What is the mechanism of rejection in organ transplantation and how is it prevented?

Mechanism of Organ Transplant Rejection

Organ transplant rejection occurs through two primary pathways: T-cell mediated rejection (cellular rejection) involving direct lymphocyte infiltration and activation, and antibody-mediated rejection (AMR) where recipient antibodies target donor HLA antigens on the vascular endothelium, triggering complement activation and tissue injury. 1

Cellular (T-Cell Mediated) Rejection Mechanism

The cellular rejection pathway begins when recipient T cells recognize donor major histocompatibility complex (MHC) antigens, requiring two signals for activation: antigen recognition and costimulation. 2

• The alloimmune response is initiated by recognition of donor MHC antigens by the host immune system, with upregulation of MHC antigens on donor tissue enhancing this recognition phase during active rejection 3
• Current antirejection treatments achieve immunosuppression by depleting lymphocytes, diverting lymphocyte traffic, or blocking lymphocyte activation pathways 1
• Memory T cells, present in most transplant recipients due to heterologous immunity, have less stringent activation requirements than naive T cells, making them particularly problematic 2

Antibody-Mediated Rejection (AMR) Mechanism

AMR develops when recipient antibodies bind to donor HLA antigens on the vascular endothelium, triggering complement fixation and activation that results in tissue injury. 1

• The vascular endothelium serves as the primary point of contact for anti-donor antibody in the allograft, with myocardial capillaries, arterioles, and venules being readily affected 1
• Complement activation results in endothelial cell activation, cytokine upregulation, macrophage infiltration, increased vascular permeability, and microvascular thrombosis, ultimately manifesting as allograft dysfunction 1
• Enlarged or swollen endothelial cells (both cytoplasm and nuclei) are consistently seen, reflecting endothelial activation from antibody and complement binding to surface antigen epitopes 1

Types of AMR by Timing

• Hyperacute rejection occurs within 0-7 days post-transplantation in patients sensitized to donor HLA antigens 1
• Early AMR occurs during the first month, associated with higher prevalence of allograft dysfunction and hemodynamic compromise 1
• Late AMR occurs months to years after transplantation, with approximately 50% of heart transplant recipients developing rejection >7 years post-transplant showing evidence of AMR 1

Prevention Strategies

Pre-Transplant Screening

Flow cytometry or complement-dependent cytotoxicity assays detect preformed antibodies against donor tissues to predict hyperacute rejection risk. 4

• A positive crossmatch using sera with IgG antibodies to HLA antigens is an absolute contraindication to transplantation 4
• Optimal matching of donor and recipient HLA antigens reduces acute rejection episodes and improves long-term graft survival 4

Immunosuppressive Medications

Calcineurin inhibitors (cyclosporine and tacrolimus) form the cornerstone of maintenance immunosuppression, blocking T-cell activation pathways. 1, 5, 6

• Tacrolimus and cyclosporine are indicated for prophylaxis of organ rejection in kidney, liver, heart, and lung transplants in combination with other immunosuppressants 5, 6, 5
• These agents are substrates of cytochrome P450 3A4 (CYP3A4) and require close therapeutic drug monitoring due to complex drug interactions 1
• Mycophenolate and anti-thymocyte globulin are used for maintenance immunosuppression targeting different aspects of T-cell function 4

Critical drug interaction warning: All azole antifungals inhibit CYP3A4, with fluconazole being the weakest inhibitor, leading to elevated serum levels of calcineurin inhibitors and sirolimus when used concomitantly. 1

Treatment of Established Rejection

For antibody-mediated rejection, rituximab targets B cells while plasma exchange removes circulating donor-specific antibodies. 4

• Therapeutic plasma exchange is recommended for selected patients with AMR, though it has not been shown to improve overall survival 4
• For severe or rapidly progressing infections in transplant recipients, reduction of immunosuppression is recommended without risking organ rejection whenever possible 1
• Photopheresis has shown promise in treating recurrent rejection and may reduce coronary artery intimal thickness in cardiac transplant recipients, though its mechanism in preventing rejection is not fully defined 1

Clinical Pitfalls

The most common pitfall is failing to recognize that rejection is usually multifactorial, resulting from integration of both cellular and humoral mechanisms rather than being purely T-cell or antibody-mediated. 2

• AMR can present concurrent with cellular rejection in up to 24% of cases 1
• Subclinical AMR exists as a spectrum ranging from histological/immunologic findings without graft dysfunction to overt AMR with hemodynamic compromise 1
• In organ transplant recipients receiving immune checkpoint inhibitors for cancer, PD-1 inhibition appears more commonly associated with graft rejection than CTLA-4 blockade, suggesting the PD-1 pathway plays a critical role in allograft immune tolerance 1