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1 Department of Medicine, University of Chicago Medical Center, Chicago, Illinois
Correspondence and requests for reprints should be addressed to Sangeeta M. Bhorade, M.D., Department of Medicine, University of Chicago Medical Center, 5841 S. Maryland Ave, Chicago, IL 60611. E-mail: sbhorade{at}medicine.bsd.uchicago.edu
ABSTRACT
Immunosuppression remains the mainstay of therapy for successful outcomes after lung transplantation. The need for optimal immunosuppression became evident to maintain long-term graft survival and to navigate the delicate balance between infection and rejection. Over the past two decades, immunosuppression for solid organ transplantation has evolved to target multiple immune pathways with the hope of decreasing both acute and chronic allograft rejection. Although current maintenance therapy after lung transplantation typically includes a calcineurin inhibitor, antimetabolite and corticosteroid therapy, newer therapies including induction therapy with biological agents, mTOR inhibitors, and salvage therapies including photopheresis and total lymphoid irradiation have emerged as alternate therapeutic options. This review will discuss both the current immunosuppressive medications that are used as well as different therapeutic combinations that are currently employed. In addition, we will discuss the current literature regarding the efficacy of these agents in lung transplantation.
Key Words: immunosuppression • lung transplantation
Dr. James Hardy and colleagues at the University of Mississippi performed the first surgically successful lung transplant on a 58-year-old gentleman with squamous cell cancer of the left main bronchus on June 11, 1963 (1). This patient, who succumbed on postoperative day 18 from renal insufficiency and complications of his underlying malignancy, received immunosuppression with azathioprine, prednisone, and cobalt therapy focusing on the thymic region (2). Although the immunosuppressive regimen was thought to contribute to his renal failure, on autopsy the transplanted lung showed only minor evidence of rejection.
In the ensuing 15 years, nearly 40 patients underwent lung transplantation, with only two patients surviving greater than 2 months and none surviving until hospital discharge (3, 4). In these initial unsuccessful attempts at lung transplantation, immunosuppressive medications were implicated due to presumed effects on weakening of the bronchial anastomoses in addition to being ineffective at preventing rejection.
With the discovery of cyclosporine A, lung transplantation as a potential therapeutic option for select end-stage lung disease was again revisited. In 1981 Dr. Bruce Reitz and colleagues at Stanford University performed the first combined heart-lung transplant, and in 1983 Dr. Joel Cooper and colleagues at the University of Toronto performed the first isolated single lung transplant resulting in greater than 1 year of survival (5). With these initial successes, there was renewed interest in lung transplantation as a life-sustaining therapeutic.
As experience with lung transplantation increased, early postoperative survival improved, exposing long-term sequelae, most notably chronic rejection in the form of bronchiolitis obliterans syndrome (BOS). The need for optimal immunosuppression became evident to navigate the delicate balance between infection risk and rejection. With an increased armamentarium of medications, transplant physicians now have more immunosuppressive combinations to simultaneously target multiple immune pathways, although no specific regimen has proven superior. In addition, new treatment protocols have emerged including induction therapy to deter early alloreactivity and its potential chronic long-term consequences as well as new salvage therapies for refractory acute and chronic rejection. This review will detail the current immunosuppressive medications being used, as well as different therapeutic combinations currently employed.
MAINTENANCE IMMUNOSUPPRESSIVE AGENTS
While details unique to specific immunosuppressive agents will be discussed under specific medications, certain side effects are true of immunosuppression in general. Transplant recipients are at risk of post-transplant lymphoproliferative disorder (PTLD), a mono- or polyclonal expansion of lymphocytes often associated with Epstein-Barr Virus infection or reactivity. In addition, transplant patients are at increased risk for other malignancies, most notably dermatologic cancers. As with immunosuppression for all indications, these patients are prone to opportunistic infections. Historically, cytomegalovirus (CMV) has resulted in much morbidity and mortality, but this has decreased recently with improved prophylaxis while bacteria and filamentous fungi now predominate (6). Lastly, transplant patients are unavoidably subject to polypharmacy and resultant undesired drug interactions.
Cyclosporine A
Cyclosporine (CsA) was initially discovered in 1968 as a product of Tolypocladium inflatum gams isolated from the soil of the Norwegian plain of Hardanger Vidda, although it has also been retrieved from fungi imperfecti native to Wisconsin (7, 8). The clinical use of this lipophilic endecapeptide was first reported in cadaveric donor kidney transplantation in 1978, with FDA approval for transplantation being granted in 1983. CsA has been used in all solid organ transplantation, but is not FDA approved for use in lung transplantation as there are no immunosuppressive medications with FDA approval for lung transplant.
An antiproliferative agent, cyclosporine inhibits transcription of IL-2 as well as other inflammatory proteins, including IL-3, IL-4, CD40L, GMCSF, TNF-
, and interferon (9). CsA binds cyclophilin, an immunophilin, and prevents calcineurin dephosphorylation of nuclear factor of activated T cells (NFAT), preventing translocation to the nucleus, its site of transcriptional activity in production of inflammatory proteins. This prevents activation and proliferation of CD4+ T cells through the IL-2 pathway (10). In addition, CsA has been shown to inhibit FOXP3 expression and potentially diminish regulatory T cell (CD4+CD25+FOXP3) suppressor function in animal models as well as in renal transplant patients (11, 12).
CsA was initially prepared and administered as an oil-based formulation known as Sandimmune. Bioavailability of this first preparation was unpredictable, ranging from 1 to 89% with a mean bioavailability of 30% (13). The second-generation microemulsion preparation, Neoral, lead to a more consistent bioavailability of 30 to 45%, with more rapid absorption than Sandimmune, resulting in higher blood concentrations (10). Blood levels can be followed by either trough (C0) or 2-hour post-dosage levels(C2). This 2-hour post-dose level is thought to correlate better with systemic concentrations of CsA as determined by area under the curve monitoring, although neither method has been effectively correlated to clinical outcome or rejection (14). In general, blood levels correlate more closely with risk of drug-related toxicity than with immunosuppressive efficacy. In particular, utilization of C2 levels has been correlated with decreased cyclosporine dosage and resultant improved renal insufficiency (15). At our institution, CsA trough levels are maintained from 200 to 400 ng/ml, depending upon time from transplant, while C2 levels are targeted between 900 and 1,200 ng/ml. CsA has a half-life of 19 hours, with greater than 90% excretion occurring in bile. Metabolism occurs mainly in the liver by the cytochrome P450 family, although the kidney and GI mucosa also contribute.
Because CsA is metabolized via the hepatic cytochrome P-450 system, any alteration of this system either by medications or hepatic dysfunction will result in variable CsA trough levels. Specifically, any medication that decreases cytochrome P450 activity can potentially lead to increased cyclosporine levels and increased toxicity while coadministration of medications that increase P450 activity can lead to decreased cyclosporine blood levels and potentially ineffective immunosuppression. One of the most common side effects of CsA is nephrotoxicity. This may range from mild renal dysfunction to end-stage renal disease requiring hemodialysis. This nephrotoxicity is often dose dependent, but may also be idiosyncratic (16). Renal dysfunction due to CsA may be reversible if CsA is stopped early. Other common side effects of cyclosporine include: hypertension, dyslipidemia, electrolyte disturbances, hirsutism, gingival hyperplasia, neurologic sequelae including seizures, and rarely, Hemolytic Uremic Syndrome (HUS) (17).
Tacrolimus
Tacrolimus (FK506) is a macrolide antibiotic originally isolated from the actinomycte Streptomyces tsukubaensis by Fujisawa Pharamceuticals in 1984, where it was noticed to inhibit the mixed lymphocyte reaction (18, 19). It was not until almost ten years later that tacrolimus received approval for use in suppression of liver allograft rejection, with subsequent approval in other solid organ transplants except lung transplantation.
Like cyclosporine, tacrolimus is an antiproliferative agent that binds to an immunophilin, FK-binding protein 12 (FKBP12), to exert its impact upon T cell activation and proliferation. This drug–cytosolic protein complex again inhibits calcineurin, thereby preventing activation and translocation of NFAT, with the ultimate effect being decreased IL-2 production and resultant decreased IL-2–mediated proliferation of T cells. Tacrolimus binds its cytosolic immunophilin more efficiently than does cyclosporine, resulting in 10 to 100 times more potency, although this does not translate into greater therapeutic immunosuppression but simply decreased dosage requirements (20). In addition, tacrolimus has been shown to decrease antibody production to a greater extent than cyclosporine (19). Similar to CsA, tacrolimus has been shown to decrease regulatory T cell concentration and possibly inhibit their potential suppressor effect (11, 12).
Tacrolimus is administered orally, sublingually, or by intravenous injection. The bioavailability is approximately 20 to 25%, although the medication should be administered 1 hour before or 2 hours after meals as fatty meals can decrease bioavailability by up to 37% (10). Tacrolimus has a half-life of 12 to 22 hours, with metabolism occurring in the liver by the cytochrome P450 family. As a result, tacrolimus and CsA have similar interactions with medications that alter the P450 family. At our institution, trough levels are followed with the goal of 10 to 20 ng/ml, depending on time after transplant. In addition, the side effect profiles vary slightly, although both medications are associated with acute and chronic renal insufficiency as well as dyslipidemia, hypertension, electrolyte disturbances, and rarely HUS (17). Tacrolimus is more strongly associated with neurologic complications including seizures, tremors, and headaches as well as with post-transplant diabetes.
Azathioprine
Azathioprine has a long history of use as a disease-altering agent in autoimmune diseases and neoplastic processes. An antimetabolite, azathioprine is an imidazole derivative prodrug for the active compound 6-mercaptopurine. Azathioprine exerts its immunosuppressive effect by halting DNA replication (21). In addition, azathioprine metabolites have been shown to turn the costimulatory signal CD28 into an apoptotic signal, resulting in lymphocyte depletion (22–24).
Azathioprine is both an oral and intravenous medication requiring once-daily dosing with a consistent oral bioavailability of approximately 40% (10). Drug levels are not routinely monitored, although accumulation of the metabolite 6-thioguanine may occur in renal disease and lead to toxicity. Like most immunosuppressive agents, azathioprine has multiple drug interactions. Most notable among these is allopurinol, an inhibitor of xanthine oxidase. Treatment of gout or hyperuricemia with allopurinol leads to decreased metabolism of 6-mercaptopurine and severely elevated circulating levels, resulting in potentially fatal toxicity from pancytopenia. If coadministration of azathioprine and allopurinol cannot be avoided, then azathioprine should be administered at 20 to 30% of normal dosage with routine monitoring of blood counts (25, 26). The main toxicity associated with azathioprine in general is a dose-dependent myelosuppression potentially resulting in thrombocytopenia, leucopenia, and macrocytic anemia. In addition, hepatotoxicity and malignancy have been reported.
A special consideration with azathioprine relates to patient thiopurine methyl transferase (TPMT) activity levels. TPMT metabolizes and subsequently inactivates azathioprine and its metabolites. Approximately 11% of the population have low TPMT levels, and 1 in 300 people have very low to inactive TPMT, resulting in increased toxicity of azathioprine with conventional treatment doses (27–29). In susceptible patients, therapy with azathioprine results in early myelosuppression. Measurement of TPMT activity levels can be assayed before initiation of azathioprine therapy.
Mycophenolate Mofetil
Mycophenolate Mofetil (MMF) is an antimetabolite immunosuppressant whose active component, mycophenolic acid (MPA), was first isolated from cultures of Penicillium brevicompactum by Gosio in 1896 and then purified by Alsberg and Black in 1913 (19, 30). In the early 1980s, MMF was selected for its ability to produce an intentional immunosuppressed phenotype equivalent to adenosine deaminase deficiency seen in pediatric T and B cell immunodeficiency (30). MMF gained FDA approval in 1995 for prevention of renal allograft rejection.
Immunosuppression by MMF occurs by its active component MPA through inhibition of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in de novo synthesis of guanine nucleotides. T and B cells are more dependent on this pathway than are other cells (31). Other potential mechanisms of immunosuppression include inducing apoptosis of activated T cells, decreasing expression of adhesion molecules resulting in decreased recruitment of inflammatory cells, and decreasing inducible nitric oxide production and the resultant tissue damage (31). MMF has been shown to have no effect on T regulatory cell survival or suppressor function (11).
MMF may be administered either orally or intravenously. MMF is rapidly absorbed and metabolized to its active form MPA, which is nearly completely protein bound. With a half-life of 18 hours, MMF is believed to undergo a secondary peak plasma level at 6 to 12 hours as a result of enterohepatic recirculation (22). Drug levels of MPA can be monitored, although this is not done routinely. Coadministration of antacids, cholestyramine, and iron should be avoided as they can decrease bioavailability. In addition, cyclosporine has been shown to decrease MPA levels by interfering with enterohepatic recirculation, although MMF does not have any true metabolic drug interactions (32). Diarrhea and GI distress are the most notable side effects although leucopenia and general bone marrow suppression have also been observed (33). Recently a new formulation of MMF, enteric coated MMF, has been developed to improve the mycophenolate exposure with decreased GI side effects. Clinical trials in heart and renal transplantation have found this formulation of comparable safety and efficacy to the original formulation of MMF (34, 35).
Sirolimus
Sirolimus is a macrocyclic lactone produced by the actinomycete Streptomyces hygroscopicus and was initially isolated from soil of the Vai Atari region of Easter Island (Rapa Nui) in 1975 (36, 37). Initial interest was in the use of sirolimus as either an antifungal or oncologic agent, although its lymphopenic properties quickly became apparent. In 1999, sirolimus received FDA approval for the prevention of acute rejection in kidney transplantation.
Although sirolimus has a molecular structure similar to tacrolimus and also binds to the cytosolic immunophilin FKBP12, it has a different mechanism of action. The sirolimus–FKBP12 complex does not inhibit calcineurin, nor does it inhibit pathways of IL-2 production. The sirolimus–FKBP12 complex binds proteins downstream of IL-2 in T cell activation pathways known as mammalian target of rapamycin (mTOR) that prevent DNA and protein synthesis, ultimately arresting T cells in the late G1 phase as they attempt to progress to the S phase of the cell cycle (38). In addition, sirolimus is a potent antifibroproliferative agent, resulting in poor wound healing and anastomotic site complications including fatal airway dehiscence in the perioperative period (39–41). In vitro, sirolimus has been shown to inhibit B cells independent of its effect on T cells, and has been shown to block immune cell responsiveness to essential proliferative cytokines (36). Similar to MMF, Sirolimus does not appear to negatively impact survival nor function of T regulatory cells as calcineurin inhibitors do, although this sparing of T regulatory cells has yet to be correlated to improved outcome in transplant recipients (11, 12).
Sirolimus is a once-daily oral medication with a bioavailability of 15%. It is highly lipophilic, with a half-life of approximately 60 hours (although this may be shorter in the pediatric population). Metabolized by the cytochrome P450 family of enzymes, sirolimus is subject to drug interactions, especially in the setting of the transplant patient population. Sirolimus is mainly excreted in feces and is not subject to dosage decreases in renal insufficiency. Drug levels are routinely monitored, with a goal of 10 to 20 ng/ml at our institution. Often lower therapeutic levels (5–10 ng/ml) are targeted when sirolimus is prescribed with tacrolimus or cyclosporine. In addition, given the pharmacokinetic interaction between sirolimus and CsA (not tacrolimus), sirolimus should be administered 4 hours after CsA administration. Sirolimus does not independently cause renal insufficiency, but can potentiate calcineurin inhibitor–induced nephrotoxicity by both increasing levels and potentiating mechanisms of nephropathy (42). In addition, sirolimus is associated with dyslipidemia, hypertension, myelosuppression, and thrombotic microangiopathy. Multiple different pulmonary pathologies have been associated with sirolimus, ranging from interstitial pneumonitis to organizing pneumonia, lymphocytic alveolitis, alveolar hemorrhage, and pulmonary vasculitis (43–45).
Everolimus
Everolimus is a rapamycin derivative that is synthesized to have an increased bioavilability compared with sirolimus. It can be administered either once or twice daily and has a shorter half-life with more rapid onset steady state than its parent compound. This medication shares mechanism of action with sirolimus as well as drug interactions and toxicities. Interestingly, everolimus does not affect the pharmocokinetics of CsA, in contrast to the CsA–sirolimus interaction, and may be administered simultaneously with CsA (46). In general, effective and tolerable levels for everolimus range between 3 and 12 ng/ml when used in conjunction with CsA and corticosteroids (47).
Glucocorticoids
From the beginnings of solid organ transplantation, corticosteroids, mainly in the form of prednisone, prednisolone, and methylprednisolone, have played a central role in maintenance immunosuppression as well as treatment of acute rejection. Despite their historic role in transplantation, many transplant clinicians continue to search out steroid-sparing regimens given their many deleterious side effects. Steroids persist, though, as an integral component in the lung transplant immunosuppressive armamentarium. In general, high doses of methylprednisolone (500–1,000 mg) are administered perioperatively with a subsequent reduction in steroid dosages to approximately 5 to 10 mg per day of oral prednisone over the ensuing months.
Although corticosteroids have long been used for their antiinflammatory and immunosuppressive activity, their exact mechanism of action remains incompletely understood. This is partly due to their nonspecific and broad-ranging actions (48). In a murine model, T regulatory cells were found to highly express the glucocorticoid receptor, resulting in corticosteroid-mediated T regulatory FOXP3 expression, suppressor activity, and cell survival (11, 49). Many of the sequelae specific to prolonged steroid exposure are well described and include: diabetes, hypertension, peptic ulcer disease, osteoporosis, dyslipidemia, growth retardation, and poor wound healing, along with changes in physical appearance with acne and Cushingoid features.
MAINTENANCE IMMUNOSUPPRESSION REGIMENS
Much of our understanding of immunosuppression in lung transplantation originates from studies in other solid organs. Original research in lung transplantation is limited by small sample sizes and often contradictory results. Complicating matters further, patients receive lung transplants for a heterogeneous group of pulmonary diseases, resulting in different patient phenotypes and individual pharmacogenomics. Given the lack of certainty as to optimal regimen, individual transplant centers follow different protocols with respect to initial immunosuppression, indications to transition medications, and hierarchical ordering of medications. Nonetheless, most patients receive an antiproliferative agent, an antimetabolite, and a steroid. Historically, this regimen consisted of cyclosporine, azathioprine, and low-dose prednisone. Currently, multiple combinations of the previously discussed medications are possible. Per the International Society of Heart and Lung Transplantation Registry (ISHLT), tacrolimus was reported to be used more commonly compared with CsA at both 1 and 5 years after transplantation. Similarly, MMF was prescribed more commonly than azathioprine at both 1 and 5 years after transplantation. The combination immunosuppressive therapy consisted of tacrolimus and MMF (35%) most commonly, followed by tacrolimus and azathioprine (20%), CsA and MMF (15%), and CsA and azathioprine (5%). Sirolimus use remains relatively low, with less than 20% of lung transplant recipients receiving the drug at either 1 or 5 years after transplantation (50).
In two prospective randomized trials comparing cyclosporine-based regimens against tacrolimus, differing results were obtained. In the first single-center study of 133 patients comparing cyclosporine and tacrolimus in the setting of concomitant azathioprine and steroids, there was no survival difference at 1 or 2 years, but the tacrolimus group had a statistically significant decrease in BOS and a trend toward decreased episodes of acute rejection (51). In the second study of 74 patients treated with MMF and steroids and randomized to either cyclosporine or tacrolimus, there was no difference in survival, acute rejection, or BOS (52).
Historically, azathioprine has been the first-line antimetabolite, although transplant centers are now using MMF. Two prospective randomized trials have evaluated azathioprine versus MMF. The first, using a cyclosporine and steroid regimen, found no statistical difference in episodes of acute rejection and survival at 6 months (53). The second multicenter trial, in which patients received induction with antithymocyte globulin and maintenance therapy with cyclosporine and steroids in addition to either azathioprine or MMF, demonstrated no difference in incidence, severity, or rate of BOS onset, nor was there any survival difference between the two arms of the study (54).
In a randomized double-blind clinical trial, everolimus was compared with azathioprine in combination with CsA and corticosteroids. Stable lung and heart-lung recipients were enrolled between 3 and 36 months after transplantation. The primary endpoint was defined as efficacy failure (decline in FEV1 > 15%, graft loss, death, or loss to follow-up at 12 mo). There was significant reduction in the incidence of efficacy failure with everolimus compared with azathioprine at 12 months after transplantation but not at 24 months after transplantation. The authors conclude that replacement of azathioprine by everolimus may benefit patients when added after 3 months after transplantation (55).
INDUCTION AGENTS
At the time of transplantation, many centers are now using induction chemotherapeutic agents to deplete the recipient immune system in the immediate post-transplant period to decrease early interaction between the recipient immune cells and donor allograft antigens. There is concern that early alloreactivity not only leads to increased acute rejection but to chronic low level inflammation. In 2005, approximately 45% of lung transplant recipients received an induction agent with transplantation (56).
OKT3
OKT3 is a murine monoclonal antibody directed against the epsilon chain of the T cell receptor–CD3 complex, resulting in prevention of T cell activation and depletion of circulating T cells with relative sparing of T regulatory cells (11, 57, 58). In the first hours after initial exposure to OKT3, T cells are actually activated by OKT3 resulting in a cytokine release syndrome with fevers, chills, headaches, and myalgias that can in its most severe form lead to circulatory collapse (59). Patients are premedicated with steroids, acetaminophen, and diphenhydramine to prophylax against this systemic inflammatory response. Within 48 hours of discontinuing OKT3, CD3+ T cells reemerge. OKT3 is dosed on a daily basis, beginning within 24 hours of transplant for up to 7 days after transplant. Other less frequent adverse effects include pulmonary edema, seizures, aseptic meningitis, and renal insufficiency (60).
Antithymocyte Globulin
Antithymocyte globulin is a polyclonal antibody nonspecifically directed at lymphocytes produced by inoculating animals with human thymocytes. The resulting 
immunoglobulin preparation is then filtered, resulting in a product specific for lymphocytes. Currently two products are available, with Atgam derived from horse serum and Thymoglobulin from rabbit serum. Antithymocyte globulin also depletes circulating lymphocytes through multiple mechanisms, including complement-mediated lysis and opsonization, resulting in clearance in the reticuloendothelial system (61). In addition, these globulin solutions may induce anergy or immune tolerance as antibodies within the preparation bind lymphocyte costimulatory molecules (62). Similar to OKT3 and alemtuzumab, antithymocyte globulin results in an expansion of T regulatory cells in vitro and a relative depletional sparing of these same cells in vivo (11). Antithymocyte globulin is dosed on a daily basis for up to 14 days, with Atgam having a half-life of 5.7 days and Thymoglobulin 30 days. Many patients have an acute reaction to initial administration of the globulin solution consisting of fevers and rigors, with some patients experiencing true anapahylaxis. As a result, acetaminophen, diphenhydramine, and steroids are used for prophylaxis. Notable later complications include immune complex–mediated glomerulonephritis and serum sickness symptomatic with fever, joint pain, and erythema. In addition, blood counts must be followed, as antithymocyte globulin has been associated with leucopenia and thrombocytopenia.
Daclizumab and Basiliximab
Daclizumab and Basiliximab are chimeric human-murine monoclonal antibodies targeting the subunit, or tac subunit, of the IL-2 receptor (CD25). By binding this cell surface receptor, these antibodies inhibit T cell proliferation and differentiation without T cell depletion. Although the two antibodies have the same mechanism of action, they have markedly different half-lives and duration of IL-2 receptor saturation owing to different proportions of human and murine components. Basiliximab is 25% murine with a half-life of approximately 13 days and an IL-2 receptor saturation of 30 days (63). Since daclizumab is only 10% murine, it has a longer half-life of 20 to 40 days and an effective IL-2 saturation of 120 days (64). Basiliximab is currently approved for dosing 20 mg on the first and fourth days after transplant, while daclizumab is dosed at 1 mg/kg within the first day after transplant and then every 2 weeks for a total of five doses. Being humanized, these monoclonal antibodies are generally well tolerated, although basiliximab has been associated with pulmonary edema and ARDS-like symptoms (10).
Alemtuzumab
Alemtuzumab is a humanized rat monoclonal antibody directed against CD52 originally prescribed in chronic lymphocytic leukemia and lymphoma. Although the function of CD52 remains incompletely clear, it is present on the cell surface of B and T cells as well as monocytes, macrophages, NK cells, and thymocytes (65). Through binding to CD52, alemtuzumab causes a depletion of leukocytes by multiple pathways, including complement-mediated cytolysis, antibody-mediated cellular toxicity, and apoptosis induction. Although alemtuzumab has a half-life of 12 days, different inflammatory cells have differential rates of recovery after alemtuzumab therapy, with monocyte recovery at 3 months, B cells at 12 months, and T cells 50% recovery at 36 months (65). In addition, alemtuzumab has been shown to result in inhomogeneous depletion of T cells with relative sparing of T regulatory cells and memory cells (66). Given that alemtuzumab infusion can precipitate cytokine storm with hemodynamic compromise, patients are pretreated with steroids. Alemtuzumab has also been linked to paroxysmal nocturnal hematuria (66).
INDUCTION THERAPY EFFICACY
Currently there is significant debate regarding the clinical efficacy of induction therapy in the setting of lung transplantation. Although induction therapy has proven to decrease incidence and severity of acute and chronic rejection in other solid organ transplantation, the beneficial effects of induction therapy on acute rejection and BOS in lung transplantation have not been consistently demonstrated in clinical trials, despite ISHLT registry data demonstrating a small but statistically significant improvement in survival with the use of induction therapy when excluding deaths in the 2-week perioperative period (50, 67, 68). As with maintenance immunosuppression, there is no consensus as to the most appropriate induction agent. Per the ISHLT registry including the dates from January of 2002 to June of 2006, approximately 30% of transplant recipients received induction therapy with an IL-2 receptor antagonist, 10% received therapy with polyclonal antilymphocyte or antithymocyte globulin, and 5% received induction with alemtuzumab (50).
In one single-center prospective study, thymoglobulin induction therapy reduced the incidence of acute rejection and demonstrated a trend toward decreased BOS (69). A later follow-up study by this same group, though, did not confirm a benefit to thymoglobulin induction therapy in decreasing incidence of acute rejection, BOS, or survival but did demonstrate delayed onset of acute rejection (70). Several other smaller retrospective studies have shown contradictory results comparing specific induction agents. One retrospective study demonstrated decreased acute rejection, BOS, and mortality with daclizumab over antithymocyte globulin induction, while two other retrospective studies noted increased acute rejection and BOS with daclizumab or basiliximab as opposed to antithymocyte globulin induction (71–73). In one prospective randomized controlled trial, there was no difference in acute rejection comparing daclizumab and antithymocyte globulin induction, while in a second prospective controlled trial there was no distinction between OKT3, antithymocyte globulin, and daclizumab in relation to acute rejection, BOS, and 2-year survival (74, 75).
Treatment of acute and chronic rejection
Treatment of uncomplicated acute rejection.
In general, the majority of lung transplant centers in North America treat uncomplicated acute rejection with a short course of intravenous corticosteroids (500–1,000 mg/d of methylprednisonolone for 3–5 d followed by steroid taper over the ensuing 2–3 wk) per a recent survey performed in 2002 (76).
Treatment of refractory acute rejection and chronic rejection.
Despite the many therapeutic options described above, refractory acute and chronic rejection remain unfortunate realities of lung transplantation. Several small single-center retrospective studies have suggested that conversion from CsA to tacrolimus may lead to reversal of refractory acute rejection episodes and improvement in lung function in patients with chronic rejection (77–81). An international retrospective study comparing CsA to tacrolimus revealed a decreased incidence of acute rejection and a reversal of refractory acute rejection after conversion from CsA to tacrolimus (82). In addition, many of the agents used for induction therapy have also been employed to reverse refractory rejection with varying success (83). Aerosolized CsA therapy was recently evaluated as a method to deliver higher concentrations of CsA directly to the lung allograft while decreasing levels of systemic exposure and toxicity. Open-label use of inhaled CsA improved histologic rejection and lung function in a small group of patients with refractory acute rejection (84). More recently, a prospective study compared the addition of inhaled CsA or placebo to maintenance immunosuppression. There was a significantly decreased risk of death and a greater rejection-free survival in patients who received inhaled CsA (85). At the current time, aerosolized CsA is not available commercially, but a larger prospective study is underway to evaluate the benefits of this therapy for lung transplant recipients.
SALVAGE THERAPIES
Other salvage modalities include total lymphoid irradiation (TLI) and extracorporeal photopheresis (ECP) (86–89). TLI consists of 800 cGy divided into 8 to 10 weekly XRT sessions with radiation beams focusing on the splenic and paraaortic field, the upper mantle and pelvic field, and the upper femoral field. Potential side effects include leucopenia, thrombocytopenia, and infection. ECP involves harvesting a patient's peripheral blood mononuclear cells through pheresis and exposing the cells to ultraviolet light in the presence of 8-methoxypsoralen, a DNA-intercalating agent. The cells are then reintroduced into the circulation. ECP is thought to induce apoptosis of the mononuclear cells, resulting in immunologic processing of cellular components after re-injection into the circulation that ultimately leads to the production of tolerogenic T-lymphocytes (90).
FUTURE DIRECTIONS
Immunosuppression in lung transplantation remains a difficult issue, with chronic rejection continuing to plague patient outcome. Future multicenter trials assessing current immunosuppressive therapies as well as more novel therapeutic approaches are needed to overcome potential center and regional variation in a genuinely heterogeneous patient population. In addition, continued research into the alloreactivity of the transplanted organ may identify new molecular targets for innovative therapies and new pharmaceuticals. With all that is yet be known and understood, lung transplantation remains an exciting field with much current and potential benefit for patients with end-stage lung disease.
FOOTNOTES
S.M.B. received support from Astellas Healthcare, Inc. to conduct a multicenter trial.
Conflict of Interest Statement: S.M.B. has received $500,000 between 2002 and 2008 from Astellas Healthcare, Inc. as a research grant for conducting a multicenter trial. E.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form August 28, 2008; accepted in final form October 16, 2008)
REFERENCES
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