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Ann Thorac Surg 2000;69:904-909
© 2000 The Society of Thoracic Surgeons

Original Articles

Successful treatment of acute, ongoing rat lung allograft rejection with the novel immunosuppressant SDZ-RAD

Bernard Hausen, MD, PhDa, Katrin Boeke, BSa, Gerald J. Berry, MDb, Uwe Christians, MD, PhDa,c, Walter Schüler, PhDa, Randall E. Morris, MDa

a Transplantation Immunology, Department of Cardiothoracic Surgery, Stanford University, Palo Alto, California, USA
b Department of Pathology, Stanford University, Palo Alto, California, USA
c Department of Biopharmaceutical Sciences, University of California at San Francisco, San Francisco, California, USA

Address reprint requests to Dr Hausen, Transplantation Immunology, Department of Cardiothoracic Surgery, Falk CVRB, Stanford University Medical Center, 300 Pasteur Dr, Palo Alto, CA 94305-5407.
e-mail: hausen{at}leland.stanford.edu


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. Recent experimental data have shown that coadministration of microemulsion cyclosporine and the novel immunosuppressant SDZ-RAD potentiates the immunosuppressive efficacies of both drugs to suppress allograft rejection. Our study was designed to assess the potential of delayed SDZ-RAD administration, in addition to cyclosporine maintenance therapy, to reverse acute rejection in an allogeneic rat lung transplant model.

Methods. Unilateral left lung transplantation was performed using Brown-Norway donors implanted into Lewis recipients. An untreated control group and a cyclosporine monotherapy group (7.5 mg/kg) were followed for 7 days. An additional cyclosporine monotherapy group (7.5 mg/kg), and a combined therapy group treated with cyclosporine (7.5 mg/kg) plus SDZ-RAD (2.5 mg/kg), were followed for 21 days. For treatment of ongoing rejection, 7.5 mg/kg cyclosporine was given as maintenance therapy, and SDZ-RAD (2.5 mg/kg) was added on postoperative day 7. Drugs were given orally, and in the combined therapy regimens, administered 6 hours apart. Outcome variables included daily weight, radiographs, and histology.

Results. Radiographs on postoperative day 7 showed mild and moderate opacification of the left chest in the cyclosporine monotherapy groups and the untreated control group. Addition of SDZ-RAD to cyclosporine treatment on postoperative day 7 reversed opacification by postoperative days 14 and 21. Monotherapy with microemulsion CsA resulted in mild histological rejection by day 7, which progressed to moderate rejection by day 21. Addition of SDZ-RAD on postoperative day 7 reversed acute rejection, resulting in none or minimal rejection at day 21.

Conclusions. SDZ RAD reverses acute rejection under cyclosporine maintenance therapy in a stringent lung allotransplant model.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
Acute rejection, a common finding following clinical lung transplantation [1], has been identified as the predominant risk factor for chronic airway rejection, which is manifested by the presence of obliterative bronchiolitis [2, 3]. Several treatment strategies are currently available that are able to reverse the histologic changes of most initial episodes of acute rejection. Pulsed intravenous methylprednisolone has remained the cornerstone of acute rejection therapy, since the introduction of lung transplantation as a feasible clinical alternative for end-stage lung disease [4]. Patients with steroid-resistant rejection, or severe rejection with significant compromise of graft function, are often treated with cytolytic therapy [5]. Newer therapeutic options include extracorporeal photochemotherapy with UV-A in the presence of 8-methoxypsoralene [6], the short term administration of methotrexate [7], plasmapheresis [8], aerosolized cyclosporine inhalation [9], and total lymphoid irradiation [10]. In addition, physicians have often tried to use augmented baseline immunosuppression to reverse rejection. Increase of both cyclosporine (CsA) [11] and tacrolimus doses [12] have been used with varying success to reverse rejection of lung transplants, but this treatment modality has not become standard practice for this indication.

Severe rejection or late treatment of acute rejection may be associated with an irreversible decline in lung function, and therefore an early treatment of lesser degrees of rejection could be advantageous. However, the currently available options for treatment of acute rejection are often associated with significant side effects and morbidity. Most importantly, these include an increased risk of lung allograft infections [13], as well as metabolic derangements especially associated with pulsed steroid therapy [14].

As novel immunosuppressants are explored in preclinical transplant models for prevention of acute rejection, they are often also evaluated for their efficacy in reversing acute rejection. Mycophenolate mofetil and leflunomide have shown promising results in reversing acute rejection in rodent heart, pancreas, and kidney transplant models [15, 16]. In individual patients, both rapamycin and mycophenolate mofetil have successfully been used as rescue therapy for heart and kidney transplant recipients with refractory rejection [17–19]. Although these results are encouraging, it is important to keep in mind that, at least in animal models, prevention of acute lung allograft rejection requires higher levels of immunosuppression to prevent acute rejection than heart or kidney allografts [20]. SDZ-RAD is a novel rapamycin derivative, which is for solid organ transplantation in clinical trials. We have previously shown that this compound prevents acute lung allograft rejection in cynomolgus monkeys and rats when coadministered with microemulsion CsA [21–23]. Since the potential of SDZ-RAD to treat acute lung allograft rejection has not yet been studied in either preclinical models or in lung transplant patients, it was our aim to evaluate the effect of SDZ-RAD on ongoing rejection in a rat lung allograft model under cyclosporine maintenance immunosuppression.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
Animals
Male Lewis (RT1l) and Brown-Norway (RT1n) viral antibody free rats (250 to 300g) were purchased from Charles River Laboratories (Wilmington, MA). The animals received humane care in compliance with the "Principals of Laboratory Animal Care" formulated by the National Society for Medical Research, and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH Publication No. 80-123, revised 1985). Approval was granted by the Institutional Animal Care and Use Committee at Stanford University.

Drugs and treatments
Microemulsion formulations of cyclosporine and SDZ-RAD for oral administration were provided to the investigators by Novartis Pharma AG (Basel, Switzerland). SDZ-RAD (20 mg/mL) was stored at 4°C and diluted in 5% (W/V) glucose before intragastric administration at a total volume of 5 mL/kg. For intragastric administration, a rigid feeding tube was passed into the stomach in the conscious animal, and the drug injected by hand. The CsA microemulsion (100 mg/mL) was kept at room temperature and was diluted in 5% (W/V) glucose for a total administration volume 5 mL/kg. For treatment of rats in the placebo control group, a solution containing the vehicle formulation without SDZ-RAD was used (Novartis Pharma AG). Treatment was initiated immediately after operation (day 0), and then drugs were given in single daily doses throughout the study. Doses were based on the individual daily weight of each rat.

Experimental groups
Thirty-one unilaterally lung transplanted rats were assigned to one of the following five treatment groups: (I) Vehicle controls (n = 5); (II) 7.5 mg/kg/day cyclosporine for 7 days (n = 6); (III) 7.5 mg/kg/day cyclosporine for 21 days (n = 8); (IV) 7.5 mg/kg/day cyclosporine and 2.5 mg/kg/d SDZ-RAD for 21 days (n = 6); and (V) 7.5 mg/kg/day cyclosporine for 21 days, with 4 mg/kg SDZ-RAD on postoperative day 7 and 2.5 mg/kg/day SDZ-RAD from day 8 to day 21 (n = 6) (graft rescue group).

When cyclosporine and SDZ-RAD were combined, SDZ-RAD was given first and cyclosporine 6 hours later to reduce drug interaction during absorption. Dosing cyclosporine and SDZ-RAD 6 hours apart has proved to be beneficial in lung transplant rats in a previous study [22]. The choices of cyclosporine and SDZ-RAD doses used in this study were based on previous reports in which these drugs were successfully used to treat rat kidney and heart allograft recipients [24, 25].

Orthotopic unilateral lung transplantation
Recipient Lewis and donor Brown-Norway rats were anesthetized with 2% isoflurane and intraperitoneal pentobarbital (50 mg/kg). Left-sided unilateral lung transplantation was performed using a modification of the technique originally described by Marck and Wildevuur [26].

Follow-up
The general health status of the recipient animals was assessed by daily weight measurements and evaluation of grooming behavior and feces. Chest radiographs were performed on postoperative days 1, 7, 14, and 21. The chest radiographs were evaluated by an investigator blinded to the individual treatment groups. The presence and distribution of densities of the left thorax were evaluated in a blinded fashion and based upon a semiquantitative scale (normal, mild, moderate, or severe opacification). Blood trough concentrations of the immunosuppressants were determined for each rat immediately preceding drug administration on postoperative days 7 (groups I and II), 14, and 21 (groups III to V).

Collection, processing, and pharmacokinetic analysis of blood specimens
EDTA-anticoagulated blood samples were collected from animals during isoflurane-induced sedation by puncture of the retro-orbital venous plexus. Drug levels of SDZ-RAD and cyclosporine were determined using HPLC/electrospray-mass spectrometry. Sample preparation was based on solid-liquid extraction following the procedure described by Streit and associates [27]. Concentrations are reported in ng/mL and were calculated based on standard curves, after correcting for losses during extraction and variability during HPLC/MS analysis using the internal standards cyclosporin D for cyclosporine and 28-,40-diacetyl rapamycin for SDZ-RAD.

Histology
At the time of sacrifice, animals were sedated and heparinized. The transplanted lungs were removed and inflated through the main bronchi with 10% neutral buffered formalin. Multiple slices of lung tissue were cut longitudinally, routinely processed, and embedded in paraffin wax. Sections were prepared and stained with hematoxylin and eosin, and elastic von Gieson. A pathologist blinded to the individual treatment groups evaluated the resulting slides. Histologic results were rated based on the classification approved by the International Society for Heart and Lung Transplantation (A0 = no rejection, A1 = minimal rejection, A2 = mild rejection, A3 = moderate rejection, and A4 = severe rejection) [28].

Statistics
Statistical analyses were performed using the statistics program SigmaStat (Jandel Scientific Software, San Rafael, CA). Values are shown as mean ± standard errors of the mean for parametric data and as medians for nonparametric data. For repeatedly assessed parametric data (animal weight), groups were compared using the repeated measure analysis of variance (ANOVA) test in combination with the Bonferoni posthoc test. One-way analysis of variance, in combination with post hoc tests, was used for nonrepeated measures of parametric data (trough levels). For nonparametric data (radiograph evaluation, histology), multiple group comparisons were performed using Kruskal-Wallis analysis of variance on ranks in combination with a Dunn’s post hoc test. A p value equal to or less than 0.05 was considered as significant.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
Chest radiographs in transplant rats
Vehicle treated controls showed complete opacification by postoperative day 7 (Table 1). The median score at postoperative day 7 for the cyclosporine monotherapy groups (II and III) and the graft rescue (group V) was mild opacification. The addition of SDZ-RAD at day 7 in the graft rescue group (group V) resulted in an improvement from mild opacification (day 7) to no opacification (day 21). Lung transplant rats treated with a combination of cyclosporine and SDZ-RAD throughout the observation period (group IV) showed no opacification after initial changes related to ischemia-reperfusion injury of the graft had cleared. The individual levels of significance are given in the legend to Table 1.


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  		Table 1. Semiquantitative Evaluation of Serial Chest Radiographsa

 
Histology of the transplanted lungs
Recipients treated with the drug vehicle completely rejected their allografts within 7 days postoperatively (Fig 1). Cyclosporine monotherapy resulted in mild rejection by postoperative day 7 (group II), which progressed to moderate rejection by day 21 (group III). In contrast, the average lung biopsy rejection score at day 21 showed no or minimal rejection in both cyclosporine and SDZ-RAD combination treatment groups (groups IV and V). The results of the one-way ANOVA analysis are shown in the legend to Figure 1.



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  		Fig 1. Comparison of the histology scores of acute lung rejection in individual rats. (A0 = no rejection, A1 = minimal rejection, A2 = mild rejection, A3 = moderate rejection, A4 = severe rejection.) One-way analysis of variance on ranks: Control versus cyclosporine + SDZ-RAD (group IV): p < 0.001; control versus graft rescue group (group V): p < 0.002; microemulsion CsA monotherapy (group III) vs cyclosporine + SDZ-RAD (group IV) p = not significant; microemulsion CsA monotherapy (group III) vs graft rescue therapy (group V) p < 0.05.

 
Cyclosporine and SDZ-RAD trough blood concentrations
Figure 2A depicts the mean cyclosporine (CsA) trough levels drawn on postoperative days 7, 14, and 21. Trough levels drawn on postoperative 21 were significantly higher in the cyclosporine monotherapy group (group III) when compared to the cyclosporine and SDZ-RAD combination treatment groups (IV and V). The mean SDZ-RAD trough levels were not significantly different between the two combination treatment groups (Fig 2B).



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  		Fig 2. Mean trough blood concentrations of cyclosporine (A) and SDZ-RAD (B) in lung transplant rats. Data are presented as mean ± standard error of the mean. Statistical significance was evaluated by one-way analysis of variance with posthoc tests.

 
Animal weights
The weight of all animals decreased after transplantation (Fig 3). The weight decrease was most pronounced in the grafts of groups IV and V. The early postoperative weight loss in group II was less pronounced than in group III despite identical treatment, however, this difference did not reach statistical significance. Recovery from the weight loss was rapid in the vehicle control and the cyclosporine monotherapy groups within the 7-day follow-up period (group II). In contrast to both the cyclosporine monotherapy groups and the vehicle control group, animals in the combination therapy groups did not regain their original weight by the end of the follow-up period (21 days). Results of the repeated measures ANOVA are shown in the legend to Figure 3.



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  		Fig 3. Mean weight as a percentage of initial weight at the day of surgery. Comparison using repeated measures analysis of variance: control versus cyclosporine + SDZ-RAD (group IV) p < 0.0001, control versus graft rescue group (group V) p < 0.04.

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
Acute rejection is the most significant predictor for the development of obliterative bronchiolitis after lung transplantation [2, 3]. Yousem [29] and Sibley and associates [1] have shown that approximately 25% of patients with mild lung rejection progress to moderate or severe acute rejection. To improve the long-term outcome following clinical lung transplantation, treatment of lesser grades of rejection may prove beneficial.

Current treatment strategies for acute moderate or severe allograft rejection include pulsed bolus methylprednisolone and cytolytic therapy, such as OKT-3 or RATG. Unfortunately, both types of therapy are associated with an increased risk of infection. The use of OKT-3 has been shown to increase the risk of cytomegalovirus disease (CMV) [30], which in turn has been shown to be a predictor of obliterative bronchiolitis in lung transplantation [2, 3]. High dose steroid therapy can significantly alter metabolic functions with the risk of a hyperglycemic crisis and deterioration of bone diseases.

Recently, a number of novel treatment options have become available for patients with steroid-resistant refractory rejection. Extracorporeal photochemotherapy with UV-A, in the presence of 8-methoxypsoralene [6], has been shown to be effective in heart transplant recipients with multiple rejection episodes [31]. Cahill and coworkers used a 6-week course of methotrexate to treat a total of 12 lung transplant recipients with steroid refractory rejection, of which 10 patients were free of rejection during the following 12 month follow-up period [7]. Although plasmapheresis has mainly been used for treatment of presensitized patients [8], case studies reported successful treatment of steroid resistant rejection [32]. In addition, aerosolized cyclosporine [9] and total lymphoid irradiation [33] are effective measures to reverse refractory rejection of lung transplants. There is a general consensus that the relative invasiveness and/or associated risks and morbidity of these novel treatment strategies, with the possible exception of aerosolized cyclosporine inhalation, again limits their use to patients with moderate to severe rejection episodes or refractory rejection.

We have previously shown that SDZ-RAD can prevent acute rejection of lung allografts in different species [22, 34]. Based on the available efficacy data for prevention of acute rejection, our aim was to test if SDZ-RAD was also efficacious in treating acute rejection.

According to the data obtained from the present rat lung allograft study 7.5 mg/kg/day of cyclosporine as monotherapy was sufficient to prevent acute severe rejection, and resulted in mild rejection by postoperative day 7. Continuous treatment with the same therapy did not prevent progression to moderate rejection by postoperative day 21. In our model, addition of SDZ-RAD to maintenance immunosuppressive therapy with cyclosporine on postoperative day 7 not only successfully halted progression of the severity of rejection, but also reversed the grade of rejection, within 2 weeks, to no or minimal rejection. The resolution of rejection, as seen in the histologic review of the lung specimens, is supported by resolution of chest radiograph changes between postoperative day 7 and postoperative day 21. The efficacy of the late addition of SDZ-RAD is underlined by the fact that the CsA levels in group V were significantly lower than those obtained in the cyclosporine monotherapy group (group III). The current study was not designed to investigate possible causes for this significant difference in CsA trough levels between group III and the two CsA plus SDZ-RAD combination treatment groups.

Staggered administration of cyclosporine and SDZ-RAD was tolerated, and the animals were free of clinically evident infection or wound healing problems. However, combined administration of CsA and SDZ-RAD in both groups IV and V did result in a significant decline in weight when compared to untreated controls at postoperative day 14. This postoperative time period represented the nadir in weight loss, after which animals in both combination treatment groups either stabilized or started to regain weight. The cause of this weight loss is unclear, and has been observed in numerous studies in which rats had been treated with SDZ-RAD or sirolimus alone, or in combination with CsA [16, 22, 34].

In conclusion, SDZ-RAD completely reversed mild to moderate rejection of lung transplants and, therefore, its potential to treat severe and refractory rejection should also be investigated. Since SDZ-RAD was generally well tolerated in animal and clinical studies, and can be given orally on an outpatient basis, SDZ-RAD seems to be a promising candidate for clinical studies to assess its benefits for the early treatment of minimal and mild stages of rejection in lung transplant patients under cyclosporine immunosuppression.


   Acknowledgments
 
We would like to thank Laurie Hook, Department of Cardiovascular Surgery, Stanford University, for the preparation and critical review of the manuscript. The technical input and the efforts of Frank Schröder, in respect to animal care and treatments, are greatly appreciated.

This study was funded in part by the Ralph and Marian Falk Medical Research Fund, the HEDCO Foundation and Novartis Pharma AG, Basel, Switzerland.


   References
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 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

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Accepted for publication August 12, 1999.




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