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 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).
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Liver Immune Tolerance Marker Utilization Study (LITMUS, NCT NCT02541916)
Studies with random withdrawal of immunosuppression have suggested that up to 20% of liver transplant recipients are operationally tolerant, meaning they don’t need drugs to support the transplanted organ. The main issue is that currently, we cannot identify these tolerant patients.
In the Liver Immune Tolerance Marker Utilization Study (LITMUS, NCT NCT02541916), we gradually wean patients off their immunosuppressive drugs if they have a specific pattern of gene expression. We are investigating if measuring the activity of genes (gene expression profile) could give us an insight into how the body cells function. This can help us detect liver transplant recipients who are operationally tolerant and can be safely weaned off immunosuppression.
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Autologous Hematopoietic Stem Cell Transplantation for Allogeneic Organ Transplant Tolerance trial (ASCOTT, NCT02549586)
This trial aims to help liver patients who are struggling with rejection by “resetting” the immune system with a transplant of their own (autologous) bone marrow stem cells in a procedure known as autologous hematopoietic stem cell transplantation (HSCT). Autologous HSCT has previously been shown to induce tolerance in autoimmune diseases, such as multiple sclerosis, and we are investigating if autologous HSCT can induce tolerance in solid organ transplantation.
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.
