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Influence of macrophage depletion on bacterial translocation and rejection in small bowel transplantation
Abstract:
Rejection and sepsis can be intimately related following small bowel transplantation when rejection compromises normal intestinal barrier mechanisms and bacterial translocation results. Macrophages play a role in controlling the egress of intestinal luminal bacteria--and they have also been implicated in allograft rejection. In this study, the role of macrophages in rejection and bacterial translocation was evaluated by depleting macrophages in donors and/or recipients of rat small bowel allografts with injection of liposome-encapsulated dichloromethylene diphosphonate (CL2MDP). In preliminary studies, we demonstrated that a single intraperitoneal injection of liposome-encapsulated CL2MDP (350 mg/kg) depleted ED2-positive macrophages by > 90% in the liver mesenteric lymph nodes and proximal and distal small bowel, and by approximately 50% in the spleen. ED1-positive macrophages were depleted by > 90% in the liver and by approximately 50% at the other sites. ED3-positive macrophages were completely depleted. Dendritic cells were > 90% depleted in the spleen and mesenteric lymph nodes, but were not depleted in the small bowel. Macrophage depletion in the donor resulted in increased translocation of bacteria to the peritoneal cavity (P = 0.03) if recipient macrophages were present. With histopathologic analysis, a significantly milder rejection with less arteritis was seen in the allografts of the recipient macrophage-depleted group compared with nondepleted controls (P = 0.045). This suggests that recipient macrophages play an important role in rejection. With macrophage depletion in both the donor and the recipient, graft survival was prolonged significantly (13.2 +/- 1.9 days) compared with non-macrophage-depleted controls (9.2 +/- 1.3 days) (P = 0.003). These studies suggest that strategies targeting recipient macrophages may be useful in controlling small bowel allograft rejection without increasing bacterial translocation.
Insights
Targeting macrophages in small bowel transplantation may prevent rejection and sepsis. Depleting recipient macrophages reduced rejection and prolonged graft survival without increasing bacterial translocation.
Area of Science:
- Immunology
- Transplantation Biology
- Gastroenterology
Background:
- Rejection and sepsis are linked in small bowel transplantation due to compromised intestinal barriers and bacterial translocation.
- Macrophages are involved in controlling intestinal bacteria and have been implicated in allograft rejection.
Purpose of the Study:
- To investigate the role of macrophages in small bowel allograft rejection and bacterial translocation.
- To evaluate the effect of macrophage depletion in donors and recipients on graft survival and bacterial translocation.
Main Methods:
- Rats received small bowel allografts after macrophage depletion in donors and/or recipients using liposome-encapsulated dichloromethylene diphosphonate (CL2MDP).
- Macrophage depletion levels were assessed in various tissues.
- Bacterial translocation and histopathological rejection were evaluated.
Main Results:
- Depleting donor macrophages increased bacterial translocation when recipient macrophages were present.
- Recipient macrophage depletion led to milder rejection and reduced arteritis.
- Simultaneous depletion of donor and recipient macrophages significantly prolonged small bowel allograft survival.
Conclusions:
- Recipient macrophages play a critical role in mediating small bowel allograft rejection.
- Targeting recipient macrophages may offer a strategy to control rejection without increasing bacterial translocation.
- Macrophage depletion strategies hold promise for improving outcomes in small bowel transplantation.