1. Epidemiology and Incidence

Acute rejection remains a leading cause of early graft dysfunction across all solid organs. Incidence varies by organ type and time since transplant, with patient comorbidities and social factors modulating risk.

Organ-Specific Incidence and Outcomes

The risk of acute rejection within the first year is highest for lung allografts and varies for other organs, directly impacting long-term survival.

Temporal Distribution and Risk Modifiers

• Early Rejection (<6 months): Primarily driven by preformed alloimmunity or suboptimal initial immunosuppression.
• Late Rejection (>6 months): Often linked to medication nonadherence, chronic immune activation, or the development of de novo donor-specific antibodies (DSAs).
• Chronic Comorbidities: Conditions like diabetes mellitus and chronic kidney disease can foster microvascular injury and complicate immunosuppressant pharmacokinetics.
• Social Determinants of Health: Financial constraints, low health literacy, and transportation barriers are major contributors to nonadherence, which may account for up to 15% of allograft losses.

2. Immunologic Risk Factors

The strength and quality of the alloimmune response are determined by Human Leukocyte Antigen (HLA) disparity, prior sensitization events, antibody formation, and medication adherence.

HLA Mismatch and Allorecognition

• Direct Pathway: Recipient T cells recognize intact donor HLA molecules presented on the surface of graft antigen-presenting cells (APCs).
• Indirect Pathway: Recipient APCs process and present peptides from shed donor HLA molecules to recipient T cells.
• A higher degree of HLA mismatch between donor and recipient correlates with an increased risk of rejection and reduced long-term graft survival.

Allo-sensitization and Donor-Specific Antibodies (DSAs)

Prior exposure to foreign antigens through blood transfusions, pregnancies, or previous transplants can expand memory T and B cell pools, “sensitizing” the recipient. Preformed DSAs can mediate hyperacute rejection, while de novo DSAs that develop post-transplant contribute to late antibody-mediated rejection and chronic graft injury.

3. Pathophysiology of Acute Cellular Rejection (ACR)

ACR is orchestrated by an antigen-driven T cell response. The activation and differentiation of these T cells are modulated by a series of costimulatory signals and balanced by regulatory immune cell subsets.

Three-Signal T Cell Activation

Full T cell activation requires three distinct signals, each representing a therapeutic target for immunosuppressive drugs.

Key T Cell Subsets in Rejection

• CD4+ T Helper Cells: Th1 cells secrete IFN-γ to activate macrophages, while Th17 cells secrete IL-17 to recruit neutrophils and promote tissue inflammation.
• CD8+ Cytotoxic T Lymphocytes (CTLs): These are the primary effectors of cellular rejection, directly killing graft cells via perforin/granzyme and Fas-FasL pathways.
• Regulatory T cells (Tregs): These CD4+Foxp3+ cells are immunosuppressive, secreting IL-10 and TGF-β to dampen effector T cell responses and maintain tolerance. An imbalance in the Th17/Treg ratio is often predictive of rejection.
• T follicular helper (Tfh) cells: Residing in lymphoid structures, these cells provide critical help to B cells, driving the production of high-affinity DSAs.

4. Antibody-Mediated Rejection (AMR) Mechanisms

AMR is driven by DSAs that bind to donor HLA antigens on the vascular endothelium of the graft. This binding initiates a cascade of inflammation and complement activation, leading to microvascular injury that is pathologically and clinically distinct from ACR.

Complement Activation and DSA Dynamics

The classical complement pathway is triggered when DSAs bind to their targets. This leads to the generation of anaphylatoxins and the membrane attack complex, causing endothelial cell damage. The deposition of complement split product C4d in peritubular or glomerular capillaries is a key diagnostic hallmark of AMR, though C4d-negative AMR also occurs.

5. Clinical Presentation

Acute rejection may present subclinically (detected only on surveillance testing) or with overt signs of organ-specific dysfunction. A combination of laboratory changes, imaging, and ultimately biopsy is required to confirm the diagnosis and guide treatment.

Organ-Specific Laboratory and Clinical Signs

Histopathology and Case Example

The definitive diagnosis of rejection relies on histopathology. ACR is characterized by mononuclear infiltrates, while AMR shows signs of endothelial injury and capillary inflammation, with or without C4d staining.