Transplantation of Organs and Tissues
During the 1960’s and 70’s, corticosteroids and azathioprine were the only basis of immunosuppression therapy for organ transplantation. These mainly worked for acute rejection of the transplanted organ. In the 1980’s, cyclosporine A was introduced that substantially improved the one-year transplant survival rate. This triple immunosuppressive regimen became the standard protocol for most transplant centers in the world.
The next decade saw the addition of immunosuppression agents such as tacrolimus, mycophenolate mofetil, rapamycin, daclizumab and basiliximab.
Years later, an international clinical trial revealed that everolimus at 3 mg/day (a drug similar to rapamycin) may reduce the rate of progression of chronic rejection after lung transplantation. Everolimus is a proliferation signal inhibitor with immunosuppressive activity for bronchiolitis obliterans syndrome (BOS) occurring after lung transplantation. Researchers feel that ‘for the first time, a drug has demonstrated significant slowing of loss in lung function, suggesting that patients kept on prolonged maintenance treatment with everolimus may benefit from replacing azathioprine with everolimus 3 months after lung transplantation.’
Similarly, an FDA-approved drug for intravenous administration, ZENAPAX (daclizumab) is now used in cases of acute organ rejection in patients receiving renal transplants. It is used as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids.
The latest FDA-approved drug for kidney transplant patients is Nulojix. Nulojix (belatacept), a selective T-cell costimulation blocker, prevents acute rejection in adult kidney transplant patients and can be used with other immunosuppressants, such as basiliximab and corticosteroids.
Table: Approved immunosuppressive drugs in organ transplantation
· Cyclosporine A
Anti-lymphocyte polyclonal antibodies
Anti-CD3 monoclonal antibodies
Anti-interleukin 2 receptor monoclonal antibodies
· Mycophenolate mofetil
Unfortunately, these immunosuppressive drugs have to be taken life long. However, there is a ray of hope – new studies are working on the possibility of having a transplant without resorting to lifelong immunosuppressive drugs by inducing tolerance to the organ. For example, a study from the Massachusetts General Hospital and Harvard Medical School in Boston involving five patients with end-stage kidney disease who received combined bone marrow and kidney transplants from mismatched living-related donors with the use of a ‘nonmyeloblative peri-operative regimen’ showed that it was possible for all but one patient to discontinue all immunosuppressive therapy about 9 to 14 months after the transplantation, and renal function has remained stable for 2.0 to 5.3 years since transplantation. The study was published in the New England Journal of Medicine.
Then again, E K Geissler and H J Schlitt in their study titled ‘Immunosuppression for liver transplantation,’ and published in the journal Gut, reiterated the need for clear understanding of the positives and negatives of each immunosuppressive agent available so that ‘an optimal balance of efficacy with side effects for each individual’ could be found. For example, they said, clinical observations indicated that ‘liver transplants tend to be relatively resistant to rejection compared to other organs such as kidney and heart and therefore less pharmacological immunosuppression is generally required.’
All said and done, the search for ideal immunosuppressive drugs for transplant rejections still continues.