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

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 galactomannan-induced 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. 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.

Factors that Influence Soft-tissue Injury in Fractures of the Distal Tibia.

BACKGROUND: Soft tissue injury associated with fractures of the distal tibia is a predictive factor for a poor prognosis. The purpose of this study was to investigate factors associated with the need for a flap coverage after distal tibial fracture, and whether there was a difference in functional outcomes between patients with flap coverage or no flap coverage for a distal tibial fracture. METHODS: All fractures of the distal tibia treated in our department between 2010 and 2017 were reviewed. The functional result was assessed using the SF-36 Quality of Life Questionnaire, the Visual Analog Scale (VAS) when walking and the AOFAS scale (American Orthopedic Foot and Ankle Society). RESULTS: 132 distal tibia fractures were reviewed, of which 51 required soft tissue flap reconstruction, which was associated with open fractures (P<0.001, OR 5.25), high energy trauma (P<0.001, OR 1.7)), the use of external fixation (p <0.001, OR 12.5) and the presence of vascular alterations on the Angio-CT scan (P<0.001). No significant differences were found in any of the scales that assessed the functional results between the group of patients who required soft tissue flap reconstruction and the group of patients who did not. CONCLUSION: We found that the need for a soft tissue flap was associated with the following parameters: open fracture, high energy of trauma, presence of skin necrosis, the use of external fixation and the existence of vascular injury. In relation to functional results, differences were not found between the group that needed coverage with a flap and the one that did not.

Inducción de tolerancia a endotoxina en un modelo de trasplante de tejido compuesto / Tolerance induction to endotoxin in a composite tissue transplant

Introducción y Objetivo: La tolerancia a endotoxina (TE) es un fenómeno biológico que consiste en la desensibilización de las células del sistema inmune ante exposiciones bajas al lipopolisacárido (LPS), haciendo que entren en un estado de anergia ante otros estímulos. El objetivo de este trabajo es valorar el efecto inmunomodulador del precondicionamiento con lipopolisacárido en el contexto de un trasplante de tejido compuesto. Material y Método: Realizamos transferencias de patas traseras entre ratas cruzando el Complejo Mayor de Histocompatibilidad. Los animales se dividieron en 2 grupos según el precondicionamiento que recibieron, LPS y suero salino fisiológico. Resultados: El grupo control presentó una mediana de supervivencia del alotrasplante menor a 15 días tras el cese del tratamiento inmunosupresor. El grupo precondicionado con LPS presentó una mediana de supervivencia superior a 30 días (p= 0.001). Conclusiones: El mecanismo de tolerancia a endotoxina aumenta la supervivencia del alotrasplante de tejido compuesto

Background and Objetive: Endotoxin tolerance is a biological phenomenon which consists in desensitization of immune system cells to low exposures to lipopolysaccharide (LPS). It leads to antigens anergy. The aim of this study is to asses the development of tolerance after precondicioning with LPS in the context of a composite tissue transplant. Methods: Transferences of hind legs were made between rats crossing the Main Histocompatibility Complex (MHC). The animals were divided into 2 groups according to the preconditioning they received, LPS and physiological saline. Results: The control group presented a median survival of the allograft less tan 15 days after the cessation of inmunosupressive treatment. The group preconditioned with LPS presented median survival greater than 30 days (p=0.001). Conclusions: The mechanism of tolerance to endotoxin increases the survival of composite tissue allotransplantation