T cells are specialized immune defenders that distinguish between “self” and “non-self” components. In transplantation, the immune system encounters cells from another individual. When T cells react to these genetically different tissues, it’s termed “alloreactivity.” This immune response is a primary challenge in organ and stem cell transplantation.
Understanding Alloreactive T Cells
T cells identify foreign substances (antigens) presented on Major Histocompatibility Complex (MHC) molecules. Alloreactive T cells specifically recognize genetic differences between individuals, even without a conventional foreign antigen. This recognition, known as allorecognition, is potent; up to 10% of an individual’s T cells can recognize these “alloantigens.”
Allorecognition occurs through direct and indirect pathways. In direct allorecognition, recipient T cells directly recognize intact donor MHC molecules on donor cells, particularly antigen-presenting cells (APCs). This pathway drives early immune responses after transplantation.
The indirect pathway involves recipient APCs processing and presenting peptides from donor MHC molecules. These donor-derived peptides are then presented in the context of the recipient’s own MHC molecules to recipient T cells. A third, semi-direct pathway also exists where recipient APCs acquire and present intact donor MHC molecules.
Their Role in Transplant Rejection
Alloreactive T cells are central to transplanted organ rejection. Recognizing the donor organ as foreign, these T cells attack, damaging the tissue. This immune response is a major hurdle to long-term transplant success.
Rejection manifests as acute or chronic, both influenced by T cells. Acute rejection occurs within weeks or months post-transplant, involving a rapid T cell-mediated response against donor MHC. This leads to inflammation and damage within the transplanted organ.
Chronic rejection develops months or years later, characterized by a slower, progressive decline in organ function. The indirect pathway of allorecognition and antibody production by B cells contribute to this long-term damage. Alloreactive T cells pose a continuous challenge to transplanted organ survival.
Graft-versus-Host Disease
Alloreactive T cells cause Graft-versus-Host Disease (GVHD), a serious complication after hematopoietic stem cell transplantation (HSCT), or bone marrow transplantation. Here, donor T cells in the graft recognize the recipient’s healthy tissues as foreign, attacking the recipient’s body.
GVHD affects organs like the skin, gastrointestinal tract, and liver. Skin symptoms include rashes or itching. Gastrointestinal issues range from nausea to severe diarrhea. Liver involvement can cause elevated enzymes or jaundice.
GVHD is acute (within 100 days post-transplant) or chronic (developing later, persisting for months or years). This differs from solid organ rejection, where the recipient’s immune system attacks the donor organ. Managing GVHD while preserving the donor T cells’ anti-cancer effects is a complex balance.
Controlling Alloreactive T Cells
Controlling alloreactive T cells is crucial for transplant success. Immunosuppressive drugs are the primary strategy, dampening the recipient’s immune response to prevent solid organ rejection or control GVHD. These medications broadly suppress immune cell function. While effective, they cause side effects like increased infection susceptibility due to their broad impact.
Research focuses on more specific strategies to induce immune tolerance. This involves reprogramming the immune system to accept transplanted tissue without lifelong immunosuppression. Approaches include targeting alloreactive T cells, enhancing regulatory T cells (Tregs) to suppress responses, or inducing donor-specific tolerance.
Emerging techniques, such as gene editing to remove alloreactive T cell receptors or using donor stem cells to promote chimerism (where donor and recipient immune cells coexist), are being explored. These strategies aim for long-term acceptance, minimizing continuous immunosuppression and its complications.