Allogeneic rejection, also known as allograft rejection, is the immune system's response to a transplanted organ or tissue (allograft) from a genetically different individual (allogeneic donor). It occurs because the recipient's immune system recognizes the donor's tissue as foreign and mounts an attack against it.
Understanding the Mechanism of Allogeneic Rejection
After an allograft transplant, the recipient's immune system identifies differences in the major histocompatibility complex (MHC), also known as human leukocyte antigens (HLA), between the donor and recipient tissues. These differences trigger an immune response, leading to rejection. This immune response is complex and involves both cellular and humoral immunity:
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T cell-mediated rejection: T cells, particularly cytotoxic T lymphocytes (CTLs) and helper T cells, play a central role. CTLs directly kill donor cells expressing foreign MHC molecules. Helper T cells release cytokines that activate other immune cells, amplifying the rejection process.
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Antibody-mediated rejection (AMR): B cells produce antibodies against donor HLA antigens. These antibodies can bind to the allograft endothelium, activating complement and leading to endothelial cell damage, thrombosis, and graft dysfunction.
Pathways of Antigen Presentation
There are primarily two pathways through which the recipient's immune system is exposed to donor antigens:
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Direct Pathway: Recipient T cells directly recognize intact MHC molecules on donor antigen-presenting cells (APCs) within the transplanted organ.
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Indirect Pathway: Recipient APCs process and present donor-derived peptides to recipient T cells. This pathway involves the presentation of processed allogeneic MHC molecules by the recipient's own APCs.
Types of Allograft Rejection
Allogeneic rejection can be classified based on the timing and characteristics of the rejection process:
| Type of Rejection | Timing | Mechanism | Characteristics |
|---|---|---|---|
| Hyperacute | Minutes to hours after transplantation | Pre-existing antibodies against donor antigens | Immediate graft failure due to vascular thrombosis and necrosis. |
| Acute | Weeks to months after transplantation | T cell-mediated and antibody-mediated responses | Inflammation, cellular infiltration of the graft, and graft dysfunction. |
| Chronic | Months to years after transplantation | Chronic inflammation, fibrosis, and vascular changes mediated by both cellular and humoral immunity. | Gradual loss of graft function, often manifested as fibrosis and vascular occlusion. |
Prevention and Treatment of Allogeneic Rejection
Immunosuppressive drugs are crucial for preventing and treating allogeneic rejection. These drugs suppress the recipient's immune system, reducing its ability to attack the transplanted organ. Common immunosuppressants include:
- Calcineurin inhibitors (e.g., cyclosporine, tacrolimus): Block T cell activation.
- mTOR inhibitors (e.g., sirolimus, everolimus): Inhibit T cell proliferation.
- Antimetabolites (e.g., azathioprine, mycophenolate mofetil): Interfere with DNA synthesis and cell proliferation.
- Corticosteroids (e.g., prednisone): Reduce inflammation and suppress immune cell activity.
- Antibodies (e.g., anti-thymocyte globulin (ATG), anti-CD25 antibodies): Deplete or block specific immune cells.
The specific immunosuppressive regimen is tailored to each patient based on the type of transplant, the risk of rejection, and the patient's overall health. Regular monitoring of graft function and immunosuppressant levels is essential to optimize treatment and minimize side effects.
