October 28, 2024, Immune Tolerance
After kidney transplantation, medication cannot be discontinued.
Organ transplantation can indeed save lives; however, recipients of such procedures, akin to Sun Wukong restrained by a golden headband, are bound by a “tight spell”—the lifelong necessity of taking immunosuppressants.
The human body naturally rejects “new foreign entities,” much like strangers struggling to become close siblings upon first meeting. The relationship between the body and the transplanted kidney must begin with gradual acquaintance and mutual adaptation. During this period, all unpleasant discomforts and minor conflicts constitute rejection reactions.
No one enjoys taking medication.
Taking medication imposes financial burdens, with global annual healthcare costs associated with this estimated to reach hundreds of billions of yuan. Even more concerning and alarming than the financial burden are the “side effects of immunosuppressants.” Prolonged use of immunosuppressants generally reduces immunity in kidney transplant recipients, potentially leading to serious complications such as infections, cardiovascular diseases, diabetes, malignancies, and drug-induced toxicity, thereby impacting the long-term survival of both the patient and the transplanted organ.
Therefore, achieving harmonious coexistence between the transplanted organ and the body while ensuring the health and safety of post-transplant patients—professionally known as “organ transplant immune tolerance”—enabling organ transplant recipients to escape the “tight spell” of lifelong immunosuppressant dependency, has been a common aspiration of transplant doctors and patients alike. It is also one of the enduring challenges in the global field of organ transplantation.
Ensuring a Safe and Peaceful Environment for Transplanted Organs
The “organ transplant immune tolerance” we describe refers to a state where, without using immunosuppressants, the recipient’s immune system can differentiate between self and non-self—absolutely refraining from attacking the newly transplanted organ while promptly countering any external threats, eliminating all factors that jeopardize health.
Currently, the primary strategies for inducing immune tolerance include:
(1) Inducing central immune tolerance through clonal deletion of T cells in the thymus and B cells in the bone marrow;
(2) Inducing peripheral immune tolerance by blocking costimulatory signaling pathways, infusing or inducing the generation of regulatory immune cells, rendering T and B cells immunologically incompetent, and inhibiting their proliferation or function. Since inducing immune tolerance in organ transplantation entails complex immune system remodeling and the maintenance of immune regulation, additional theoretical and clinical research is still required to develop safe and effective induction strategies.
Exciting News: A Glimmer of Hope for Clinical Immune Tolerance
In recent years, Massachusetts General Hospital, Stanford University, Northwestern University, and the Kidney Transplantation Specialty at Zhongshan Hospital, affiliated with Fudan University, have each conducted more than 10 clinical studies on inducing immune tolerance through hematopoietic stem cell infusion combined with kidney transplantation.
This approach initially subjects kidney transplant recipients to total lymphoid irradiation pretreatment while infusing donor hematopoietic stem cells. These clinical studies have achieved varying levels of success, with some patients completely discontinuing immunosuppressants. This has substantially reduced treatment costs while significantly enhancing quality of life.
Research has revealed that “donor-recipient chimerism” persists long-term in the peripheral blood and bone marrow of kidney transplant recipients, with recipients exhibiting specific immune non-responsiveness or low responsiveness to donor organs. In simpler terms, by infusing donor hematopoietic stem cells into the recipient, the recipient’s immune system is “remodeled” to no longer recognize the transplanted organ as a “foreign entity,” ceasing its “attacks” and ultimately freeing transplant recipients from reliance on immunosuppressants.
The Kidney Transplantation Specialty at Zhongshan Hospital, affiliated with Fudan University, believes that “donor hematopoietic stem cell infusion” could represent a major breakthrough in clinically inducing immune tolerance for kidney transplantation.
Possible Mechanisms of Immune Tolerance: Hematopoietic Stem Cells Reshape the Recipient’s Lymphatic System
The potential mechanism of immune tolerance involves infusing donor hematopoietic stem cells, enabling them to develop, differentiate, and evolve within the recipient, mutually educating one another, modifying the recipient’s immune response pattern, and ultimately achieving specific immune tolerance.
Specific mechanisms include the following:
1.Precursor T and B cells derived from donor and recipient hematopoietic stem cells induce central tolerance in the recipient’s central immune organs, such as the bone marrow and thymus, through immune recognition, clonal selection, deletion, and the formation of cell-in-cell structures;
2.Mature T and B cells from donor and recipient hematopoietic stem cells migrate from central immune organs to peripheral lymphoid tissues, inducing the formation of chimeric regulatory immune cells to achieve peripheral immune tolerance;
3.Donor hematopoietic stem cells, or recipient hematopoietic stem cells educated by the donor, directly exert local immunosuppressive effects on the transplanted kidney by secreting inhibitory cytokines or microvesicles, promoting peripheral immune tolerance.
Future Hope: Promoting Hematopoietic Stem Cell-Induced Immune Tolerance
The clinical research conducted by the Kidney Transplantation Specialty at Zhongshan Hospital, affiliated with Fudan University, has achieved significant breakthroughs in inducing immune tolerance in some kidney transplant patients. However, the overall success rate has yet to meet our expectations. There is considerable potential for improvement in optimizing protocols to increase the success rate of immune tolerance induction.
We believe that, with the promotion of hematopoietic stem cell-induced immune tolerance, the swift clinical adoption and application of these new methods will offer a brighter future for kidney transplant patients.
Written by | Zhu Tongyu, Photography | Elliott C. Mei, Grace
Renowned Doctor Profile: Zhu Tongyu
Zhu Tongyu
Graduated from Qingdao Medical College with a Bachelor’s degree in Clinical Medicine in 1989, earned a Doctor of Surgery degree from the Graduate School of Shanghai Medical University in 1994, and conducted postdoctoral research at the Faculty of Medicine, University of Hong Kong, from 1999 to 2000.
With over 20 years of experience in clinical and basic research on kidney transplantation, he has published more than 150 academic papers, including over 40 SCI-indexed articles, and co-authored more than 10 academic monographs. Recognized as a Shanghai Leading Talent, an Outstanding Academic Leader in Shanghai, and a member of Shanghai’s New Hundred Talents Plan in the healthcare sector.
He has conducted China’s first living-related kidney transplant for a child with Denys-Drash syndrome, a highly complex fourth kidney transplant, and Asia’s first sequential heart-liver-kidney multi-organ transplant, receiving coverage from CCTV’s “Science and Technology Spotlight,” Xinhua News Agency, and other media outlets.
Currently serves as Vice President of Zhongshan Hospital, affiliated with Fudan University; Executive President of Zhongshan Hospital, Fudan University Xiamen Branch; President of Zhongshan Hospital, Fudan University Qingpu Branch; Professor, Chief Physician, and Doctoral Supervisor in the Department of Urology at Zhongshan Hospital, Fudan University.
Currently serves as the Director of the National Key Clinical Specialty in Organ Transplantation, Member and Deputy Chair of the Kidney Transplantation Group of the Chinese Medical Association Organ Transplantation Branch, Deputy Chair of the Kidney Transplantation Group of the Chinese Medical Doctor Association Organ Transplantation Physicians Branch, Deputy Chair of the Shanghai Medical Association Organ Transplantation Branch, Director of the Shanghai Key Laboratory of Organ Transplantation, and Deputy Director of the Fudan University Organ Transplantation Center.
Serves on the editorial boards of more than 10 domestic and international academic journals, including The International Journal of Clinical Practice, and has led over 10 research projects funded by the National Natural Science Foundation of China, the National 11th Five-Year Science and Technology Plan, and major Shanghai research initiatives. Maintains robust communication and collaboration with internationally renowned organ transplantation centers, having been invited as a keynote speaker or co-chair at more than 10 international academic conferences.
“Saving lives and curing diseases is my lifelong vocation, relieving suffering and advancing medical knowledge are my pursuits, and nurturing medical talent is my lifelong aspiration.”
