It takes two – immune evasion in kidney organoid transplantation

Professor Ton Rabelink, Netherlands Node Director

Researchers from the lab of reNEW PI Ton Rabelink have discovered in collaboration with Arnaud Zaldumbide (LUMC) that knockout of HLA class 1 by itself is insufficient to protect transplanted kidney organoids from T-cell mediated rejection. The results, published in Stem Cells Translational Medicine, are a next step towards the generation of iPSC-derived kidney tissue that can evade the immune system.

Transplant rejection by the immune system is a major hurdle to bring stem cell therapies to the clinic. To overcome this challenge, the researchers here aimed to generate stealth kidney organoids that are able to evade the immune system after transplantation. To this end, they generated a hiPSC line deficient of HLA class 1. HLA class 1 are surface molecules specialized to present antigenic peptides from within cells to T cells of the immune system. In the context of transplantation, they can thereby activate T-cells of the recipient’s immune system by presenting foreign peptides from donor tissue. By preventing this interaction, immune recognition and subsequent rejection could potentially be blocked.

The kidney organoids derived from these iPSCs without HLA class 1 were protected from T cell reactivity in vitro. However, upon transplantation in a mouse model with a human immune system, the researchers found to their surprise that the organoids lacking HLA class 1 were rejected in a similar manner as control organoids. Lonneke Gaykema, first author of the paper: “The transplanted kidney organoids upregulated HLA class 2. This HLA class is mostly limited to antigen presenting cells, but it turned out that it is also present at low levels in our organoids before transplantation. The results suggest there is a need to modulate not only HLA class 1 but also HLA class 2 to prevent rejection of the organoids”.

The study is a new step towards the mission of reNEW to bring stem cell based therapies to the clinic. Cathelijne van den Berg, reNEW Leiden AI concludes: “Stealth hiPSC lines hold great promise to generate new stem cell therapies that are available off-the-shelf, thereby making this new generation of therapies available to society. The present study provides new insights for future research to achieve this goal.”

Read the full story here: T-Cell Mediated Immune Rejection of Beta-2-Microglobulin Knockout Induced Pluripotent Stem Cell-Derived Kidney Organoids | Stem Cells Translational Medicine | Oxford Academic (oup.com)

Ton Rabelink is reNEW PI at the Leiden University Medical Center and director of the reNEW Leiden Node. His work focuses on developing stem cell based therapies that offer a lifelong cure to patients with kidney failure.

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