Induction of Endotoxin Tolerance Delays Acute Rejection in a Hindlimb Transplantation Model in Rats

Abstract

Background: Acute rejection is seen in 85 percent of composite vascular allogeneic transplants despite long-term immunosuppression. Recently, it was reported that the induction of endotoxin tolerance prolonged heart allograft survival in mice. However, it produced side effects in all the animals secondary to the inflammatory reaction. Galactomannan has shown endotoxin tolerance without this side effect in vitro. The authors hypothesized that galactomannaninduced endotoxin tolerance delays acute rejection in vascular allogeneic transplantation without the side effects produced by lipopolysaccharide. Methods: Twenty-four rat hindlimb transplants were divided into four groups according to the preconditioning received: control, lipopolysaccharide (0.16 ml/kg), galactomannan 72 hours before (galactomannan-72) (8 ml/kg), and galactomannan 24 hours before (galactomannan-24) (8 ml/kg). Median acute rejection time, weight loss, and diarrheal episodes were monitored. Blood samples were collected at 0, 7, 21, 30, 45, and 60 days. Plasma cytokines (i.e., tumor necrosis factor alpha, interferon gamma), peripheral chimerism, and lymphocyte percentages were analyzed. Results: Median allograft survival was 40 days (range, 40 to 44 days) in the control group, 68 days (range, 61 to 71 days) in the lipopolysaccharide group, and 70 days (range, 69 to 73 days) in both galactomannan groups (p = 0.001). Weight loss was higher in the lipopolysaccharide group (p < 0.001), as was the 83.3 percent rate of diarrheal episodes (control, 0 percent, p = 0.015; galactomannan-72, 0 percent, p = 0.015; and galactomannan-24, 16.7 percent, p = 0.02). Preconditioned rats had higher peripheral blood chimerism (lipopolysaccharide, 2.30 ± 0.13 percent; galactomannan-72, 2.63 ±1.46 percent; and galactomannan-24, 2.47 ± 0.19 percent) compared to the control group (2.06 ± 0.36 percent) (lipopolysaccharide, p = 0.04; galactomannan-72, p = 0.002; and galactomannan-24, p = 0.002). Conclusions: Induction of endotoxin tolerance delays acute rejection in the rat hindlimb transplantation model. Galactomannan preconditioning has no lipopolysaccharide side effects and was equally effective in delaying acute rejection. (Plast. Reconstr. Surg. 149: 216e, 2022.) Clinical Relevance Statement: The contributions of this experimental work are very incipient. Although the use of galactomannan in clinical practice requires more studies to assess its safety, there is no doubt that immunomodulation may be one of the responses that solve the problem of long-term immunosuppression.

Modulation of allograft immune responses by Porphyromonas gingivalis lipopolysaccharide administration in a rat model of kidney transplantation

“…A previous report suggested that inducing ET in donor mice extended heart allograft survival in a murine heart transplantation model by promoting the generation of myeloid-related dendritic cells and Th2 responses [26]. Additionally, inducing ET in recipient rats delayed acute rejection in a hindlimb transplantation model by suppressing proin ammatory cytokines [27]. However, these previous studies used LPS derived from E. coli for ET induction.…”

Modulation of allograft immune responses by Porphyromonas gingivalis lipopolysaccharide administration in a rat model of kidney transplantation

“…A previous report suggested that inducing ET in donor mice extended heart allograft survival in a murine heart transplantation model by promoting the generation of myeloid-related dendritic cells and Th2 responses 26 . Additionally, inducing ET in recipient rats delayed acute rejection in a hindlimb transplantation model by suppressing proinflammatory cytokines 27 . However, these previous studies used LPS derived from E. coli for ET induction.…”

“…LPS-PG or PBS was administered to each rat via the tail vein. A dose of 0.8 mg/kg LPS-PG was administered to the LPS-PG group rats, determined according to a previous study on the effect of ET on transplant immunity 27 . Blood samples from the tail vein were collected and serum samples were stored at − 80 ℃ until analyzed.…”