Introduction

It has now been more than 50 years since the first successful kidney transplant was performed between monozygotic twins (1).At that time, the field of immunology was in its infancy, and transplants between non-identical twins ended in organ failure because of acute graft rejection. It was not until the introduction of azathioprine (a nucleotide analogue less toxic than 6-mercaptopurine) in the early 1960s that chemical immunosuppression and prolonged kidney allograft survival became possible (2). Azathioprine by itself was not potent enough to prevent acute graft rejection. However, the combination of azathioprine and corticosteroids was shown to provide effective chemical immunosuppression, with 1-year kidney allograft survival rates ranging from 40 to 50% (3). This combination of chemical immunosuppression continued to be the cornerstone of transplant programs for the next 20 or so years until cyclosporine (CsA) entered the transplantation arena in the late 1970s (4).

In the late 1980s, other immune cell modulators such as tacrolimus and sirolimus were discovered and added to the arsenal of chemical immunosuppressive agents (5,6). Mycophenolic acid (MPA) (as the prodrug mycophenolate mofetil) became available in the mid 1990s based on reports from multicenter clinical trials demonstrating that it could further reduce the incidence of renal graft rejection when used in combination with CsA and steroids (7-9).

The number of solid organ transplants performed in the USA continues to increase each year (Table 1) (10). There has been a 17% increase in kidney, a 29% increase in liver, a 2% reduction in heart, and an overall increase of 17% over the last 5 years, when comparing organ transplants performed in 2005 with 2001 (10). Sadly, the limiting factor in the number of transplanted organs is the availability of donor organs. There were more than 94,000 patients on the U.S. organ transplant waiting list at the end of 2005 (11).

The discovery that CsA had immunosuppressive activity that specifically targeted T lymphocytes was a major breakthrough in organ transplantation because it dramatically reduced acute graft rejection and improved long-term graft and patient survival (12,13). The identification of other immunosuppressive drugs that modulate immune responses by additional molecular pathways enabled treatment options to evolve and has permitted combination therapies to be individualized based on patient requirements. Classes of immunosuppressive drugs along with generic and brand names currently approved

Table 1

Solid Organ Transplants in the USA

Year

Table 1

Solid Organ Transplants in the USA

Year

Organ Transplanted

2001

2002

2003

2004

2005

Kidney

14,100

14,527

14,856

15,671

16,477

Liver

4984

5061

5364

5780

6441

Heart

2171

2112

2026

1961

2126

All Organs3

23,942

24,552

25,083

26,539

28,098

a Includes pancreas, kidney-pancreas, intestine, lung, and heart-lung transplants.

a Includes pancreas, kidney-pancreas, intestine, lung, and heart-lung transplants.

Table 2

Immunosuppressive Drugs Used in Solid Organ Transplantation

Table 2

Immunosuppressive Drugs Used in Solid Organ Transplantation

Drug Class

Generic Name

Brand Names

Corticosteroids

Prednisone

Orasone, Deltasone

Methylprednisolone

Solu-Medrol, A-methaPred, Medrol

Dexamethasone

Decadron

Anti-metabolites

Azathioprine

Imuran

Cyclophosphamide

Cytoxan, Neosar

Mycophenolate mofetil

CellCept

Mycophenolate sodium

Myfortic

Calcineurin inhibitors

Cyclosporine A

Sandimmune, Neoral, many generic forms of Cyclosporines

Tacrolimus (FK-506)

Prograf

mTOR inhibitors

Sirolimus (Rapamycin)

Rapamune

Everolimusa (RAD0001)

Certican

mTOR, mammalian target of rapamycin. a Everolimus is currently in phase III clinical trials in the USA and has not been approved by the Food and Drug Administration (FDA) for use as an immunosuppressive agent.

mTOR, mammalian target of rapamycin. a Everolimus is currently in phase III clinical trials in the USA and has not been approved by the Food and Drug Administration (FDA) for use as an immunosuppressive agent.

by the United States Food and Drug Administration (FDA) for use in solid organ transplantation are listed in Table 2.

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