Transplants without Immunosuppressant Drugs: UCSF’s Transplant and Stem Cell Immunobiology Lab

Dr. Sonja Schrepfer Bio:

Sonja Schrepfer, M.D., Ph.D., Professor of Surgery, founded the Transplant and Stem Cell Immunobiology (TSI) Lab in 2009 in Germany. In 2015, she joined the faculty of the Department of Surgery at the University of California San Francisco and was Director of the TSI Lab at UCSF. Sonja is scientific co-founder of Sana Biotechnology Inc. which she joined as SVP in 2019.

Dr. Schrepfer’s research career has been dedicated to making fundamental discovers in transplant and stem cell immunobiology. Pluripotent stem cell (PSC)-based approaches are effective in immunosuppressed/deficient animal models; but in humans, systemic immunosuppression cannot be justified, due to severe side effects and significant risk of infections and malignancies. So far, only a few immunological strategies have been proposed to overcome these hurdles. Work by Dr. Schrepfer is at the forefront of PSC immunobiology and paves the way for treatment of a wide range of diseases – from supporting functional recovery of failing myocardium to the derivation of other cell types to treat diabetes, blindness, cancer, lung, neurodegenerative, and related diseases. She spent many years examining in detail the fetomaternal interface for application to the envisioned cell therapy. Her work with one of the most antigenic phenotypes, antigen-presenting endothelial cells, demonstrates that hypo-immunogenic cells reliably evade immune rejection in allogeneic recipients that are entirely mismatched in their major histocompatibility complex profile, and further, these cells show long-term survival without immunosuppression in mice and humanized mice (published in Nature Biotechnology in 2019).

Sonja is currently Adjunct Professor at UCSF investigating the immunobiology in “tissue chips in space”; that is sending tissue chips to the international space station (ISS). She participated in three flight missions as collaborator and was the PI on the SpaceX16 mission (December 2019). This research will provide insight into what physiological effects time in outer space might have on astronauts, with potentially important implications for future longer-term missions, and has the possibility to open the door to fascinating new discoveries that could be used in earth-bound immunology research.

Dr. Tobias Deuse Bio:

Tobias Deuse, M.D. is a cardiac and heart and lung transplant surgeon internationally renowned for his pioneering work in the development of minimally-invasive techniques for mitral valve repair.

Dr. Deuse graduated the University of Stuttgart (Germany) in 1994 with a BS in Physics, and in 2000 earned an M.D. from University of Wuerzburg. Dr. Deuse thereafter received advanced training in cardiothoracic surgery at the University Hospital Munich-Grosshadern and University Heart Center Hamburg-Eppendorf. After obtaining his board certification in Germany in 2007 as a heart surgeon, Dr. Deuse completed a surgical fellowship in Lung and Heart-Lung Transplantation at Stanford and joined the UCSF faculty in 2015.

Dr. Deuse’s laboratory at UCSF is working on the immunobiology of pluripotent stem cells. To circumvent rejection, techniques such as somatic cell nucleus transfer (SCNT) into an enucleated oocyte (formation of a SCNT stem cell), fusion of a somatic cell with an embryonic stem cell (ESC; formation of a hybrid cell), and reprograming of somatic cells using certain transcription factors (induced PSCs, iPSCs) have been used. However, his work has shown that SCNT stem cells and iPSCs may have immune incompatibilities with the nucleus or cell donor, respectively, despite having identical nuclear DNA (published in Cell Stem Cell 2014). Further, he has demonstrated that mitochondrial (mt) DNA-encoded proteins as well as mtDNA mutations and genetic instability associated with reprograming and iPSC expansion can create minor antigens, producing rejection. His work also demonstrated that even autologous iPSC derivatives are not inherently immunologically inert for autologous transplantation (published in Nature Biotechnology in 2019). This has provided an important, promising avenue for selection of optimal stem cell therapeutics for future clinical applications ¾ via identifying the most compatible starter cell line and monitoring “near match” autologous iPSC products for mtDNA mutations and single nucleotide polymorphism (SNP) enrichments during the manufacturing process.

Director Sonja Schrepfer, M.D., Ph.D., and co-director Tobias Deuse, M.D., explain the lab’s research towards understanding and overcoming transplant rejection.

They touch on

• Why finding ways to reduce rejection and successfully find transplantation avenues that don’t require immunosuppression drugs is so important,
• How their research starts with pluripotent stems cells that must be differentiated and then transplanted, 
• Why using a patients’ specific stem cells still face rejection due to mitochondrial proteins that eventually form despite gene editing, and
• How the lab is working toward an “off the shelf” solution by altering proteins that trigger rejection and other means.

Dr. Schrepfer and Deuse run the Transplant and Stem Cell Immunobiology Lab (TSI) at the University of California in San Francisco and specialize in heart and lung transplant issues through CRISPR, gene editing,and stem cell therapy.

They begin by explaining the many complications a person taking immunosuppressant drugs faces and why their research seeks to address these issues and make for a safer system for patients.

Further, they explain that patient-tailored stem cell therapy approaches are not suitable for large populations for several reasons, including the frequent need to treat a patient almost immediately for heart damage or other similar issues.

They explain that while they can generate cardiac cells that don’t get rejected at first, these cells can develop mutant proteins that causes rejection later. They are following a couple of approaches to address the rejections including learning how fetuses survive the mother’s immune system.

A big leap forward for the lab was learning how to knock out the molecule that signaled to the immune system its foreignness through CRISPR: in other words, they are learning how to make these introduced cells silent to the immune system.

Finally, they describe their “off the shelf” goal of producing non-immunogenic cells ready for injection for a majority of patients and alternatively generating a hypo-immunogenic environment in the patient to prevent long-term rejection.

For more, see the lab’s web page at https://tsilab.ucsf.edu/

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