Two Main Types of Organ Rejection and Their Treatments
The two main types of organ rejection are T-cell mediated rejection (TCMR) and antibody-mediated rejection (ABMR), with TCMR treated primarily with high-dose corticosteroids and anti-thymocyte globulin, while ABMR requires a multi-pronged approach targeting antibody removal (plasmapheresis), B-cell depletion (rituximab), plasma cell suppression (bortezomib), and intravenous immunoglobulin (IVIg). 1
T-Cell Mediated Rejection (TCMR)
TCMR occurs when effector T lymphocytes infiltrate the graft and orchestrate an inflammatory response. The T cells engage antigen-presenting cells, activating macrophages and producing intense interferon-gamma expression, leading to interstitial inflammation, parenchymal deterioration, and intimal arteritis 1.
Treatment for TCMR:
- High-dose corticosteroids: Methylprednisolone 500-1000 mg IV daily for 3 consecutive days 2
- Anti-thymocyte globulin (ATG): 1.5 mg/kg IV daily for 3-7 days for severe cases 2
- Optimization of baseline immunosuppression: Switch from cyclosporine to tacrolimus, or from azathioprine to mycophenolate mofetil 2
TCMR typically becomes infrequent 5-10 years post-transplant due to adaptive immune mechanisms, though inadequate immunosuppression or non-adherence can trigger episodes even later 1.
Antibody-Mediated Rejection (ABMR)
ABMR occurs when HLA IgG alloantibodies produced by plasma cells bind to donor antigens on the graft microcirculation, leading to complement activation, NK cell and neutrophil margination, and endothelial injury 1. Unlike TCMR, ABMR can present decades post-transplant and represents a more challenging therapeutic target 1.
Treatment Algorithm for ABMR Based on Severity:
For pAMR2 without graft dysfunction or donor-specific antibodies (DSA):
- Pulse corticosteroids alone 2
For pAMR2 with graft dysfunction and/or DSA, or any pAMR3:
The treatment strategy targets three mechanisms simultaneously 2:
Antibody removal:
B-cell depletion:
Immunoglobulin replacement and immunomodulation:
High-dose corticosteroids:
- Methylprednisolone 500-1000 mg IV daily for 3 days 2
For hemodynamically compromised patients:
- Add ATG 1.5 mg/kg per day for 3 consecutive days with plasmapheresis 2
For refractory ABMR:
- Bortezomib (plasma cell depletion): 1.3 mg/m² on days 1,4,7, and 10 2
- Consider photopheresis or total lymphoid irradiation 2
- Eculizumab (complement inhibition) for severe cases 2
Optimization of Maintenance Immunosuppression:
The American Heart Association guidelines emphasize modifying baseline therapy for ABMR 2:
- Switch azathioprine to mycophenolate mofetil (MMF) - both MMF and sirolimus are potent B-cell inhibitors 2
- Switch cyclosporine to tacrolimus 2
- Consider switching MMF to sirolimus for resistant cases 2
- Add or increase corticosteroid dose 2
Critical Decision Points:
When to treat: pAMR3 should always be treated regardless of clinical evidence due to poor outcomes 2. For pAMR0-2, treatment decisions should incorporate clinical evidence of graft dysfunction, symptoms, and presence of new or increasing DSAs 2. The presence of complement-binding antibodies warrants more aggressive treatment 2.
Common pitfall: Do not rely solely on pathology grading. Biopsy-negative allograft dysfunction can still represent ABMR and may require evaluation for cardiac allograft vasculopathy with microvascular disease or non-HLA antibodies 2.
Mechanical support: For ABMR with hemodynamic compromise refractory to medical therapy, extracorporeal membrane oxygenation (ECMO) can be considered as salvage therapy, with preemptive use conferring better survival than salvage therapy (26% vs 7% at 1 year) 2.