Congenital Athymia Overview

The thymus transplant procedure is a highly specialized and life-saving intervention, primarily performed for infants born with congenital athymia, a condition where the thymus gland is absent or severely underdeveloped, leading to a profound deficiency in T-cells and a compromised immune system.

1. Donor Tissue Procurement:

• Source: The thymus tissue used for transplantation is typically obtained from healthy infants, usually under 9 months of age, who are undergoing heart surgery. During these complex cardiac procedures, it's often necessary to remove a portion of the thymus to gain access to the heart. This otherwise discarded tissue is then donated with the informed consent of the parents.
• Screening: Rigorous screening of the donor and the donor tissue is performed. This includes tests for infectious diseases like HIV, hepatitis B and C, and common viruses such as CMV and EBV, as these can be detrimental to an immunocompromised recipient. HLA (Human Leukocyte Antigen) and ABO typing are also done, but a tissue match between donor and recipient is not required for thymus transplants, which is a significant advantage compared to other organ transplants.

2. Tissue Processing and Culturing:

• Preparation: Once retrieved, the thymus tissue is meticulously transported to a specialized laboratory. It is then carefully sliced into very thin strips (e.g., 0.5 mm) to maximize surface area for cell migration and interaction.
• Culturing: The tissue slices are then cultured for a period, typically 3 weeks. During this culturing process, mature T-cells that might be present in the donor tissue are removed. This step is crucial to prevent Graft-versus-Host Disease (GVHD), where donor T-cells could attack the recipient's body. The culture also helps to preserve the epithelial cells within the thymus tissue, which are essential for educating the recipient's developing T-cells.

3. Transplantation:

• Recipient Preparation: Infants awaiting a thymus transplant are in strict protective isolation due to their extreme vulnerability to infections. They may receive supportive care, including antimicrobial prophylaxis and immunoglobulin replacement therapy, while awaiting the procedure.
• Surgical Implantation: The processed and cultured thymus tissue slices are implanted into the recipient. The most common site for implantation is the quadriceps muscles of the thighs. The surgeon creates individual pockets in the muscle for each tissue slice, sometimes utilizing both thighs to accommodate the necessary amount of tissue. 
• No Immunosuppression (Typically): A unique aspect of thymus transplantation for complete athymia is that, unlike most other organ transplants, it generally does not require lifelong immunosuppressive drugs. This is because the recipient's body lacks functional T-cells, and therefore, cannot mount an immune response to reject the transplanted tissue. The goal is for the newly developed T-cells to be "educated" by the donor thymus, recognizing the recipient's body as "self." In some "atypical" cases where the recipient may have some existing T-cell function, brief immunosuppression might be used prior to transplant to enhance the success rate.

4. Post-operative Care and Immune Reconstitution:

• Continued Isolation: Even after the transplant, infants remain in strict isolation and continue infection control measures for up to several years as the immune system develops. 
• T-cell Development: The transplanted thymus tissue acts as a "school" for the recipient's own hematopoietic stem cells (which originate in the bone marrow). These stem cells migrate to the implanted thymus, where they are educated and differentiate into functional T-cells. This process of immune reconstitution is slow, typically taking 12 to 24 months for sufficient T-cell function to develop.
• Monitoring: Regular monitoring of T-cell counts and function is crucial to track the progress of immune reconstitution.
• Potential Complications: While life-saving, potential complications can include infections (especially pre-transplant), and in some cases, the development of autoimmune conditions (like thyroiditis) as the new immune system learns to differentiate self from non-self. Graft-versus-host disease is a theoretical risk, but minimized by the tissue processing.

The thymus transplant, particularly the cultured tissue approach pioneered at Duke University, has revolutionized the prognosis for children with complete athymia, offering them a chance at a life with a functioning immune system.

The history of thymus transplants is a fascinating journey in medical science, particularly in the field of immunology and transplantation. It represents a persistent effort to address severe immune deficiencies in individuals born without a functional thymus.

Early Attempts and Challenges (1960s-1970s): The earliest attempts at thymus transplantation emerged in the 1960s and 1970s. These initial efforts often involved transplanting fetal thymus tissue. However, the overall results were largely disappointing. The complexity of immune reconstitution and the challenges of donor tissue viability made consistent success elusive. Despite some sporadic successes, the procedure was not widely adopted as a reliable treatment.

Pioneering Work at Duke University and the Advent of Cultured Thymus Tissue (1990s - Present): A significant breakthrough came with the work of Dr. M. Louise Markert and her team at Duke University Medical Center in the United States. In the 1990s, they pioneered a novel approach involving the transplantation of cultured postnatal allogeneic thymus tissue. This method utilizes thymus tissue from a donor (often removed during heart surgeries in infants) which is then processed and cultured before transplantation.

This approach proved to be much more promising for children born with complete DiGeorge Syndrome, a rare condition characterized by the absence of a functional thymus, leading to severe combined immunodeficiency (SCID). Without a thymus, these infants lack the ability to produce T-cells, which are crucial for fighting infections, and usually die within their first two years of life.

Key Developments and Current Practice:

• Targeted for Complete DiGeorge Syndrome: Thymus transplantation, particularly with cultured tissue, has become a recognized and often life-saving investigational treatment for children with complete DiGeorge Syndrome and other forms of congenital athymia.
• Mechanism of Action: The transplanted cultured thymus tissue, typically implanted into the quadriceps muscles, acts as a "training ground" for the recipient's bone marrow stem cells. These stem cells migrate to the new thymus tissue and differentiate into functional T-cells, effectively reconstituting the immune system. Naïve T-cells typically develop 3-5 months after transplantation.
• Improved Survival Rates: Studies, largely from Duke University, have shown encouraging survival rates. For instance, a 2021 study reported a one-year survival rate of 77% among children with congenital athymia treated with cultured thymus tissue. This is a dramatic improvement over the  100% mortality rate without intervention.
• FDA Approval: In October 2021 (one month before Luca was born), the regenerative treatment using cultured thymus tissue, known as Rethymic, received FDA approval, marking a significant milestone after decades of research and development.
• Challenges and Complications: While highly effective, thymus transplantation is not without challenges. Patients can experience complications, including infections (especially pre-transplantation), and a notable percentage may develop autoimmune complications, such as thyroiditis, hemolysis, or thrombocytopenia, as the new immune system learns to distinguish "self" from "non-self."
• Combined Organ Transplants: More recently, pioneering procedures like the world's first combined heart and thymus transplant (performed at Duke in 2022) are pushing the boundaries further. The goal of such combined transplants is to induce immune tolerance to the transplanted organ, potentially reducing or eliminating the need for lifelong immunosuppressive drugs, which can have significant side effects.

The history of thymus transplants is a testament to persistent medical research and innovation, transforming a previously fatal condition into one with a promising outlook for many children. It highlights the critical role of specialized centers, like Duke University, in advancing highly complex and life-saving therapies. Luca was the 4th child to receive a thymus post FDA approval, and the 104th in America overall. 

Treatments like this are a pivotal reason that federal funding for medical research is necessary. The children featured on the "Faces of Athymia" page would likely not be with us today and would not have had a chance at life outside of isolation without the research and treatment. Congenital Athymia shows us children that are rare not disposable, thanks to the efforts of the team at Duke and those that came before them we can continue to celebrate their incredible lives.