Detailseite
Projekt Druckansicht

Effekt der exogen applizierten Endothelialzellen in Thymusregeneration nach hämatopoietischer Stammzelltransplantation

Antragstellerin Dr. Hana Andrlova
Fachliche Zuordnung Hämatologie, Onkologie
Förderung Förderung von 2018 bis 2021
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 411447633
 
Erstellungsjahr 2022

Zusammenfassung der Projektergebnisse

Allo-HCT is a curative-intent therapy of numerous hematological malignancies. Despite advances in the field, the broader implementation of allo-HCT is limited by high rates of transplant-related complications, with 3-year overall mortality approaching 50% (41). The goal of my postdoctoral projects was to study immune reconstitution after allo-HCT, factors influencing the reconstitution of specific immune cell subsets and strategies to improve immune reconstitution and diminish the risk of relapse. In Aim 1, I was able to demonstrate a novel link between early post-transplantation gut microbiome and its metabolic activity and MAIT and Vd2 cell populations. I was also able to link their early reconstitution to a positive effect on allo-HCT outcomes, especially the GVHD development. Although the mechanism of protection remains not completely clear, I speculate that the upregulation of the proinflammatory and cytotoxic genes in microbiota-responsive populations could reflect a role for these populations in controlling pathogenenic bateria or cell populations. In Aim 2, I was able to demonstrate that genetic modification of precursor T cells with orthogonal interleukin 7 receptor and their consecutive stimulation with the corresponding orthogonal cytokine in vivo leads to improved thymic reconstitution early post-transplantation and higher CD4 and CD8 proportions in the lymph nodes compared to the precursor T cells without stimulation. I also showed that precursor T cells can be transduced with a CAR construct and migrate to the thymus when the CAR is not signaling. Further experiments are needed to develop genetically modified precursor T cells into a more potent booster of post-transplantation T cell immunity and mature, donor unrestricted CAR T cells fighting possible relapse after allo-HCT. I feel that my research has helped to gain some additional understanding of immune reconstitution and function and the factors influencing these processed, such as gut microbiome. I have also had a deeper insight in developing new cellular therapies to improve immune reconstitution and anti-tumor responses. I have extended my postdoctoral time in the van den Brink lab and am currently still working on the Aim 2 of the proposal.

Projektbezogene Publikationen (Auswahl)

 
 

Zusatzinformationen

Textvergrößerung und Kontrastanpassung