The immune system identifies and attacks threats to our bodies, such as invading bacteria or viruses, and has systems to recognize what tissues are part of our selves. When an organ is transplanted, the immune system treats it as an invader and attack – just like it would for a bacterial infection. This is the core mechanism behind rejection in transplantation.
Although organ transplantation is a highly effective therapy for organ failure, rejection remains a major concern. To reduce the likelihood of rejection, post-transplant patients must take immunosuppressant drugs for the rest of their lives. While immunosuppressants have made modern organ transplantation possible, they weaken the immune system, making the patient susceptible to serious health risks ranging from infections and diabetes to kidney dysfunction and cancer. Therefore, immunosuppressant drugs limit the long-term effectiveness of organ transplantation.
Immune tolerance is a state in which the immune system does not reject the donor organ while still responding to challenges from the environment, such as infections. Tolerant post-transplant patients do not require immunosuppressive drugs and their new organs function normally. Achieving tolerance is possible in animals but has only been documented in limited circumstances in humans.
Drug-free transplant acceptance (tolerance) would greatly enhance the benefits of transplantation. Our ultimate goal is to develop approaches to establishing robust tolerance in patients, so that we could treat end-stage organ diseases of the lung, kidneys, liver, and heart with a single organ transplant procedure, and restore function and quality of life without the need for immunosuppressive drugs. We aim to develop diagnostics that will help us identify and monitor tolerance in the clinical setting and protocols to induce tolerance in transplant recipients.
We use experimental models to study novel mechanisms of tolerance and rejection. These give us insights into the key processes that may be relevant in human organ transplantation. We are investigating basic mechanisms of tolerance using various experimental models. We also make use of samples, such as tissue and blood, from organ transplant patients to better understand the biological processes that underlie rejection and tolerance in human beings.
Our technical approaches involve profiling the immune system using flow and mass cytometry as well as molecular techniques, such as sequencing, polymerase chain reaction (PCR), and epigenetic studies. These approaches help us to understand how the immune system is interacting with the transplanted organ. In order to tip the balance in favour of tolerance, we are also developing a variety of cell therapeutic approaches that will harness the transplant recipient’s own immune system to promote long-term acceptance of the organ.
We are translating basic studies into two clinical trials of tolerance in liver transplantation: the Liver Immune Tolerance Marker Utilization Study (LITMUS) and Autologous Hematopoietic Stem Cell Transplantation for Allogeneic Organ Transplant Tolerance trial (ASCOTT).
In the next few years, we are aiming to incorporate some of the lessons learned from these and other trials to deliberately induce tolerance in transplant recipients and/or modify the transplanted organ to promote tolerance using a variety of approaches. Ultimately, we hope to be able to apply such novel therapies across all types of organ transplants.
The Immune Tolerance Pillar LeadsDr. Andrzej ChruscinskiEmail:
Dr. Stephen JuvetEmail: