Detection of canine allograft lung rejection by pulmonary lymphoscintigraphy

Abstract

We previously demonstrated that Iymphoscintigraphy could be used to study pulmonary lymphatic flow. RadiocoUoids, high-molecular-weight proteins tagged with radioactive markers, are injected percutaneously in the periphery of the lung. These molecules enter the lymph, are transported via lymphatic channels, and concentrate in the tributary hilar and mediastinal lymph nodes, where they can be visualized by nuclear scan. The goal of this study was to determine whether pulmonary Iymphoscintigraphy could be used to detect aUograft rejection after lung transplantation. Thirteen mongrel dogs underwent left lung aUotransplantation. Cyclosporine 15 mg/kg per day and azathioprine 1 mg/kg per day were given oraUy for postoperative immunosuppression. Lymphoscintigraphic studies were obtained 1 week after the operation and then at weekly intervals. In five dogs (group A), immunosuppression was continued until the animal died or was put to death 6 weeks later. Lymphoscintigraphy demonstrated reestablishment of lymphatic drainage between the lung graft and the mediastinum' in all the animals 2 to 4 weeks after transplantation. In eight dogs (group B), immunosuppression was discontinued after reestablishment of graft lymphatic drainage was documented by two consecutive Iymphoscintigraphic studies. The dogs continued to be studied with weekly scans. In group B, lymphatic drainage from the lung graft to the mediastinum disappeared 1 to 4 weeks after immunosuppression was stopped. Rejection was diagnosed clinicaUy and confirmed histologicaUy with open lung biopsies and/or autopsies in all animals. This study shows that canine aUograft lung rejection is. associated with disappearance of lymphatic drainage from lung graft to mediastinum, which can be documented by pulmonary Iymphoscintigraphy, a minimally invasive technique that can be easily repeated. Pulmonary Iymphoscintigraphy may be useful for early detection of lung allograft rejection.

Lymphatic impairment leads to pulmonary tertiary lymphoid organ formation and alveolar damage

“…The left lungs from donor iDTR VEGFR3-Cre ERT2 mice were transplanted into control littermates. Although lymphatic vessels were not surgically reconnected after lung transplantation, studies in mice and large animals have demonstrated that lymphatic drainage is reestablished 7-21 days after transplantation (33,48,49). We administered DT 21 days after transplantation of the iDTR VEGFR3Cre ERT2 lung to ensure that lymphatic function was first reestablished in the transplanted lungs ( Figure 6A).…”

Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection

“…Reestablishment of a lymphatic continuum after transplantation relies on formation of new lymphatic vessels (lymphangiogenesis), the exact roles of which remain enigmatic and somewhat controversial in transplant pathophysiology (10,11). While some studies have shown a beneficial role of lymphatic vessels in transplantation (12)(13)(14)(15), the prevailing view holds that they contribute to alloimmune responses that will result in the exacerbation of allograft rejection (16)(17)(18)(19). Therefore, it has been suggested that inhibiting lymphangiogenesis could be critical for graft tolerance and survival (20,21).…”

“…Therefore, it has been suggested that inhibiting lymphangiogenesis could be critical for graft tolerance and survival (20,21). However, lung allografts are acutely rejected within 7 days after transplantation in animal transplant models (22)(23)(24)(25), whereas spontaneous restoration of lymphatic drainage from the transplanted lung to the lymph nodes occurs no earlier than day 7 after transplantation (26,27). Since the onset of lung rejection precedes the reestablishment of lymphatic continuity, it is possible that insufficient lymphatic drainage could be responsible, at least in part, for acute lung allograft rejection.…”

Is Lymphoid Neogenesis a Therapeutic Target for Chronic Rejection?

“…Instead, we strongly believe that lymphoid neogenesis is a stereotypic response of the immune system confronted with persistent antigenic stimulation in a tissue disconnected from the professional secondary lymphoid organs (6). While rejected grafts display an increased lymphatic density (as observed by the authors and others (3)), they are also characterized by reduced lymphatic outflow (7). This apparent discrepancy may be explained by the fact that the expansion of lymphatic network is orchestrated by activated B lymphocytes (8).…”