Immunosuppression in Transplantation

Organ Rejection

Broadly, the recipient response to the donor organ can be classified as hyperacute rejection, acute rejection, or chronic rejection. Presentation varies between the transplanted organ involved, yet diagnosis will require a tissue biopsy for definitive confirmation.

Hyperacute rejection occurs due to preformed cytotoxic antibodies directed against donor HLA or ABO antigens. There is often graft destruction within 24 hours, especially if left untreated. Hyperacute rejection can be avoided by pre-operative blood group and HLA matching.

Acute rejection is the most common type of rejection, occurring in up to 30% of kidney transplants and can vary in different organ types. Acute rejection is most common in the first 6-12 months following transplantation. Acute rejection occurs over weeks to months with apparent graft dysfunction. It is most commonly caused by a T-cell mediated immune response* against the graft MHCs, with increased risk with previous HLA sensitising episodes (such as previous transplants or blood transfusions). Patients can be treated with high-dose steroids, with second line treatment options including plasma exchange, intravenous immunoglobulin or lymphocyte-cell depleting agents. Without treatment acute rejection will lead to graft failure.

Chronic rejection usually occurs after 6 months and will present as a progressive decline in organ function. It usually occurs as a result of subtherapeutic immunosuppression. As such, treatment requires optimisation of immunosuppression. Unfortunately, therapies have limited effectiveness in reversing damage and loss of function resulting from chronic rejection.

*A humoral acute rejection can also occur, although is much less common

Nephron [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)]

Figure 1
Histology of acute lung transplant rejection, showing features of perivascular lymphocytic infiltration

Modern Immunosuppression

The primary goal of immunosuppression is to prevent graft rejection and minimise adverse reactions. Despite current immunosuppression regimens, rejection does still occur but graft loss due to rejection with appropriate treatment is uncommon.

Immunosuppressive drugs can be classified as induction therapies, maintenance therapies, and antirejection therapies. Current immunosuppression agents are given as combination therapies, with constituents depending on both patient and operative factors:

• Calcineurin inhibitors, such as cyclosporine or tacrolimus
• Anti-proliferative agents, such as mycophenolate mofetil or azathioprine
• mTOR Inhibitors, such as sirolimus and everolimus
• Corticosteroids, such as prednisolone or methylprednisolone
• Monoclonal antibodies, such as Basiliximab or Alemtuzumab

Induction Agents

Basiliximab is a monoclonal antibody that blocks IL-2 receptors, thereby inhibiting IL-2-induced T-cell activation. It is most often used as an induction agent in kidney transplantation, or may be used as part of steroid-free protocols in pancreas transplantation. The use of Basiliximab as an induction agent allows for early steroid withdrawal and a substantial reduction in other immunosuppressive agents early after transplantation. Side effects include oedema, hypertension, and tremor.

Alemtuzumab is a monoclonal antibody directed against CD52; CD52 is widely expressed on the surface of immune cells (all B and T cells and most macrophages and natural killer cells), allowing Alemtuzumab to act as a lymphocyte-depleting agent. Its use is generally for patients with high immunological risk or may be used routinely in pancreas transplantation. Whilst effective in reducing the risk of rejection, it is also associated with a high risk of post-operative opportunistic infections and post-transplant lymphoproliferative disease.

Early Maintenance Agents

Benjah-bmm27 [Public domain]

Figure 2
Tacrolimus molecular structure

Calcineurin Inhibitors

Calcineurin inhibitors (CNIs), such as cyclosporine and tacrolimus, are strong inhibitors of the T-cell response, acting by blocking IL-2 production. They are the mainstay of most initial post-operative immunosuppression, with tacrolimus the first-line immunosuppressant in most transplant centres.

They have a narrow therapeutic window and are nephrotoxic, through vasoconstrictive action, therefore their levels should be regularly monitored. Other less common side effects of CNIs include hypertension, neurotoxicity (more common with tacrolimus which causes tremor, headache, irritability), diabetes mellitus, and hyperlipidaemia. Hirsutism and gingival hyperplasia are additional adverse events specific to cyclosporine.

Anti-Proliferatives

The most common anti-proliferative agents currently used are mycophenolate mofetil (MMF) and azathioprine. Neither agent requires regular therapeutic drug monitoring.

Ayacop [Public domain]

Figure 3
Azathioprine molecular structure

Azathioprine is a precursor of 6-mercaptopurine, which in turn, once metabolised, acts to inhibit nucleotide synthesis. The most prominent side effect is severe myelosuppression, and in such cases, dose reduction or swapping to other anti-proliferative agents is required.

MMF is converted via first-pass metabolism into the active compound mycophenolic acid (MPA), which acts by blocking lymphocyte proliferation through inhibiting DNA formation. Its most prominent side effect is also myelosuppression.

mTOR Inhibitors

Sirolimus and everolimus are inhibitors of the Mammalian Target of Rapamycin (mTOR) and inhibit lymphocyte proliferation and differentiation.

Both agents can be used in combination with low-dose CNIs in recipients with CNI-induced nephrotoxicity, in an attempt to improve renal function without decreasing the efficacy of the immunosuppressive regimen.

They are rarely used as primary immunosuppressant and side effects include bone marrow suppression, hyperlipidaemia, peripheral oedema, and delayed wound healing.

Steroids

Corticosteroids are potent non-specific anti-inflammatory agents, are used both in induction and maintenance immunosuppression, acting on intra-cellular receptors. They are also the first-line therapy for acute cellular rejection (commonly given as high-dose intravenous methylprednisolone).

Their side effects are numerous* when taken long term, including diabetes mellitus, hypertension, increased infections, osteoporosis, hyperlipidaemia, delayed wound healing, and neuropsychiatric symptoms.

*Steroid withdrawal protocols (MPA plus CNI) are currently used to reduce the long-term complications associated with corticosteroids

Long-Term Maintenance Therapy

Gradually after transplantation, rejection prophylaxis doses can be reduced (i.e. steroid tapering and gradually lowering of CNI levels), as the patient enters the late maintenance phase. Regimens vary between centres and patients, however patients typically end up tailored to one or two treatments.

Long-term maintenance therapy is associated with an increased cardiovascular risk and CNI-related nephrotoxicity. Other important side effects include increased risk of opportunistic infections (e.g. cytomegalovirus or Pneumocystis jirovecii) and malignancies (e.g. post-transplant lymphoproliferative disorder and skin cancers).