Immunosuppressive therapy, as currently available, generally suppresses all immune responses, including those to bacteria, fungi, and even malignant tumors. In the 1950s, when clinical renal transplantation began, sublethal total-body irradiation was employed. We have now reached the point where sophisticated pharmacologic immunosuppression is available, but it still has the hazard of promoting infection and malignancy. In general, all clinically useful drugs are more selective to primary than to memory immune responses. Agents to suppress the immune response are discussed in the following paragraphs, and those currently in clinical use are listed in Table 282-4.
Azathioprine, an analogue of mercaptopurine, was for two decades the keystone to immunosuppressive therapy in humans but has given way to more effective agents. This agent can inhibit synthesis of DNA, RNA, or both. Therapy with azathioprine in doses of 1.5–2 mg/kg per d is generally added to cyclosporine as a means of decreasing the requirements for the latter. Reduction in the dose is required because of leukopenia and occasionally thrombocytopenia. Excessive amounts of azathioprine may also cause jaundice, anemia, and alopecia. If it is essential to administer allopurinol concurrently, the azathioprine dose must be reduced. As inhibition of xanthine oxidase delays degradation, this combination is best avoided.
Mycophenolate mofetilor mycophenolate sodium, both of which are metabolized to mycophenolic acid, is now used in place of azathioprine in most centers. It has a similar mode of action and a mild degree of gastrointestinal toxicity but produces minimal bone marrow suppression. Its advantage is its increased potency in preventing or reversing rejection. Patients with hyperuricemia can be given allopurinol without adjustment of the mycophenolic acid dose. The usual dose is 2–3 g/d in divided doses.
Glucocorticoids are important adjuncts to immunosuppressive therapy. Among all the agents employed, prednisone has effects that are easiest to assess, and in large doses it is usually effective for the reversal of rejection. In general, 200–300 mg prednisone is given immediately before or at the time of transplantation, and the dose is reduced to 30 mg within a week. The side effects of the glucocorticoids, particularly impairment of wound healing and predisposition to infection, make it desirable to taper the dose as rapidly as possible in the immediate postoperative period. Many centers now have protocols for early discontinuance or avoidance of steroids because of long-term adverse effects on bone, skin, and glucose metabolism. For treatment of acute rejection, methylprednisolone, 0.5–1 g IV, is administered immediately upon diagnosis of beginning rejection and continued once daily for 3 days. When the drug is effective, the results are usually apparent within 96 h. Such "pulse" doses are not effective in chronic rejection. Most patients whose renal function is stable after 6 months or a year do not require large doses of prednisone; maintenance doses of 10–15 mg/d are the rule. Many patients tolerate an alternate-day course of steroids without an increased risk of rejection. A major effect of steroids is on the monocyte-macrophage system, preventing the release of interleukin (IL) 6 and IL-1.
Cyclosporine is a fungal peptide with potent immunosuppressive activity. It acts on the calcineurin pathway to block transcription of mRNA for IL-2 and other proinflammatory cytokines, thereby inhibiting T cell proliferation. Although it works alone, cyclosporine is more effective in conjunction with glucocorticoids and mycophenolate. Clinical results with tens of thousands of renal transplants have been impressive. Among its toxic effects (nephrotoxicity, hepatotoxicity, hirsutism, tremor, gingival hyperplasia, diabetes), only nephrotoxicity presents a serious management problem and is further discussed below.
Tacrolimus (previously called FK506) is a fungal macrolide that has the same mode of action as cyclosporine as well as a similar side-effect profile; it does not, however, produce hirsutism or gingival hyperplasia. De novo diabetes mellitus is more common with tacrolimus. The drug was first used in liver transplantation and may substitute for cyclosporine entirely or be tried as an alternative in renal patients whose rejections are poorly controlled by cyclosporine.
Sirolimus (previously called rapamycin) is another fungal macrolide but has a different mode of action; i.e., it inhibits T cell growth factor signaling pathways, preventing the response to IL-2 and other cytokines. Sirolimus can be used in conjunction with cyclosporine or tacrolimus, or with mycophenolic acid, to avoid calcineurin inhibitors. Its use with tacrolimus alone shows promise as a steroid-sparing regimen, especially in patients who would benefit from pancreatic islet cell transplantation, where steroids have an adverse effect on islet survival.
Antibodies to Lymphocytes
When serum from animals made immune to host lymphocytes is injected into the recipient, a marked suppression of cellular immunity to the tissue graft results. The action on cell-mediated immunity is greater than the action on humoral immunity. A globulin fraction of serum [antilymphocyte globulin (ALG)] is the agent generally employed. For use in humans, peripheral human lymphocytes, thymocytes, or lymphocytes from spleens or thoracic duct fistulas have been injected into horses, rabbits, or goats to produce antilymphocyte serum, from which the globulin fraction is then separated. A rabbit antithymocyte globulin (thymoglobulin) is the agent most commonly in use currently. Monoclonal antibodies against defined lymphocyte subsets offer a more precise and standardized form of therapy. OKT3 is directed to the CD3 molecules that form a portion of the T cell antigen-receptor complex and is thus expressed on all mature T cells.
Another approach to more selective therapy is to target the 55-kDa alpha chain of the IL-2 receptor, which is expressed only on T cells that have been recently activated. Two such antibodies to the IL-2 receptor, in which either a chimeric protein has been made between mouse Fab with human Fc (basiliximab) or the antibody has been "humanized" by splicing the combining sites of the mouse into a molecule that is 90% human IgG (daclizumab), are in use for prophylaxis of acute rejection in the immediate posttransplant period. They are effective at decreasing the acute rejection rate and have few adverse side effects.
More recently, two new strategies have involved administration of engineered biologic agents: a depleting T cell antibody (alemtuzumab) as induction therapy to minimize maintenance immunosuppression and a fusion protein (Belatacept) to block B7 T cell costimulatory signals. The latter has shown promise in phase 2 trials and is currently being tested in phase 3 trials in kidney transplantation. Both of these new biologics as well as antilymphocyte globulin are increasingly being used as "induction" therapy at the time of transplantation to minimize or eliminate the use of either steroids or calcineurin inhibitors because of their perceived toxicities. The next step in the evolution of this therapeutic strategy, which has already been achieved in the short term in small numbers of immunologically well-matched patients, is the elimination of all maintenance immunosuppression therapy altogether.