Transplant rejection

Introduction

Rejection is a process by which the immune system of the recipient of an transplant attacks the transplanted organ or tissue. This is because a normal healthy human immune system can distinguish foreign tissues and attempts to destroy them, just as it attempts to destroy infective organisms such as bacteria and viruses.

Types of rejection

Hyperacute rejection is a complement-mediated response in recipients with pre-existing antibodies to the donor (for example, ABO blood type antibodies). Hyperacute rejection occurs within minutes and the transplant must be immediately removed to prevent a severe systemic inflammatory response. This is a particular risk in kidney transplants, and so a prospective cytotoxic crossmatch is performed prior to kidney transplantation to ensure that antibodies to the donor are not present. For other organs, hyperacute rejection is prevented by not transplanting ABO-incompatible grafts.

Acute rejection is antibody-mediated, generally first occurs around 5-10 days after a transplant, and can destroy the transplant if it is not recognised and treated appropriately. It occurs in around 60-75% of first kidney transplants, and 50-60% of liver transplants. A single episode is not a cause for concern if recongnised and treated promptly, but recurrent episodes are associated with chronic rejection and graft failure.

Chronic rejection was a term used to describe all long term loss of function in organ transplants associated with fibrosis of the internal blood vessels of the transplant, but this is now termed chronic allograft vasculopathy and the term chronic rejection is reserved for those cases where the process is shown to be due to a chronic alloreactive immune response.

Prevention of rejection

Rejection is prevented with a combination of drugs including:

• Calcineurin inhibitors
  • Cyclosporine
  • Tacrolimus
• mTOR inhibitors
  • Sirolimus
  • Everolimus
• Anti-proliferatives
  • Azathioprine
  • Mycophenolate mofetil
• Corticosteroids
  • Prednisolone
  • Hydrocortisone
• Antibodies
  • Monoclonal anti-IL-2Rα receptor antibodies
    • Basiliximab
    • Daclizumab
  • Polyclonal anti-T-cell antibodies
    • Anti-thymocyte globulin (ATG)
    • Anti-lymphocyte globulin (ALG)

Generally a triple-therapy regime of a calcineurin-inhibitor, an anti-proliferative and a corticosteroid is used, although local protocols vary. Antibody inductions can be added to this, especially for high-risk patients and in the United States. mTOR inhibitors can be used to provide calcineurin-inhibitor or steroid-free regimes in selected patients.

Treatment of rejection

Acute rejection is normally treated initially with a short course of high-dose methylprednisolone, which is usually sufficient to treat successfully. If this is not enough, the course can be repeated or ATG can be given. Acute rejection refractory to these treatments may require plasma exchanges to remove antibodies to the transplant.

The monoclonal anti-T cell antibody OKT3 was formerly used in the prevention of rejection, and is occasionally used in treatment of severe acute rejection, but has fallen out of common use due to the severe cytokine release syndrome and late post-transplant lymphoproliferative disorder which are both commonly associated with use of OKT3; in the United Kingdom is a available on a named-patient use only.

Chronic rejection is irreversible and cannot therefore be treated effectively. The only definitive treatment is re-transplantation, if necessary.