© 2003 American Thoracic Society
Paying a Toll for Acute Lung Allograft RejectionDavid Geffen School of Medicine at UCLA Los Angeles, California Innate immunity plays a major role in host defense during early phases of infection and involves the recognition of invading pathogens (1–3). This response is mediated by toll-like receptors that recognize specific microbial surface molecules (1–3). The signaling of toll-like receptors produces proinflammatory cytokines and upregulates the expression of costimulatory molecules, aiding the transition from innate to adaptive immunity (1–3). Toll-like receptor 4 is 1 of the 10 known toll-like receptors and is present on leukocytes and airway epithelial cells (1–3). The ligand for this receptor is lipopolysaccharide of gram-negative bacteria. Interestingly, this receptor has also been found to be upregulated at sites of sterile inflammation, suggesting a role in the regulation of noninfectious inflammation (1–3). Bronchiolitis obliterans syndrome is chronic lung allograft rejection and is characterized by persistent peribronchiolar/vascular leukocyte infiltration leading to fibro-obliteration of the airways (4, 5). Bronchiolitis obliterans syndrome is the primary reason for the high morbidity/mortality after lung transplantation (4, 6–9). The major risk factor for the development of bronchiolitis obliterans syndrome is the number and severity of episodes of acute rejection (9, 10). Other risk factors include noncompliance with immunosuppressive medication, infections, and human leukocyte antigen mismatches (9, 10). In this issue of AJRCCM (pp. 628–632), Palmer and colleagues (11) studied the role of innate immunity during the pathogenesis of acute lung allograft rejection by evaluating two functional polymorphisms of toll-like receptor 4. These polymorphisms (Asp299GLY and Thr3999Ile) have been associated with cellular hyporesponsiveness to lipopolysaccharide (12). Thus, theoretically the presence of these polymorphisms could lead to a reduction in inflammatory responses, decreased extravasation of leukocytes in the allograft, and reduced rejection (1–3). Palmer and colleagues screened DNA from 147 lung transplantation recipients and their respective donors for heterozygosity of the two toll-like receptor 4 polymorphisms. In these patients, immunosuppression consisted of combined corticosteroids, azathioprine, and tacrolimus. Monoclonal interleukin-2 receptor antibody was used for induction immunosuppression. The degree of human leukocyte antigen mismatch and number of recipients with elevated panel reactive antibody were similar among the patients. Bronchoscopy with biopsies was performed at 3 and 6 months and if clinically indicated. Seventy-nine patients developed biopsy-proven acute allograft rejection. The toll-like receptor 4 polymorphisms were found in 10% of the recipients and 16% of the donors. There was a trend for delay in the time to first episode of allograft rejection and a significant reduction in the incidence of acute allograft rejection at 6 months in recipient patients with toll-like receptor 4 polymorphisms. Moreover, the presence of these polymorphisms was predictive of no acute allograft rejection episodes for the first 6 months. No difference, however, was found in severity of grade of allograft rejection. In contrast, the presence of these polymorphisms in the donor did not influence the frequency, time, or severity of rejection. Interestingly, toll-like receptor 4 does not appear to have a direct effect in reducing allograft rejection in pathogen-free animals (13). This study in humans, however, suggested that toll-like receptor 4 may play an important role in the development of acute lung allograft rejection (11). The authors hypothesized that the innate immune response through toll-like receptor 4 may contribute mechanistically to acute rejection by the intermittent release of circulating lipopolysaccharide that may occur during transplantation surgery, reimplantation response, and pulmonary pathogen colonization and/or infections. Therefore, toll-like receptor 4 activation plays a role in pathogen recognition, priming innate immunity, enhancing the evolution of adaptive immunity to alloantigen recognition, and promoting acute allograft rejection. The authors demonstrated no significant endogenous immunologic differences (i.e., human leukocyte antigen and panel reactive antibody) between groups. Nevertheless, it should be realized that nonadherence to immunosuppressive medications, which was not addressed in this study, is a significant risk factor for the development of bronchiolitis obliterans syndrome (9, 10). The findings of this study, however, may be mechanistically important for chronic rejection. The authors established a significant reduction in the rate of overall acute rejection (grade 1 or higher) at 6 months in recipients with the toll-like receptor 4 polymorphisms. Grade 1 rejection is not a major risk factor for the development of bronchiolitis obliterans syndrome before 6 months, although it becomes a significant risk factor after 6 months (9, 10). Clinically significant grade 2/3 rejection requires treatment and is a major risk factor for the development of bronchiolitis obliterans syndrome at any time after transplantation (9, 10). This suggests that a more long-term follow-up of the patients in this study may demonstrate more profound results, including a reduction in bronchiolitis obliterans syndrome. Toll-like receptor 4 is expressed on macrophages, dendritic cells, B-cells, and airway epithelial cells (13). Yet, only recipient, not donor, polymorphisms in toll-like receptor 4 influenced rejection. This suggests that recipient leukocytes with toll-like receptor 4 polymorphisms, rather than donor cells, are pivotal in reducing acute allograft rejection. Furthermore, increasing evidence suggests that recipient epithelial cells traffic to the donor lung and become integrated with donor epithelial cells (14). This would result in the donor lung having recipient epithelial cells expressing toll-like receptor 4 polymorphisms and reduced responsiveness to airway bacterial colonization and/or infection. The question is whether targeting toll-like receptor 4 would be beneficial in reducing allograft rejection. One concern would be the potential risk of having an already immunosuppressed transplant recipient more susceptible to infections because of reduced pathogen recognition. Previous studies have demonstrated that patients with toll-like receptor 4 polymorphisms experience reductions in acute phase reactants, inflammatory cytokines, and soluble adhesion molecules and are at increased risk of gram-negative infections (15, 16). Moreover, we do not know whether different immunosuppressive regimens play a role in suppressing toll-like receptor 4 immune responsiveness. Future studies should be performed in transplant recipients in the presence and absence of these polymorphisms during healthy states, rejection of the allograft, or infection of the allograft to provide more insight into the role played by toll-like receptors during allograft rejection. Furthermore, multicenter studies will be critical for assessing specific mechanisms of the role of toll-like receptor 4 and other toll-like receptors during the pathogenesis of allograft rejection. FOOTNOTES Conflict of Interest Statement: J.A.B. has no declared conflict of interest. REFERENCES
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