Ann Thorac Surg 2006;82:1043-1050
© 2006 The Society of Thoracic Surgeons
Original article: General thoracic
Respiratory Viral Infection in Obliterative Airway Disease After Orthotopic Tracheal Transplantation
Elbert Kuo, MD*,a,
Ankit Bharat, MD*,a,
Trudie Goers, MDa,
Will Chapmana,
Le Yan, BSc,
Tyler Street, BAa,
Wei Lu, MDa,
Michael Walter, MDc,
Alexander Patterson, MDa,
Thalachallour Mohanakumar, PhDa,b,*
a Department of Surgery, Washington University, St. Louis, Missouri
b Department of Pathology and Immunology, Washington University, St. Louis, Missouri
c Department of Pulmonary and Critical Care, Washington University, St. Louis, Missouri
Accepted for publication March 31, 2006.
* Address correspondence to Dr Mohanakumar, Washington University School of Medicine, Department of Surgery, Box 8109, 660 S Euclid Ave, St. Louis, MO 63110 (Email: kumart{at}wustl.edu).
Presented at the Poster Session of the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30–Feb 1, 2006.
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Abstract
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BACKGROUND: The long-term survival after human lung transplantation is limited by bronchiolitis obliterans syndrome (BOS). Clinically, community-acquired respiratory viral infections have been correlated with an increased incidence of BOS. The goal of this study was to investigate the role of respiratory viral infections in chronic lung allograft rejection using the murine orthotopic tracheal transplantation model.
METHODS: Eighty orthotopic tracheal transplants were performed using BALB/c and C57BL/6 mice. Recipient mice were infected intranasally with Sendai virus (SdV), a murine parainfluenza type I virus. Experiments altering the infectious dose, infection time, harvest time, allogeneic response, and viral response were performed. Tracheal allograft rejection was monitored using percent fibrosis and lamina propria to cartilage ratio measurements. Interferon-
ELISPOT analysis against irradiated donor (BALB/c) splenocytes was used as immunologic indicator of alloreactivity after transplantation.
RESULTS: Sendai virus infection revealed a dose-dependent transient suppression of alloreactivity with a decrease in tracheal allograft fibrosis and frequency of alloreactive T cells at 30 days. This immunosuppression was reversed by day 60, leading to increased tracheal allograft fibrosis with a concomitant increase in the frequency of interferon- producing alloreactive T cells. Pretransplant sensitization with donor antigens prevented the initial suppression of alloreactivity due to SdV infection. Furthermore, pretransplant immunization against SdV infection resulted in rapid clearing of the infection and reduced the immunopathology of rejection.
CONCLUSIONS: Respiratory viral infections can cause enhanced tracheal allograft rejection despite the initial phase of transient immunosuppression. Early treatment or vaccination against the respiratory infections may represent a viable intervention to reduce the risk of chronic rejection.
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Introduction
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For several end-stage lung diseases, lung transplantation is the only treatment option that can improve survival and enhance the quality of life in patients. The long-term survival of lung allografts is limited by the development of bronchiolitis obliterans syndrome (BOS). Bronchiolitis obliterans syndrome develops in more than 40% to 55% of lung transplant patients at 5 years [1]. Five-year survival after the onset of BOS is only 30% to 40% [2]. While the exact etiology behind BOS is unknown, respiratory viral infections after transplantation have been identified as significant risk factors for the development of BOS [3–6].
Murine hetrotopic and orthotopic tracheal transplantation have been widely used to investigate the pathogenesis of BOS [7]. While orthotopic tracheal allografts do not undergo complete luminal obliteration, there are signs of chronic rejection as evident by increased intramural fibrosis compared with isografts [8]. To study the role of respiratory viral infections in the development of BOS, we infected mice that underwent orthotopic tracheal transplantation with SdV. Sendai virus is a murine parainfluenza type I virus that infects rodents and causes reversible lesions in the mucosal epithelium of the nose, trachea, bronchioles, as well as the alveoli [9–11]. The purpose of this study was to determine if SdV infection would promote the rejection of murine orthotopic tracheal allografts.
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Material and Methods
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Experimental Design
Orthotopic tracheal transplants were performed using 6- to 8-week-old age-matched BALB/c (H2d) or C57BL/6 (H2b) donor tracheal segments into C57BL/6 mice (Jackson Laboratories, Bar Harbor, Maine; Table 1) according to standard techniques described in our earlier report [12]. The intraoperative mortality during orthotopic tracheal transplantation was less than 2%, and there was no difference between the experimental groups. All animal studies were performed in accordance with the Animal Studies Committee, Washington University, St Louis, Missouri, guidelines. The mice were housed at the Washington University School of Medicine, in a pathogen-free environment with climate controlled rooms and free access to standard pelleted food and sterile water.
Sendai Viral Infection of Mice
Sendai Virus (SdV), Fushimi strain VR-105, (American Type Culture Collection, Manassas, Virginia) was stored at -70°C. Titration experiments were performed, and a dose of 5,000 egg infectious dose (EID50)/animal of SdV (5 K) was selected. Mice were anesthesized and 5 K SdV diluted with 30 µL of phosphate-buffered solution was slowly dropped into the nasal canal of the mice. Mice were then placed on the backs with their head elevated until recovery.
Histopathologic Analysis
Tracheal grafts were harvested and fixed in 10% formaldehyde. Grafts were embedded in paraffin and cross sections were taken at approximately 100, 250, and 400 µm (4-µm thickness; Fig 1). Sections were stained with hematoxylin and eosin and Masson's trichrome and assessed for epithelial abnormalities, fibroproliferative changes, and lymphocytic infiltrates. Percent fibrosis and the thickness of lamina propria to cartilage ratio (LCR) were calculated with computer assistance (Fig 2). Percent fibrosis was calculated by dividing the lamina propria, the area below the basement membrane and above the cartilage, by the total area above the cartilage. The LCR was measured at 90, 180, and 270 degrees with the membranous portion of the trachea positioned at the bottom of the section. If no cartilage was present at 90, 180, or 270 degrees, the closest area with cartilage was measured (Fig 2).
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Fig 1. Orthotopic tracheal transplant model in which a 6-ring segment of trachea is transplanted and secured with three 10-0 nylon sutures at both ends. Sections for analysis were taken at approximately 100 µm, 250 µm, and 400 µm (4 µm thickness), represented by the yellow lines.
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Fig 2. (A) Using Image Pro Express v 4.0, percent fibrosis was calculated by dividing the area between the basement membrane and the cartilage by the total area enclosed by the tracheal cartilage. (B) The ratio of the lamina propria to cartilage thickness (LCR) was measured at 90, 180, and 270 degrees, with the membranous portion of the trachea positioned at the bottom of the section.
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The ELISPOT assays for interferon- (IFN-) were performed as previously described [13]. Briefly, multiscreen 96-well filtration plates were coated overnight at 4°C with 5.0 µg/mL of capture human cytokine-specific mAb (BD Biosciences, San Jose, CA). The plates were then blocked with 1% BSA for 2 hours. Subsequently, 3 x 105 recipient (C57BL/6) splenocytes were cultured in triplicate in the presence of irradiated (3,000 rads) stimulators at a 1:1 ratio. BALB/c, C57BL/6, 129SVE Light Bellied Black Ago (third-party contro [Taconic, Germantown, New York]) irradiated splenocytes along with Con A (positive control) and media (negative control) served as stimulators. After 48 hours, the plates were washed and 2.0 µg/mL of biotinylated human cytokine-specific mAb (BD Biosciences) was added to the wells. After an overnight incubation at 4°C, the plates were developed using horseradish peroxidase-labeled streptavidin (BD Biosciences), and 3-amino-9-ethylcarbazole substrate reagent (BD Biosciences). The spots were analyzed in an ImmunoSpot Series I analyzer (Cellular Technology, Cleveland, OH).
Statistical Analysis
Percent fibrosis and LCR data in this study are presented as the mean ± SEM. Weight data are presented as mean ± SD. For all parametric data, one-way analysis of variance with post hoc comparisons was performed using the Fisher's least significant difference test. Statistical significance in all cases was defined as p less than 0.05.
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Results
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SdV Induces Transient Suppression of Alloreactivity
While orthotopic tracheal allografts do not develop luminal obliteration, they demonstrate signs of chronic rejection with a significant increase in intramural fibrosis (22.97% ± 0.82 versus 18.93% ± 0.79; p = 0.01) and LCR (0.82 ± 0.03 versus 0.60 ± 0.04; p = 0.01) compared with isografts at 30 days (group I). Immunohistochemical analysis at day 30 revealed increased lymphocytic infiltration in allografts compared with isografts: CD4+, allografts 3.89 ± 0.56 cells in each high-power field versus isografts 0.78 ± 0.11 cells per high-power field; and CD8+, allografts 4.44 ± 0.44 cells per high-power field versus isografts 0.67 ± 0.19 per high-power field (p < 0.05 for both). The epithelium on the tracheal allografts was of recipient origin, as we have demonstrated previously [12].
We next investigated the role of SdV infection in the rejection of the orthotopic tracheal allografts (group II). Fifteen days after orthotopic tracheal transplantation, recipients of orthotopic isografts (group IIA) and allografts (group IIB) were infected with a sublethal 5 K dose of SdV intranasally. As controls, native tracheas of naïve mice (group IIC) and SdV infection after a sham operation (group IID) were included. After infection, recipients of allografts (group IIB) lost a significantly higher percentage of their preinfection weight (25.50% ± 3.35% versus 18.24% ± 3.52%; p = 0.03) for a significantly longer period of time (9.06 ± 1.11 days versus 7.33 ± 0.48 days; p = 0.03) compared with isografts (group IIA). Serial sections of grafts at 30 days after transplantation demonstrated normal tracheal architecture with ciliated columnar epithelium in isografts (data not shown) but a multicellular mixture of squamous and ciliated cubiodal epithelium in the allografts (Fig 3). Interestingly, there was a significant decrease in the percent fibrosis (18.45% ± 0.39% versus 22.97% ± 0.82%; p = 0.02) and LCR (0.55 ± 0.02 versus 0.82 ± 0.03; p = 0.02) in infected allografts (group IIB) compared with uninfected allografts (group IB) at 30 days (p < 0.01; Fig 4). In contrast, no significant change in fibrosis was found in infected isografts (group IIA) or infected naive tracheas after sham operation (group IID). The mild but statistically insignificant increase in intramural fibrosis in the isograft at day 30 was most likely a result of increased tissue remodeling due to initial ischemic insult and viral infection. No fibrosis was observed in the native tracheas of the recipients to which the allograft was anastomosed. The infected tracheal allograft recipients also demonstrated a significant decrease in the frequency of alloreactive IFN-–producing T cells compared with uninfected recipients at day 30: 349.33 ± 63.80 spots/million cells versus 920.81 ± 66.83 spots/million (p = 0.02).
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Fig 3. Serial sections at 30 days after transplantation demonstrated incomplete reepithelialization with a multicellular matrix of squamous and ciliated cubiodal epithelium in the (A) allografts infected with a 5 K dose of Sendai virus (SdV) 15 days after transplantation. (B) As control, orthotopic isografts harvested at day 30 are presented. (F = fibrosis; I = infiltration.)
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Fig 4. Allografts infected with 5 K Sendai virus (SdV) at 15 days had a significantly decreased (A) percent fibrosis and (B) thickness of lamina propria to cartilage ratio (LCR) compared with noninfected allografts. This decrease was not seen in isografts and nontransplanted controls infected with SdV. (White bars = no viral infection; black bars = 5 K SdV infection.)
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Dose-Dependent Suppression of Alloreactivity With SdV
Mice were infected with ultraviolet-inactivated, 1 K, 5 K, or 25 K dose of SdV 15 days after transplantation and sacrificed at day 30 for histologic analysis of the tracheal allografts (group III). With the exception of recipients that were infected with ultraviolet-inactivated and 1 K dose of SdV, all animals demonstrated significant but transient weight loss and decreased activity that subsequently improved. There was no statistical difference in percent fibrosis and LCR in allografts infected with ultraviolet-inactivated (22.41% ± 0.69% and 0.77 ± 0.04, respectively) or 1 K (22.86% ± 0.81% and 0.75 ± 0.06, respectively) compared with the uninfected allografts (Fig 5A). There was also no significant difference in the frequency of alloreactive IFN-–producing cells in both these groups: 910.37 ± 24.01 spots/million cells and 914.44 ± 56.67 spots/million cells, respectively (Fig 5B). At the 25 K dose, recipients of allografts appeared more ill. They had significant clinical stridor, decreased activity, and a significant weight loss of 27.41% ± 3.92% for 9.33 ± 1.21 days compared with those infected with ultraviolet-inactivated virus or 1 K dose (p < 0.05 for both). The epithelium was significantly damaged with multiple areas of squamous epithelium and minimal ciliated cells. There was a progressive decrease in intramural allograft fibrosis as the viral dose increased from 5 K to 25 K: percent fibrosis 18.45% ± 0.39% versus 13.76% ± 0.55% and LCR 0.55 ± 0.02 versus 0.46 ± 0.05. The ELISPOT analysis also showed a concomitant decrease in the frequency of alloreactive IFN-–producing cells as the viral dose increased from 5 K to 25 K: 349.33 ± 63.80 spots/million cells versus 123.70 ± 30.94 spots/million cells (p = 0.01).
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Fig 5. (A) Allografts infected with Sendai virus (SdV) showed a dose-response decrease in percent fibrosis and thickness of lamina propria to cartilage ratio (LCR) at the 5 K and 25 K doses. Allografts infected with ultraviolet-inactivated, 1 K, and no virus showed no difference in fibrosis and LCR. (B) ELISPOT analysis showed parallel results with a dose-dependent decrease in the number of interferon-–producing cells as the SdV dose increased.
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Altering Time Between Allograft Transplantation and SdV Infection Did Not Influence Transient Immunosuppression After SdV Infection
To determine the effect of time interval between transplant and infection, recipients of allografts were infected after 30 days and harvested on day 45 (group IV). There was no significant difference in mice infected on posttransplantation day 15 versus day 30 and harvested 15 days after infection: percent fibrosis (18.45% ± 0.39% versus 18.09% ± 0.84%; p = 0.89) and LCR (0.55 ± 0.02 versus 0.59 ± 0.04; p = 0.79). Noninfected allografts had a percent fibrosis of 21.06% ± 0.41% and a LCR of 0.79 ± 0.07 when harvested at 45 days.
Reversal of Immunosuppression by SdV on Long-Term Follow-Up
On long-term follow-up of 60 days (group V), allografts infected with SdV 15 days after transplantation showed a significant increase in percent fibrosis (28.63% ± 1.41% versus 18.45% ± 0.39%; p = 0.01) and LCR (1.21 ± 0.12 versus 0.55 ± 0.02; p = 0.01) compared with that observed at 30 days (Fig 6A and B). The percent fibrosis (28.63% ± 1.41% versus 18.77% ± 1.35%; p = 0.01) and LCR (1.21 ± 0.12 versus 0.74 ± 0.06; p = 0.01) in the infected allografts at day 60 was also significantly greater compared with the noninfected allografts at day 60. A significant increase in the frequency of IFN-–producing cells was found in the infected allografts at day 60 compared with the uninfected allograft recipients: 1174.44 ± 38.56 spots/million cells versus 909.17 ± 53.17 spots/million cells (p = 0.02; Fig 6C). Therefore, a reversal of the initial immunosuppression was observed in the infected recipients leading to enhanced allograft rejection by 60 days. The infected isografts, on the other hand, had returned to baseline levels comparable to the naïve tracheas: percent fibrosis, 15.93% ± 1.99% versus 15.85% ± 2.03; LCR, 0.41 ± 0.08 versus 0.34 + 0.02; p > 0.05 for both.
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Fig 6. Allografts infected with Sendai virus (SdV) 15 days after transplantation, showed an increase in (A) percent fibrosis and (B) thickness of lamina propria to cartilage ratio (LCR) at 60 days compared with at 30 days. (C) In addition, allografts infected with virus had increased frequency of interferon-–producing alloreactive T cells. (White bars = no viral infection; black bars = 5 K SdV infection.)
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Presensitization With Donor Antigens Abrogated the Transient Suppression of Alloreactivity With SdV Infection
To augment the allogenic immune response to donor antigens, mice underwent a sensitization procedure in which they were administered two intraperitoneal injections of 107 BALB/c splenocytes a week apart before transplantation. Development of antibodies to donor splenocytes was confirmed by flow cytometry analysis (Fig 7A). Sensitized mice (group VIA) showed no significant difference in allograft rejection compared with nonsensitized mice when sacrificed at 30 days: percent fibrosis (25.44% ± 0.53% versus 22.97% ± 0.82%; p = 0.39) and LCR (0.89 ± 0.06 versus 0.82 ± 0.03; p = 0.77). There was also no significant difference in the number of IFN-–producing cells/1 x 106 when stimulated by BALB/c donor antigens (935.56 ± 17.78 versus 920.81 ± 66.83) between the two groups. Interestingly, sensitized mice infected with SdV at 15 days (group VIB) did not show a significant decrease in percent fibrosis (25.50% ± 0.72%) or LCR (0.88 ± 0.04) at 30 days. In addition, there was no significant difference in the number of IFN-–producing cells/1 x 106 when stimulated by BALB/c donor antigens between the sensitized animals infected (906.30 ± 43.44) or noninfected with SdV (Fig 7). These data suggest that pretransplant sensitization with donor antigens conferred resistance to the suppression of alloreactivity due to SdV.
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Fig 7. (A) Confirmation of sensitization of recipient mice with donor antigens (black) as evident by a shift in mean channel fluorescence compared with naïve recipients (red). Sera from sensitized recipients were reacted against donor splenocytes. Mice sensitized with donor antigens pretransplant showed no significant decrease in (B) percent fibrosis or (C) thickness of lamina propria to cartilage ratio (LCR) after Sendai virus (SdV) infection compared with nonsensitized allografts at day 30. (D) The number of interferon-–producing alloreactive T cells was not significantly decreased in sensitized mice after SdV infection on ELISPOT analysis. (White bars = no viral infection; black bars = 5 K SdV infection).
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Pretransplant Immunity to SdV Prevents Initial Immunosuppression and Increased Allograft Rejection Associated With SdV Infection
We further hypothesized that preexisting immunity to SdV would prevent the increased allograft rejection caused by the virus. To test this hypothesis, C67BL/6 mice were first infected with 5 K dose of SdV and then allowed to recover for 30 days before transplantation. After transplantation, these mice were reinfected with 5 K SdV 15 days later and then sacrificed at day 30 (group VIIA) to analyze the allograft fibrosis and alloreactivity. These previously infected mice demonstrated minimal clinical effects after the second infection with almost no decrease in activity or weight loss after infection. Interestingly, tracheal allografts from these mice did not show a significant decrease in percent fibrosis (25.42% ± 1.36%) and LCR (0.95 ± 0.06) when compared with noninfected controls (22.85% ± 1.11% and 0.79 ± 0.07, respectively) or those that received the first infection after transplantation (18.45% ± 0.39% and 0.55 ± 0.02). However, on 60-day follow-up (group VIIB), recipients with a prior SdV infection demonstrated a significantly decrease in percent fibrosis (21.63% ± 0.92%; p = 0.03) and LCR (0.75 ± 0.03; p = 0.02) compared with 30 days (Fig 8). This finding was the opposite of the trend seen in previously uninfected recipients. These data suggest that immunity to the virus can significantly limit the airway epithelial damage caused by the infection and thereby reduce the allograft rejection.
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Fig 8. Mice previously infected with Sendai virus (SdV) did not show any reduction in (A) percent fibrosis and (B) thickness of lamina propria to cartilage ratio (LCR) at 30 days. At 60 days, mice previously infected with SdV showed significant reduction in tracheal allograft percent fibrosis, an opposite trend of allografts with no prior exposure. (White bars = 30 days after transplant; black bars = 60 days after transplant.)
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Comment
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Community-acquired respiratory viral infections after transplantation have been associated with increased incidence of BOS. In our study, we demonstrated that SdV infection after orthotopic tracheal transplantation in mice results in increased allograft rejection. Viral infections may amplify the chronic rejection process by damaging airway epithelial cells and up-regulating lymphocyte alloreactivity. In addition, cross-reactive viral specific T cells with alloantigens present on the allografts may contribute to the enhanced rejection. Importantly, viral infections can activate the innate immunity through toll-like receptor pathways leading to the induction of an inflammatory cascade that recruits antigen presenting cells. The allograft provides an antigenic source and helps in maintaining the inflammation. In contrast, inflammation subsides in the isograft as there is no persistent antigenic stimulus. The inflammatory mediators can also promote the ability of airway epithelial cells to stimulate recipient lymphocytes [14–16]. Airway epithelial cells play an important role in the development of OAD in the murine tracheal allotransplant models [17]. Tracheal isografts denuded of native airway epithelial cells develop OAD after heterotopic tracheal transplantation. Furthermore, reepithelialization of the tracheal orthografts by recipient airway epithelial cells confers protection against OAD after orthotopic tracheal transplantation [12, 18]. Interestingly, retransplantation of orthotopic tracheal allografts that have reepithelialization of recipient airway epithelial cells, back into the recipient strain heterotopically prevents OAD [12].
Sendai virus infection is known to cause necrosis and partial loss of epithelial cells lining the airways, typically lasting 7 to 10 days [9, 19]. This damage to the airway epithelial cells by SdV may prevent the protective effects of airway epithelial cells. Furthermore, it may release alloantigens to the recipient immune system. In our experiments, there was a significant increase in the frequency of IFN-–producing cells in allografts infected with SdV at 60 days. Clinically, viral infections have been found to increase lymphocyte alloreactivity. Respiratory viral infections have been reported to precede the development of BOS in lung transplant patients [4].
Interestingly, at 30 days after transplantation (15 days after infection) a decrease in percent fibrosis, LCR, and the frequency of IFN-–producing cells was found. This effect was directly proportional to the dose of SdV given. Altering the time between transplantation and infection did not alter this effect. A reversible systemic immunosuppression after respiratory viral infections has been noted in rats with lung, heart, and spleen allografts [20, 21]. Antiviral responses have been shown to affect the alloreactive suppressor mechanisms involved in graft rejection. A bystander suppression of alloresponse has also been documented in the literature [22–24]. In rat lung allografts, both the systemic and local antibody responses were impaired after SdV infection [21]. Rats that underwent allogenic lung transplants were unable to generate an adequate antibody response in response to SdV infection. In our study, allograft recipients infected with SdV lost significantly more weight for a longer period of time compared with isograft recipients. By suppressing the immune response, SdV infection limited the amount of fibrosis seen in allografts. However, this effect was transient and limited to the active phase of the SdV infection. As the infection cleared, it is likely that airway epithelial cell damage, release of alloantigens, and priming of alloreactive T cells enhanced the rejection process on long-term follow-up. Preexisting donor-specific immunity negated this transient suppression of alloreactivity.
It is noteworthy that recipients that were exposed to SdV before transplant completely recovered and had antiviral immunity during the time of second infection. That was most likely responsible for the rapid clearing of the second infection and lack of the initial immunosuppression observed with the first SdV infection. But importantly, the recipients with preexisting antiviral immunity revealed a lower degree of allograft rejection. We hypothesize that the rapid clearing of the second infection in these recipients due to the preexisting antiviral immunity limited the airway epithelial cells damage. This may have a potential implication in early institution of antiviral treatment and possibly the introduction of vaccination in lung transplant recipients in order to limit the damage by respiratory viral pathogens. The limitations of this study include the use of murine tracheal transplant model that does not precisely resemble human BOS, predominantly a small airway disease. However, it is noteworthy that this remains the only viable murine model to investigate the pathogenesis of BOS and has been widely used in the literature. Lung transplantation has so far not been successful in mice [7].
In conclusion, our findings indicate that respiratory viral infection after allogenic orthotopic tracheal transplantation results in an initial dose-dependent immunosuppression that is followed by increase allograft rejection on long-term follow-up. Preexisting antiviral immunity significantly limits the allograft rejection contributed by the respiratory viral infections.
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Acknowledgments
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This work was supported by NIH/RO1-HL66452 (TM) and NIH/T32-AI07163 (EK). The authors would like to express their thanks to Billie Glasscock and Dr Celeste Kuo for their assistance in preparing this manuscript, and to Dr Richard Schuessler for his statistical analysis of our data.
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Footnotes
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* Both authors contributed equally to this work. 
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Abstract
Introduction
