Transplant Rejection

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Introduction

Recognition of immune response to transplanted tissue, called rejection, occurs in three patterns.

The transplant operation causes both mechanical trauma and disruption of blood supply, leading to activation of the innate immune response, cytokine release, and T cell recruitment. Complement activation leads to mast cell degranulation and neutrophil chemotaxis.

Rejection involves both cellular- and antibody-mediated responses.

The Case of...

a simple case introducing clincial presentation and calling for a differential diagnosis to get students thinking.

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Causes and Risk Factors

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Pathophysiology

T Cell-Mediated Reactions

It is believed that dendritic cells in the donor tissue are responsible for activating host T cells, either in the transplant or in the host lymph nodes. In the direct pathway, activation of CD4+ and CD8+ cells induces delayed-type hypersensitivity and macrophage recruitment and cyctoxic activity, respectively.

In the indirect pathway, host APCs can also present graft antigen to host T cells, activating CD4+ cells and resulting in delayed-type hypersensitivity.

It is believed that the direct pathway contributes primarily to acute cellular rejection, while the indirect pathway contributes to chronic rejection.

Antibody-Mediated Rejection

Antibodies can be developed against foreign HLAs during pregnancy if a fetus's HLA molecules do not match those of the mother. They can also develop during blood transfusions, as platelets and white blood cells are rich in HLAs. These pre-existing antibodies are reponsible for hyperacute rejection.

Antibodies can also be developed in response to the graft following host APC presentation of graft antigen in nodes, and CD4+ and B cell activation. The initial target of these antibodies appears to be the graft vasculature, leading to acute rejection vasculitis.

Hyperacute Rejection

Hyperacute rejection begins within minutes to hours of transplant if pre-existing antibodies bind to the organ and will result in systemic inflammation if the transplant is not immediately removed.

Antibodies and complement are deposited in the vessel wall, leading to endothelial injury and thrombus formation.

Acute Rejection

Acute rejection can be mediated by both T cell or antibody reactions, as explained above.

Acute cellular rejection is commonly seen in the months following transplantation and is heralded by elevated levels of serum creatnine. Histology demonstrates extensive CD4+ and CD8+ infiltration of the interstitium and capillaries, with accompanying edema.

Acute humoral rejection (rejection vasculititis) is mediated by antidonor antibodies that are directly largely at graft blood vessels. This can lead to endothelial necrosis, deposition of immunoglobulins and complement, and thrombosis.

While tissue can quickly be destroyed by acute rejection, a single case of does not necessarily mean the transplant will be lost.

image of acute kidney tubule rejection (new window)

Chronic Rejection

Chronic rejection presents clinically with a progressive increase in serum creatinine levels. It is dominated by vascular and interstitial fibrosis, and tubular atrophy. THis leads to ischemia and cell death. Large numbers of plasma cells and eosinophils present in the interstitium.

image of chronic kidney rejection (opens in new window)

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