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doi:10.1378/chest.06-1257
(Chest. 2007; 131:533-538)
© 2007 American College of Chest Physicians
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Elevation of Interleukin-15 Protein Expression in Bronchoalveolar Fluid in Acute Lung Allograft Rejection*

Sangeeta M. Bhorade, MD, FCCP; Andrew Yu, MD; Wickii T. Vigneswaran, MD, FCCP; Charles G. Alex, MD, FCCP and Edward R. Garrity, MD, FCCP

* From the Departments of Medicine (Drs. Bhorade and Garrity) and Thoracic and Cardiovascular Surgery (Dr. Vigneswaran), University of Chicago, Chicago; Pulmonary/Critical Care Medicine (Dr. Yu), Dupage Medical Group, Lombard; and Department of Medicine (Dr. Alex), Loyola University Medical Center, Maywood, IL.

Correspondence to: Sangeeta M. Bhorade, MD, FCCP, Lung Transplant Program, University of Chicago, 5841 S Maryland Ave, MC0999, Chicago, IL 60637; e-mail: sbhorade{at}medicine.bsd.uchicago.edu

Abstract

Background: Acute rejection remains a major source of morbidity in lung transplantation. Although interleukin (IL)-2 has been the principal T-cell growth factor implicated in acute rejection, IL-2 blockade does not prevent acute rejection completely. Recently, IL-15, a stromal cell-derived cytokine, has been found to share a similar biological function with IL-2. We hypothesized that IL-15 levels may be elevated in acute lung rejection in the presence of IL-2 blockade.

Methods: Acute allograft rejection developed in 21 of 42 lung transplant recipients. BAL fluid (BALF) was analyzed for IL-2 and IL-15 protein expression by standard enzyme-linked immunosorbent assay.

Results: The average (± SD) BALF IL-15 level was higher in lung transplant recipients with acute rejection compared to those without rejection (25 ± 25 pg/mL vs 4.5 ± 1.5 pg/mL, respectively; p < 0.0001). In addition, there appeared to be a bimodal distribution of BALF IL-15 levels in lung transplant recipients with acute rejection. BALF IL-2 levels were not associated with acute rejection. BALF IL-15 levels were not associated with bacterial, fungal, or cytomegalovirus infection.

Conclusion: These data show that BALF IL-15 levels are elevated in acute lung allograft rejection in the presence of IL-2 receptor blockade and may be an important mediator for acute rejection in lung transplantation.

Key Words: acute rejection • allograft • BAL fluid • interleukin-15 • lung transplantation

Acute lung allograft rejection remains a major source of morbidity in lung transplantation. Interleukin (IL)-2 has been the principal T-cell cytokine that has been implicated in acute rejection. The IL-2/IL-2 receptor complex elaborates the T-cell response to the transplanted organ by promoting the differentiation and clonal expansion of activated T cells, specifically cytotoxic T cells.123 Although blockade of the IL-2/IL-2 receptor pathways by anti- CD25 monoclonal antibodies significantly decreases the number of acute rejection episodes in solid-organ transplantation, this blockade does not prevent the occurrence of acute rejection completely.4567

This observation suggests that there may be several other T-cell growth factors that may stimulate T-cell activation and proliferation. Recently, IL-15, a stromal cell-derived cytokine, has been found to share a similar biological function with IL-2.89 IL-15 has been found to be structurally similar to IL- 2 and binds to both the ß and {gamma} chains of the IL-2 receptor. IL-15 has been found to be a powerful chemoattractant for T cells into the allograft.10 Moreover, IL-15 stimulates T-cell, B-cell, and natural killer (NK) cell proliferation and differentiation into cytotoxic effector cells.111213

Previous studies14 in cardiac transplantation have found elevated levels of intragraft IL-15 messenger RNA expression after transplantation with blockade of the IL-2/IL-2 receptor pathway by anti-CD25 monoclonal antibody. In addition, Pavlakis and colleagues15 demonstrated elevated IL-15 messenger RNA expression in rejecting renal allografts in the absence of IL-2 messenger RNA expression, suggesting an alternate route for T-cell activation and proliferation. Elevated levels of IL-15 messenger RNA have also been found in liver allografts during rejection.16

We speculate that IL-15 levels may be associated with acute rejection episodes in lung transplantation in the presence of IL-2 receptor blockade. The primary aim of this study was to assess IL-15 and IL-2 protein expression in the BAL fluid (BALF) of lung transplant recipients in the presence of IL-2 receptor blockade by an anti-CD25 monoclonal antibody.

Materials and Methods

Study Population
This study was approved by the Institutional Review Board at Loyola University Medical Center, and informed consent was obtained from all participants in the study. All patients who underwent lung transplantation at Loyola University Medical Center between April 2001 to December 2002 were enrolled in the study. Forty-two lung transplant recipients were included in the study. All study patients received tacrolimus, azathioprine, and prednisone, and induction therapy with daclizumab.

Immunosuppression
Initial tacrolimus dosing was 0.03 mg/kg bid po after transplantation, with target trough levels from 10 to 20 ng/mL for the first 3 months after transplantation. Target trough tacrolimus levels were 7 to 14 ng/mL after the first 3 months after transplantation. Azathioprine was administered before implantation and then daily at 2 mg/kg/d. The azathioprine dosage was adjusted for leukopenia and thrombocytopenia. Oral steroids were initiated at 0.25 mg bid and then decreased to 5 mg/d by 3 months after transplantation. Daclizumab, an anti-CD25 monoclonal antibody, was administered per instructions of the manufacturer. The first dose was administered before implantation, and the subsequent four doses were administered every 2 weeks.

Corticosteroid therapy for acute rejection was administered in the following manner. Patients with asymptomatic grade A1 or B1 rejection did not receive augmented immunosuppression. A follow-up bronchoscopy was performed 3 to 6 weeks after the initial bronchoscopy. For patients with symptomatic grade 1 rejection or grade A2 or B2 rejection, solumedrol, 500 to 1,000 mg po qd for 3 days with a 7- to 10-day taper of prednisone, was administered. A follow-up bronchoscopy was performed 3 to 6 weeks after the initial bronchoscopy.

Bronchoscopy With BAL and Transbronchial Biopsy
Surveillance bronchoscopies with BAL and transbronchial biopsies were performed at 1, 3, 6, 9, and 12 months. In addition, bronchoscopies were performed for clinical indications including a decline in spirometry results, radiographic infiltrates, cough, fever, or dyspnea. The bronchoscope was introduced transorally, and the airway was anesthetized with 2% lidocaine. The bronchoscope was then wedged in either the right middle lobe or lingua of the engrafted organ. An initial 90 mL of normal saline solution was instilled and subsequently hand-aspirated for BAL analysis. Recovery of BALF was approximately 50% in all samples. BALF was sent for routine bacterial cultures, fungal culture, and cytomegalovirus (CMV) culture. In addition, 20 to 30 mL of BALF was processed to remove the cellular material from the supernatant. The filtered supernatant was stored at – 70°C until ready for use. IL-2 and IL-15 were measured using enzyme-linked immunosorbent assay (Quantikine; R&D Systems; Minneapolis, MN). Both IL-2 and IL-15 levels were adjusted for protein performed by bicinchoninic acid (BCA) analysis, a colorimetric detection and quantitation of total protein (Pierce; Rockford, IL). This method combines the reduction of CU+2 to CU-1 by protein in an alkaline medicum (the biuret reaction) with the highly sensitive and selective colorimetric detection of the cuprous cation using a unique reagent containing BCA. The reaction product is formed by the chelation of two molecules of BCA with one cuprous ion. We compared both unadjusted IL-2 and IL-15 levels with those adjusted for protein and found a significant correlation coefficient (r = 0.76; p < 0.0001). All data reported has been adjusted for protein levels. All adjusted levels were expressed as picograms per milligram. Each sample was run in duplicate.

After the BALF was obtained, approximately five transbronchial biopsies were performed using 2-mm fenestrated forceps from either the right or left lung allograft. Transbronchial biopsy specimens were sent for histologic diagnosis of acute rejection and/or chronic rejection.

Acute Rejection: Diagnosis and Therapy
Acute rejection was defined histologically by International Society of Heart and Lung Transplantation criteria as either grade 1 (A or B) or higher.17 Treatment of acute rejection included IV solumedrol, 500 to 1,000 mg/d for 3 days, followed by a rapid prednisone taper. Follow-up bronchoscopy was performed in 3 to 6 weeks. Treatment for refractory or persistent episodes of acute rejection included a repeat bolus of steroids and/or change of baseline immunosuppression.

Statistical Analysis
Data are presented as mean ± SD. Continuous variables were compared with the Student t test, and categorical variables were compared using Fisher exact test. Nonparametric data were compared using the Mann-Whitney rank-sum test. Repeated-measures analysis of variance was used to compare BALF IL-15 levels in eight patients with serial BALF samples. Logistic regression analysis was used to examine the independent association between IL-15 and the risk of acute rejection while controlling for covariates (CMV, Aspergillus, or bacterial infections).

Results

Forty-two lung transplant recipients underwent 86 bronchoscopies with BAL and transbronchial biopsies. Acute rejection developed in 21 patients (50%) during the study period. Bronchoscopies were performed an average of 186 ± 111 days for rejectors and 197 ± 177 days for nonrejectors. Baseline demographic characteristics between patients with acute rejection and those without acute rejection were similar (Table 1 ). The mean time to rejection developing was 152 ± 121 days.


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  		Table 1.. Demographic Data*

 
Of the 86 bronchoscopies that were performed, 33 bronchoscopies were performed in 21 nonrejectors and 53 bronchoscopies were performed in 21 rejectors. Of these, 51 were surveillance bronchoscopies, and 35 were performed for clinical deterioration or follow-up of previous acute rejection (Table 2 ). Twenty-one episodes of acute rejection in 21 patients were detected on biopsy; 17 episodes of grade 1 acute rejection, and 4 episodes of grade 2 acute rejection were detected (Table 3 ). All 10 episodes of acute rejection among the clinical bronchoscopies were treated with a corticosteroid burst. In the surveillance group, one patient with grade 2 acute rejection was treated with increased steroids. There was no significant difference in the BALF IL-15 or BALF IL-2 levels between acute rejection detected by clinical vs surveillance biopsies (33 ± 25 pg/mL in surveillance bronchoscopies vs 23 ± 25 pg/mL in the clinical bronchoscopies). BALF cell counts were similar in the two groups (Table 4 ).


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  		Table 2.. Bronchoscopy in Rejectors and Nonrejectors*

 

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  		Table 3.. Bronchoscopy in Rejection Grade*

 

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  		Table 4.. BALF Cell Counts

 
Mean BALF IL-15 levels for all lung transplant recipients are shown in Figure 1 . There was a statistically significant increase in BALF IL-15 levels in patients with acute rejection compared to those without acute rejection (25 ± 25 pg/mL vs 4.5 ± 1.5 pg/mL, respectively; p < 0.0001). More importantly, there appeared to be a bimodal distribution in the level of BALF IL-15 levels. Eleven patients had elevated levels of BALF IL-15 levels > 15 pg/mL. There was no significant difference between the high BALF IL-15 group and the low BALF IL-15 group with respect to baseline demographic data, time of rejection episode after transplant, severity of acute rejection episode, and BALF cell counts (Table 5 ). In addition, with resolution of the acute rejection episode, the BALF IL-15 level decreased significantly in eight of these patients with serial biopsy samples (Fig 2 ). In the nonrejector group, BALF IL-15 levels did not change in any identifiable pattern.


Figure 1
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  		Figure 1.. Mean BALF IL-15 protein expression of lung transplant recipients with rejection and those without rejection.

 

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  		Table 5.. Demographics Between High BALF IL-15 and Low BALF IL-15 Rejectors*

 

Figure 2
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  		Figure 2.. The level of decline in BALF IL-15 levels after treatment of the acute rejection episode with corticosteroids in eight patients. The average time to peak levels from the time of acute rejection was 55 ± 33 days, and the time to decline was 172 ± 29 days.

 
BALF IL-2 protein expression was detectable in four patients in this study. Three patients with grade 1 rejection and one patient with grade 2 rejection had detectable IL-2 levels. One patient with a negligible BALF IL-15 level had an elevated IL-2 level (21 pg/mL) that returned to undetectable with treatment of the grade 2 acute rejection episode. There was no association between IL-2 protein expression and acute allograft rejection in our patient population. In addition, there was no association between BALF IL-2 and IL-15 levels.

There was no association between BALF IL-15 levels and bacteria, fungal, or CMV infections. The number of infections was similar in both groups. In the logistic regression analysis, which was adjusted for infection (bacterial, fungal, or CMV), the elevation of BALF IL-15 levels in lung transplant recipients with acute rejection remained significant (odds ratio, 1.41; 95% confidence interval, 11 to 1.80).

Discussion

In this study, we have shown that BALF IL-15 protein expression is elevated in acute allograft rejection in the presence of IL-2 receptor blockade in a subset of patients with acute allograft rejection. In addition, therapy with augmented immunosuppression led to histologic resolution of the acute rejection and a decrease in IL-15 to negligible levels in 8 of the 11 patients with elevated BALF IL-15 levels during their acute rejection episode.

Several previous studies have cited an association of other biological mediators with acute lung allograft rejection. A few of these include the CC chemokine, RANTES (regulated upon activation, normal T cell expressed and secreted), monocyte chemoattractant protein-1, IL-6, and interferon {gamma}.181920 In addition, the Fas-Fas ligand and the perforin/granzyme pathways have also been implicated in the development of acute lung allograft rejection.21 The association between BALF IL-15 protein expression and acute lung allograft rejection in our patients suggests that IL-15 may also be an important mediator in ongoing T-cell proliferation. IL-15 is a stromal cell-derived cytokine that shares similar biological functions with IL-2, including stimulation of proliferation of T cells, B cells, NK cells, and lymphokine-activated killer cells. In addition, IL-15 promotes the differentiation of T cells and NK cells into cytotoxic effector cells.8910111213 Furthermore, in animal models and in patients with HIV infection, IL-15 leads to prolonged survival of T cells as opposed to the natural apoptosis of preactivated cytotoxic T cells.2223

The common biological function of IL-15 and IL-2 is due to shared aspects of their respective receptors. Both IL-15 and IL-2 receptors have similar ß and {gamma} chains, but each has a unique {alpha} chain. As a result, the current immunosuppressive regimen used in this study may affect IL-2–responsive T cells but not necessarily impact on IL-15–mediated T-cell activation. Indeed, previous studies2425 have suggested that cyclosporine, a calcineurin inhibitor with a mechanism of action similar to tacrolimus, inhibits transcription of IL-2 and the IL-2 receptor but has no effect on the expression on IL-15 and the IL-15 receptor. Likewise, prednisone has been found to suppress both IL-2 and IL-2 receptor but does not block IL-15/IL-15 receptor transcription.26272829 Lastly, although anti-CD25 monoclonal antibodies have been shown to block T-cell responsiveness to IL-2, both intragraft IL-15 messenger RNA levels and the quantity of IL-15 infiltrating cells were not decreased.30 Therefore, elevation of BALF IL-15 levels but not BALF IL-2 levels, as shown by this study, suggest that IL-15 may be an important factor for sustained clonal expansion of T cells in episodes of acute lung allograft rejection.

Although there has been an association between IL-15 messenger RNA expression and heart, liver, and kidney transplantation,141531 the association with acute rejection and elevated IL-15 levels has been controversial. Similar to our study, Shi and colleagues32 show an elevation of BALF IL-15 messenger RNA levels in lung transplant recipients with acute rejection. Pavlakis and colleagues15 have also shown elevated IL-15 messenger RNA expression in rejecting renal transplant biopsies as compared with nonrejecting renal allografts in the absence of IL-2 messenger RNA expression, suggesting that IL-15 may be important in supporting ongoing T-cell proliferation. However, contrary to our findings, Baan and colleagues1431 did not find a relation between rejection episodes and IL-15 messenger RNA expression in liver transplantation and heart transplantation. This discrepancy may be multifactorial and partly due to different immunosuppressive regimens and, possibly, organ-specific cytokine involvement. However, a major difference between our study and the previous study is the detection technique used to measure IL-15 levels in the allografts. While our study utilized enzyme-linked immunosorbent assay in order to measure protein expression, Baan et al1431 used quantitative reverse transcription polymerase chain reaction analysis to measure IL-15 messenger RNA expression. Since IL-15 is mainly regulated at the posttranscriptional level, IL-15 messenger RNA may not accurately reflect bioactive IL-15 protein levels in the graft. As a result, our study may provide a more accurate assessment of active IL-15 and the correlation with acute lung allograft rejection.

Interestingly, we found a bimodal distribution of BALF IL-15 levels among the rejectors. Although we were unable to identify any clinical characteristics that differed between these two groups, we could not exclude a pathologic cause for the elevation of BALF IL-15 levels in these patients. Indeed, Hu and colleagues33 describe a similar distribution of serum IL-15 levels among renal transplant recipients with acute allograft rejection, suggesting that perhaps the pathway to the development of acute rejection may be different. In addition, lung transplant recipients with a higher BALF IL-15 level at the time of rejection had an increase after treatment with corticosteroid therapy. Hu and colleagues33 also describe this phenomenon and speculate that the elevation of IL-15 with steroid therapy may be a mechanism through which memory T cells develop.

BALF IL-15 protein expression was present in many of our lung transplant recipients without acute rejection, albeit at a lower level than in transplant recipients with acute rejection. This expression of BALF IL-15 may reflect ongoing low-level transcription by lung epithelial cells or tissue-specific macrophages in the transplanted organ. Previous studies101234 have shown that donor brain death and cold ischemia time may activate these cells to increase levels of IL-15 messenger RNA transcription after transplantation. In addition, donor-infiltrating macrophages may also partly be responsible for this low level of IL-15 expression regardless of rejection status of the transplanted organ.343536 A previous study14 found that although IL-15 messenger RNA was expressed in the nontransplanted donor heart, infiltrating IL-15–positive cells significantly increased after heart transplantation, correlating with the number of increasing macrophages.

We did find an elevation of IL-2 levels in four BAL samples with acute rejection. Three of these four samples were from lung transplant recipients with an underlying diagnosis of sarcoidosis. Since IL-2 has been implicated in the development of T-cell granuloma formation in sarcoidosis, we speculate that the elevation of IL-2 in these patients was the result of ongoing systemic immune hyperactivity. Indeed, we did find recurrence of noncaseating granulomas in the transbronchial biopsies in these three samples. The fourth patient had a diagnosis of emphysema and had Aspergillus fumigatus pneumonia at the time of the bronchoscopy, which may have increased IL-2 levels despite significant IL-2 blockade by current immunosuppression.

In summary, we have found increased BALF IL-15 protein expression in acute lung allograft rejection in the presence of IL-2 receptor blockade by an anti-CD25 monoclonal antibody. This finding supports the hypothesis that IL-15 may be an alternative T-cell growth factor that mediates IL-2–independent acute rejection in lung transplant recipients. Further investigations assessing a possible causal effect of IL-15 in mediating acute allograft rejection in lung transplant recipients will be helpful in understanding the role of IL-15 in lung transplantation.

Footnotes

Abbreviations: BALF = BAL fluid; BCA = bicinchoninic acid; CMV = cytomegalovirus; IL = interleukin; NK = natural killer

This work was performed at Loyola University Medical Center, Maywood, IL.

The authors have no conflicts of interest to disclose.

Received for publication May 17, 2006. Accepted for publication July 19, 2006.

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