Induction of Immune Tolerance in Organ Transplantation

In this article, I briefly describe the induction of immune tolerance in organ transplantation. The process of organ transplantation remains limited by immune-mediated graft rejection, prompting extensive efforts to understand and control host immune responses.

Table of Contents

Allograft Acceptance Without Immunosuppression

The recipient’s immune system may occasionally accept an allograft with minimal or no immunosuppressive therapy. This is especially true for tissues such as cartilage or heart valves, which display few or no alloantigens and therefore elicit a minimal immune response. However, most allografts are vulnerable to immune-mediated damage unless preventive strategies are used. Successful acceptance occurs under two main conditions. When clinicians place the graft in an immune-privileged site with limited immune surveillance, or when they biologically induce donor-specific tolerance in the recipient toward alloantigens.

Transplantation in Areas of Immune Tolerance

When surgeons place an allograft in an area of immune tolerance, where immune surveillance is naturally limited, the graft faces a much lower risk of rejection. These sites contain few lymphatic vessels and often have restricted blood flow. This reduces the chances that recipient T cells will encounter donor alloantigens. As a result, grafts in these regions can achieve long-term survival even without close HLA matching.

The remarkably high success rate of corneal transplantation exemplifies this phenomenon. Additionally, studies in rat models have shown that transplanting allogeneic pancreatic islet cells into the thymus can lead to successful engraftment, suggesting that the thymus may also function as a site capable of promoting immune tolerance.

Likely, grafts placed in these immune-tolerant regions survive longer because they remain physically isolated from immune cell surveillance. This observation suggests that creating a physical barrier around transplanted tissues may help prevent immune attack. In one experiment, researchers encased pancreatic islet cells in semipermeable, non-immunogenic capsules and transplanted them into diabetic mice. The encapsulated islets remained functional and continued producing insulin, as the host’s immune cells were unable to breach the protective membrane. This innovative approach offers promising potential for future diabetes therapies.

Role of TREG Cells in Transplantation Tolerance

Growing evidence indicates that FoxP3-expressing regulatory T cells (TREGs) play a crucial role in promoting transplantation tolerance. In clinical operational tolerance, the graft continues to function even after clinicians withdraw immunosuppressive therapy, and TREG cell numbers increase both in the circulation and within the graft. These cells suppress alloreactive immune responses through direct cell–cell contact and by secreting immunosuppressive cytokines such as TGF-β, IL-10, and IL-35. Recent research has focused on strategies to generate alloantigen-specific TREG cells before organ transplantation to enhance graft acceptance.

Inducing Transplantation Tolerance

The current favourite method for inducing tolerance in humans involves the induction of a state of mixed hematopoietic chimerism, where donor and recipient hematopoietic cells coexist in the host before transplantation. The seed for this strategy originated from animal studies and observations in humans. For example, when clinicians administered total myeloablative therapy followed by donor bone marrow transplantation before implanting a solid organ from the same donor, transplant recipients developed enhanced tolerance to the subsequently engrafted organ.

Conclusion

Successful transplantation reflects the interplay between intrinsic mechanisms of immune tolerance and therapeutic immune modulation. Certain tissues show that allografts can survive with minimal or no immunosuppression, particularly when placed in sites with limited immune surveillance or inherent tolerogenic properties. Experimental approaches such as physical sequestration of grafted cells further reinforce the principle that restricted immune access can promote graft survival. Central to these observations is the role of regulatory T cells, which actively suppress alloreactive immune responses and contribute to long-term transplantation tolerance.

Efforts to deliberately induce donor-specific tolerance, including the expansion of alloantigen-specific TREG cells, represent an important shift toward immune regulation rather than immune suppression. While generalized immunosuppressive drugs remain essential in clinical practice, the development of targeted therapies, such as monoclonal antibodies, cytokine inhibitors, and costimulatory pathway blockers, has significantly refined rejection control. Together, these advances underscore a progressive movement toward strategies that favor immune tolerance and long-term graft acceptance with reduced reliance on lifelong, nonspecific immunosuppression.