Researchers Achieve Transplantation Tolerance in Mouse Models

One of the most challenging aspects of organ transplantation is that the immune system often targets and attacks foreign tissue, often resulting in organ rejection. Numerous drugs are on the market to combat these effects, but many induce severe side effects and risks of infection. That’s why researchers at the University of Chicago decided to investigate how to boost transplantation tolerance in mouse models, hoping their results could improve human transplant survival.

This study, recently published in the Proceedings of the National Academy of Sciences, revealed that the T cells in mouse models were more susceptible to suppression by regulatory T cells because they downregulate a critical transcription factor expression. The mice in their experiments were provided with a short-term treatment called “co-stimulation blockade,” which allowed them to accept a heart transplant successfully without using immunosuppression drugs. 

“If we can achieve transplantation tolerance in mice, we want to understand when this is successful, how is the immune system altered?” says Maria Luisa-Alegre, Md, PhD, Professor of Medicine at the University of Chicago. “And if we understand that, we may be able to design new therapies to be able to achieve transplantation tolerance in humans too.”

T cells come in many varieties, including CD4⁺ T cells, which stimulate other immune cells such as macrophages and B cells. CD4+ T cells can be divided into two subsets: conventional T cells that assist other immune cells and regulator T cells, or “Tregs,” which shut down conventional T cells at the end of the immune response.

Typically, these cells work together to increase the immune system’s response to pathogens, but once these cells recognize a transplanted organ as a foreign body, it responds the same way as they would towards bacteria or viruses.

In previous work, Alegre and her colleagues sequenced the RNA of transplant-specific conventional T cells from mice that accepted heart transplants. They found that one gene, transcription factor Satb1,  played a significant role in the immune response toward cancerous tumors. The team found that this gene was upregulated in the cancer response and during rejection of a transplanted organ but downregulated in transplant-tolerant mice.

“That made sense, because what we want to achieve in transplantation versus cancer is a mirror image,” says senior author Alegre. “Cancer researchers try to rev up the immune system to reject cancers, but we want to turn down the immune system so the transplants are not rejected.”

To explore these findings further, they tested another set of mice with Satb1 knocked out in conventional T cells. This made the transcription factor nonfunctional, and the team expected this to allow mice to accept transplants. However, they found that after adding a small number of Tregs, the mice did indeed accept the organ. This suggested that, while the conventional T cells functioned fine with or without Satb1, the lack of this transcription factor made them more susceptible to being “switched off” by Tregs.  

While Alegre notes that these findings are still a long way away from translation into human treatments, the team gained insight as to how transplant tolerance behaves at an immune cell level. Alegre notes that their work reveals two primary points: “One thing that was not known, which is that a transcription factor tunes up and down the susceptibility of conventional T cells to suppression by Tregs,” she says. “And two, it reveals another component of transplantation tolerance that maybe we can exploit to try and make transplantation tolerance more robust.”