a reduction of NK cell function and activating surface receptors, mediated through TGF-β on PLT ectosomes.
|Advisors:||Palmer, Ed and Stern, Martin and Spagnoli, Giulio|
|Faculties and Departments:||03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Nephrologie > Exp. Transplantationsimmunologie und Nephrologie (Palmer)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||1 Online-Ressource (125 Seiten)|
|Last Modified:||13 Feb 2017 10:11|
|Deposited On:||13 Feb 2017 10:11|
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