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Organ Transplantation

Graft Rejection
    Cellular Mechanisms
    Molecular Mechanisms

Immunsuppressive Agents
    Corticosteroids
    Calcineurine Inhibitors
    Antiproliferative Agents
    Monoclonal Antibodies
    Polyclonal Antibodies
    Side Effects       

Immunotherapy
    Inductive Therapy
    Maintenance Therapy
    Episodic Treatment

Current Areas of Research
    New Drugs
    Drug Efficacy
    Alternative Therapies
        Tolerance
        Tissue Engineering
        Xenotransplantation

Glossary of Terms
References

MAINTENANCE THERAPY

Maintenance immunosuppression refers to the classic combination therapy to which transplant recipients usually adhere for the rest of their lives. The combination includes a corticosteroid, a calcineurine inhibitor, and an antiproliferative. The concurrent administration of these three drugs have distinct combined effects on each individual. The balance of dosages can be altered to enhance the efficacy of the immunosuppression, but the most effective combination of prescriptions is unique for each individual patient. As with inductive therapy, the goal of maintenance immunotherapy is to balance between underimmunosuppression (which result in graft rejection) and overimmunosuppression (which expose the patient to high risks of infection and other potentially fatal side effects). The various side effects of each drug must be considered, as well as potential interactions between drugs, especially those that cumulatively present significant risk factors to certain patients. Another variable for maintenance immunosuppression is the particular drugs prescribed. For example, there are several different corticosteroids that are commonly employed as part of the immunosuppressive triple therapy. Thus, although the regimen of triple therapy is conventionally standardized, there is much room to improve immunosuppressive therapy to maximize efficacy and safety for the thousands of patients permanently on this treatment.

Corticosteroids are an important part of maintenance therapy because of their anti-inflammatory and immunosuppressive effects. They inhibit cytokine production, circulation of lymphocytes, acid metabolites, and microvascular permeability. They also block T cell activation and proliferation, and thus the clonal response. Prednisone and Methylprednisolone are two of the most commonly prescribed corticosteroids for organ transplant recipients. These drugs are non-specific and suppress the immune system in a global manner. Because this helps to induce a state of immune hyporesponsiveness, corticosteroids unfortunately have many harmful side effects for transplant patients. Corticosteroid use exemplifies the precarious balance between under- and over-prescription. Too much corticosteroid can cause hypertension, hyperglycemia, and opportunistic infection. Too little corticosteroid can result in graft rejection. However, much research has shown that a few months after transplantation, patients can be weaned off corticosteroids without increasing thefrequency of rejection episodes. This course of therapy is highly beneficial to the patient because reducing immunosuppressiondecreases negative long-term medical complications.

To combat activated T cells (which play a pivotal role in graft rejection), immunologists employ calcineurine inhibitors, which have come to be the integral cornerstone of triple therapy for transplant recipients. Calcineurine inhibitors block the clonal expansion of T cells and therefore significantly reduce acute rejection and improve graft survival. Cyclosporine and Tacrolimus are the two most prominent drugs; they have comparable immunosuppressive efficacy and nephrotoxicity, which is their most common serious side effect. Accordingly, much research is currently being conducted to find a way to reduce the toxicity of calcineurine inhibitors via new drugs and new therapies (which would employ synergistic immunosuppressive agents so that dosages might be reduced).

The final part of triple therapy includes antiproliferatives, such as Mycophenolate Mofetil, Azathioprine, and Sirolimus. These anti-mitotic drugs inhibit DNA synthesis and thus the division of T cells. Before the advent of calcineurine inhibitors, antiproliferatives were the primary form of maintenance immunotherapy. In present maintenance therapies, the role of antiproliferatives is more general and supportive to the action of the calcineurine inhibitors. Just as with corticosteroids, several studies demonstrate that transplant patients can be gradually weaned off of antiproliferatives without a corresponding increase in graft rejection incidences. Lowering antiproliferative treatment is desirable over the course of long-term immunotherapy because the incidence of side effects, like thrombocytopenia, are reduced.

The reduction of dosages in maintenance immunotherapy without graft rejection consequences is a phenomenon that has been observed by many researchers (as well as many patients who routinely disregard their doctors' prescriptions). Most notably, Dr. Tom Starzl has studied the induction of functional tolerance in transplant patients on maintenance immunotherapy. By mechanisms not entirely understood, over time some patients require less immunosuppression in order to prevent graft rejection. The medical benefits to such a reduction of therapy, as well as the cost benefits for those spending as much as $25,000 per year on immunosuppression, are outstanding. Functional tolerance is certainly a focus for future research and a realistic goal for maintenance immunotherapy treatment.

Dr. Tom Starzl presented some of his findings on functional tolerance at the 19th International Congress of the Transplantation Society. This
Tolerance Video features his insightful explanations of his recent studies.