Schoen, C. | Search bioRxiv

bioRxiv2025

MDSC depletion during immunization with heat-killed Mycobacterium tuberculosis increases protection against BCG infection.

Tuberculosis (TB) is still one of the deadliest infectious diseases globally. Although i.d. BCG immunization offers limited protection, a vaccine based on Mycobacterium tuberculosis (Mtb) has yet to be approved. Our previous findings demonstrated that s.c. immunization with heat-killed Mtb significantly increased the number of monocytic myeloid-derived suppressor cells (M-MDSC) in mice. Therefore, we hypothesized that the defense against a subsequent BCG infection would be impaired in Mtb-immunized mice. Surprisingly, mice vaccinated with Mtb were protected against a BCG infection and showed elevated frequencies and activation of DC and mycobacteria-specific T cells despite high frequencies and suppressor activity of M-MDSC. Genetic ablation of CCR2+ monocytic cells or pharmacological intervention with all-trans retinoic acid (ATRA) reduced the frequency of Mtb-induced M-MDSC, enhanced frequencies, and activation of dendritic cells (DC) and CD4+ T cells, and resulted in decreased bacterial loads in the lung and spleen. These findings offer fresh perspectives on TB vaccination using heat-killed Mtb despite parallel unwanted vaccine-induced M-MDSC. M-MDSC depletion by ATRA further tips the balance towards immunity and should be considered an adjunct host-directed therapy with TB vaccines in humans.

immunology↗

bioRxiv2021

Human stem cell-based retina-on-chip as new translational model for validation of AAV retinal gene therapy vectors

Gene therapies using adeno-associated viruses (AAVs) are amongst the most promising strategies to treat or even cure hereditary and acquired retinal diseases. However, the development of new efficient AAV vectors is slow and costly, largely because of the lack of suitable non-clinical models. By faithfully recreating structure and function of human tissues, human induced pluripotent stem cell (iPSC)-derived retinal organoids could become an essential part of the test cascade addressing translational aspects. Organ-on-Chip (OoC) technology further provides the capability to recapitulate microphysiological tissue environments as well as a precise control over structural and temporal parameters. By employing our recently developed Retina-on-chip that merges organoid and OoC-technology, we analyzed the efficacy, kinetics and cell tropism of seven first and second generation AAV vectors. The presented data demonstrate the potential of iPSC-based OoC models as the next generation of screening platforms for future gene therapeutic studies.

bioengineering↗