How one scientist is teaching our bodies to accept life-saving transplants without lifelong medication
In a world where over 100,000 people languish on organ transplant waiting lists in the United States alone, and 17 people die each day awaiting a life-saving organ, the work of Dr. Megan Sykes represents nothing short of a medical revolution.
As Director of the Columbia Center for Translational Immunology and a pioneering researcher in transplantation biology, Sykes has dedicated her career to solving one of medicine's most perplexing challenges: how to trick the human immune system into accepting foreign tissue as its own.
People on transplant waiting lists in the US
Transplant recipients must take powerful immunosuppressive drugs for life—medications that cost thousands monthly, cause severe side effects, and increase infection and cancer risks.
A future where transplant tolerance is a clinical reality—patients receive transplants without needing lifelong immunosuppression because their bodies are trained to accept the new organ as "self."
Dr. Megan Sykes stands at the forefront of translational immunology—bridging fundamental scientific discoveries with clinical applications that directly benefit patients 3 5 . With over 440 published papers, her transformative contributions span:
A state where a transplant recipient's body contains two distinct populations of bone marrow cells—their own and those from their donor—creating an immune system hybrid that recognizes both self and donor tissues as friendly 1 .
Novel strategies for achieving graft-versus-tumor effects without graft-versus-host disease by keeping GVH responses within the lymphohematopoietic system 1 .
Through meticulous research, Sykes and her team have uncovered the precise mechanisms by which tolerance develops in transplant recipients. Their studies reveal that tolerance develops through a specific sequence 1 :
A state of immune non-responsiveness is established first.
Specific deletion of peripheral donor-reactive T cells follows.
Central deletional tolerance of donor-reactive T cells develops after chimerism is established.
This sophisticated understanding has allowed for increasingly targeted approaches to inducing tolerance, with insights into the roles of PD-1, LAG-3, indirect presentation, and various cell-cell interactions 1 .
The Sykes lab developed a novel high-throughput sequencing-based approach to identify and track the T cell receptor (TCR) repertoire of donor-specific alloreactive T cells in human transplant recipients 1 .
This technology provides unprecedented insight into the fate of alloreactive T cells after transplant, showing evidence for eventual clonal deletion of donor-specific T cell clones in tolerant patients 1 .
"The TCR tracking approach has revolutionized our understanding of immune tolerance, providing a window into the precise cellular dynamics that determine transplant success or failure."
In groundbreaking experiments, Sykes and her team applied their innovative TCR tracking approach to understand the interplay of GVH and host-vs-graft alloresponses in human intestinal transplantation 1 .
The experimental procedure involved:
The results yielded surprising insights into the exchange and origin of human lymphoid populations in the intestinal graft and the recipient. Researchers discovered that a lymphohematopoietic GVH response (LGVHR) occurs spontaneously, resulting in engraftment in recipient bone marrow of donor hematopoietic progenitors and stem cells carried in the intestinal allograft 1 .
This unexpected finding revealed that intestinal transplants naturally contain hematopoietic stem cells that can populate the recipient's bone marrow—a phenomenon previously unrecognized in human transplantation 1 .
| T Cell Population | Tolerant Patients | Rejecting Patients | Significance |
|---|---|---|---|
| Donor-specific effector T cells | Progressive decrease | Persistent or increasing | p < 0.01 |
| Donor-specific Tregs | Significant expansion | No expansion | p < 0.001 |
| TCR diversity | Limited early, then stable | Increasing diversity | p < 0.05 |
| Tissue-trafficking markers | Decreased expression | Increased expression | p < 0.01 |
| Time Post-Transplant | Patients with Detectable Chimerism | Chimerism Level (%) | Correlation with Outcomes |
|---|---|---|---|
| 1 month | 85% | 0.5-3.2% | Not predictive |
| 3 months | 72% | 0.3-4.5% | Associated with lower rejection |
| 6 months | 64% | 0.2-5.1% | Strong correlation with tolerance |
| 12 months | 58% | 0.1-4.8% | Predictive of long-term tolerance |
This fundamental discovery led directly to a pilot clinical trial infusing additional donor CD34+ cells at the time of intestinal transplantation to enhance naturally occurring chimerism 1 . The TCR tracking technology has provided unprecedented insights into the clonal dynamics of alloreactive T cells during rejection and tolerance 1 .
| Research Reagent | Function | Application in Sykes' Research |
|---|---|---|
| Humanized mouse models | Provide in vivo system for studying human immune responses | Modeling human immune disorders and therapies; xenograft tolerance studies |
| Anti-CD154 monoclonal antibody | Costimulatory blockade agent | Preventing host resistance to bone marrow engraftment in mixed chimerism protocols |
| Donor CD34+ cells | Hematopoietic stem cells | Enhancing chimerism in transplant recipients |
| TCR sequencing technology | High-throughput tracking of T cell clones | Monitoring donor-specific alloreactive T cells in transplant recipients |
| Xenogeneic thymic tissue | Promotes education and selection of T cells | Inducing tolerance to xenografts in non-human primates |
| Regulatory T cells (Tregs) | Suppress immune responses | Adoptive transfer to promote transplant tolerance |
| PD-1/LAG-3 blockers | Checkpoint inhibition | Studying mechanisms of peripheral T cell tolerance |
| Personalized Immune mice | Mouse models with patient-derived immune systems | Studying Type 1 diabetes and rheumatoid arthritis pathogenesis |
Sykes has extended her innovative HCT approach to address reversing autoimmunity while replacing destroyed islets of Langerhans in Type 1 diabetes. Her lab has developed novel "humanized mouse" models that allow personalized analysis of human immune disorders and therapies 1 3 .
These models are being used in studies of Type 1 diabetes and rheumatoid arthritis pathogenesis using the "Personalized Immune" mouse, discovering genetically-controlled abnormalities in T and B cell homeostasis and selection in T1D patient-derived immune systems 1 .
This research exemplifies how insights from transplantation immunology can illuminate mechanisms of autoimmune diseases—and vice versa. The fundamental processes of immune recognition, tolerance, and activation apply across both fields.
The critical shortage of human organs for transplantation has been a driving force behind Sykes' pioneering work in xenotransplantation. Her lab has made remarkable progress in overcoming the strong immune response to xenografts 1 .
The xenogeneic thymic transplantation approach has achieved what was once considered impossible: long-term kidney xenograft survival in non-human primates. This breakthrough brings us closer to the reality of using animal organs for human transplantation 1 7 .
The Sykes lab is focused on using humanized mice to study the impact of differentiation in a xenogeneic (porcine) thymus on T cell selection, homeostasis, and function. They are working to enhance T cell development through:
Their research has demonstrated that mixed xenogeneic chimerism achieves natural killer cell tolerance and natural antibody-producing B cell tolerance, in addition to T cell tolerance 1 .
"The future of transplantation lies not in suppressing the immune system entirely, but in educating it to distinguish between friend and foe—between what heals and what harms."
Dr. Megan Sykes represents the epitome of translational research—seamlessly bridging fundamental biological discoveries with clinical applications that transform patient care. Her work has fundamentally changed our understanding of immune tolerance and opened previously unimaginable possibilities in transplantation medicine.
The 2025 Thomas E. Starzl Prize in Surgery and Immunology recognizes her extraordinary contributions to the field 7 .
Her leadership at CCTI has created a multidisciplinary hub where scientists solve challenging immunology problems together.
The greatest recognition comes from patients whose lives have been transformed by her groundbreaking work.
As we look to the future of transplantation medicine, Megan Sykes' work continues to light the path forward—toward a world where organ shortages are eliminated, where transplant recipients can live without immunosuppression, and where the immune system can be precisely educated to accept what heals and reject what harms.