Lymphocytes play critical roles in rejection of allografts. Many transplant studies have focused on functional regulation of lymphocytes, which has led to development of efficient immunosuppressive strategies. However, lymphatics or lymphatic vessels, which are an important pathway for lymphocytes, have not been well documented after lung transplantation. Indeed, until the publication by Reed et al,1 pulmonary lymphatics were thought to be re-established after lung transplantation around anastomosis in 2–3 weeks based on evidence from previous animal studies.2,3 In clinical practice, many thoracic surgeons, including the author, prefer leaving chest tubes slightly longer—usually up to 2 weeks—after lung transplantation than in other lung surgeries. Additionally, an increase in pleural effusion at this time from chest tubes can lead to clinical suspicion of acute rejection. This is based on the assumption that more lymph leaks out if rejection causes lymphatic congestion in the graft before reestablishment of anastomosis.
Using a mouse lung transplant model, Reed et al1 clearly visualized active sprouting of lymphatic vessels in the donor and recipient around the site of anastomosis after lung transplantation. This mutual sprouting appears to lead to establishment of physical connections of graft–host lymphatic vessels. Notably, their experiment was primarily performed using syngeneic combination of mouse strains, and how allogenic transplantation affects this phenomenon remains unclear.
In clinical lung transplantation, interruption of lymphatic vessels in the transplanted lung might contribute to primary graft dysfunction.4,5 Furthermore, a fulminant inflammatory response after lung transplantation may damage lymph vessels, as well as vascular endothelial cells in the graft. This delays reestablishment of lymphatic anastomosis at the donor–recipient interphase, resulting in more lymphatic congestion, and this vicious cycle may lead to graft failure. Data in other solid organ transplantation suggest lymphangiogenesis, which is likely to lead to smooth lymph flow and decrease susceptibility to rejection,6-8 while the rejection process may target donor lymphatic vessels and hinder reestablishment of lymphatic anastomosis. Regardless of which situation occurs, one of the advantages of the work by Reed et al1 is foundation of an animal model to study such basic aspects of lung transplantation.
An interesting and important implication of the work by Reed et al1 is the potential long-term effect of lymphatic interruption on the lymphoid system in allograft lungs. In their previous study, they found that transplanted mouse lungs developed tertiary lymphoid tissue/organ or lymphoid neogenesis.9 Similarly, deletion of secondary lymphoid tissue leads to lymphoid neogenesis in the lung,10,11 suggesting complementary roles of such intrapulmonary lymphoid tissue to secondary lymphoid organs.
Importantly, however, the role of such intrapulmonary lymphoid tissue after lung transplantation remains controversial. We previously demonstrated lymphoid neogenesis in human lungs that were affected by chronic lung allograft dysfunction, and additional animal experiments suggested a detrimental role of effector memory T cells.12 After recognition of restrictive allograft syndrome in 2011, such lymphoid tissue was found more frequently in this ominous form of chronic lung allograft dysfunction than in bronchiolitis obliterans syndrome, which is the conventional form of chronic lung allograft dysfunction.13 Moreover, such lymphoid tissue may contribute to local production of donor-specific antibodies.14
However, some reports have suggested that lymphoid tissue in lung allografts is found more frequently in stable lungs. Animal experiments suggest that lymphoid tissue in the lungs may have protective or regulatory roles in the immune response in association with FoxP3+ regulatory T cells.15 Such conflicting characteristics have also been reported in other solid organ transplantations, including the kidney and heart.16 Furthermore, other explanations for the protective role of tertiary lymphoid tissue mediated for example by interleukin-10–producing B cells.16 Therefore, intragraft tertiary lymphoid tissue may not simply be a strong promotor of rejection and allograft dysfunction but could be a downregulator of an aggressive local alloimmune response in certain circumstances. What determines the nature of intrapulmonary lymphoid tissue is still unclear. However, continuous or frequent inflammatory stimuli, such as bacterial colonization and silent aspiration as well as refractory or repeated episodes of rejection, are likely to contribute to establishment of a proinflammatory milieu in the lung. In contrast, long-term stabilization of a graft without rejection, infection, or other detrimental episodes might lead to creation of an anti-inflammatory or regulatory milieu, even after development of de novo lymphoid tissue in allograft lungs. Consideration of such local immunoregulatory mechanisms after lung transplantation may provide a more general indication of how to improve clinical outcomes of lung transplantation.
Because of such bidirectional roles of lymphoid neogenesis in local chronic immunoregulation in lung allografts, the implications of donor–host lymphoid anastomosis after lung transplant surgery, as demonstrated by Reed et al,1 need to be determined. As a future direction of this important issue, the following investigations are important to the field of lung transplantation and probably other organ transplantations. First, observing the sequela of lymphatic anastomosis or disruption in an allogenic circumstance using a mouse lung transplant model would be interesting. Second, the clinical relevance of the current findings should be investigated. The clinical circumstance in which lymphatic anastomosis is not well established needs to be determined. Primary graft dysfunction that leads to serious damage in endothelial cells is likely the cause of such disruption. Whether there are any other conditions that disturb the donor–recipient remain unknown. Third, identifying a factor or condition that leads to development of “protective” lymphoid tissue in allografts would be beneficial.
In conclusion, lymphatics, or the lymphoid system, have been an elusive target of therapy in lung transplantation. Recent studies have shown the potential clinical importance of this issue. This is particularly the case in light of the nature of the lung, which has been demonstrated to be a potential “lymphoid organ.” Further basic or fundamental investigations on the lymphatic system will lead to clinical insight into the complex immunology in the field of lung transplantation.
We thank Ellen Knapp, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this article.
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