Nutritional immunomodulation leads to enhanced allograft survival in combination with cyclosporine A and rapamycin, but not FK506.

BACKGROUND: Recently, specific immunonutrients were found to increase experimental allograft survival when combined with cyclosporine A (CsA). This study compared the effect on rat cardiac allograft survival when nutritional immunomodulation was used with CsA, rapamycin (Rapa), or tacrolimus (FK506). METHODS: Intra-abdominal ACI to Lewis cardiac allografts were performed and assessed daily by palpation. Study groups included untreated controls and those receiving CsA, Rapa, or FK506. Rats were fed ad libitum with Impact diet (fortified with fish oil, arginine, and RNA) or standard rat food. Further study groups were transplanted that received a donor-specific transfusion in addition to immunosuppression and diet. RESULTS: Allograft survival was extended by combining Impact with CsA (45.3+/-19 days) and Rapa (165.3+/-52 days), but not FK506 (12.4+/-3.2 days). Mean graft survival in the Rapa/Impact group met criteria for functional tolerance. The addition of a donor-specific transfusion did not lead to graft survival advantages over similar groups not receiving a donor-specific transfusion. CONCLUSIONS: The use of immunonutrients improves transplant outcome in animals treated with short courses of CsA and Rapa, but not FK506. These findings highlight the potential differences in the effects of nutritional immunomodulation with different immunosuppressive drugs in the treatment of transplant patients.

The effect of nutritional immunomodulation on cardiac allograft survival in rats receiving mycophenolate mofetil, cyclosporine A, and donor-specific transfusion.

BACKGROUND: Immunosuppressive drugs continue to pose significant risks such as infection, toxicity, or neoplasia when used in long-term therapy. The investigation of newer and safer combined treatment strategies that decrease the need for these drugs is becoming increasingly important. Immunonutrients are known to have significant modulating effects on the immune system. Feeding with Impact, a commercially available diet enriched with arginine, omega-3 fatty acids, and RNA, recently has been shown to extend rat cardiac allograft survival when combined with a donor-specific transfusion (DST) and cyclosporine A (CsA). Because mycophenolate mofetil (MMF) is now commonly used in the clinical setting, the current study was designed to examine the effect on rat cardiac allograft survival when MMF was added to this immunosuppressive regimen. METHODS: Intra-abdominal ACI to Lewis heterotopic cardiac allografts were performed. Study groups included untreated controls and recipients receiving varying combinations of a DST (1 mL) on the day prior to engraftment, MMF 45 mg/kg/day from the day of transplant through postoperative day six, and CsA 10 mg/kg on the day prior to operation and 2.5 mg/kg from the day of transplant through postoperative day 6. Animals were fed ad libitum with Impact diet or standard lab chow. Graft survival was determined by cessation of a palpable heartbeat. RESULTS: Treatment with MMF led to a prolonged allograft survival over historical untreated controls. The combination of MMF with a donor-specific transfusion, Impact, or CsA was associated with an increase in graft survival over MMF alone. The addition of Impact to the combination of MMF and CsA resulted in further improvement. The most pronounced graft survival advantage was seen when Impact was combined with a DST and both of the immunosuppressive agents. One quarter of the animals in this group had a palpable donor heart beat at greater than 150 days, indicating functional tolerance in those animals. CONCLUSIONS: The administration of Impact diet to treatment groups in this study was associated with graft survival advantages when compared to most of the other study groups receiving a similar drug regimen and standard chow. These findings support the importance of nutritional influences on allograft survival, and highlight the potential of diet therapy when used with short courses of clinically relevant immunosuppressive drugs.

Dietary amino acids as new and novel agents to enhance allograft survival.

Dietary supplementation with arginine was previously found to enhance cardiac allograft survival in rats when given with a donor-specific transfusion and a short low-dose course of cyclosporine. This study was performed to determine further the role of amino acid supplementation in prolonging allograft survival. Standard isocaloric, isonitrogenous diets were modified to contain 2 or 4% of energy from arginine, 2 or 4% from glutamine, 4% from glycine or the following combinations: 2% arginine with 2% glutamine, 2% arginine with 4% glutamine, or 1% arginine with 2% glutamine. These diets were started along with a donor-specific transfusion and a 7-d course of cyclosporine the day before cardiac transplantation from an ACI to Lewis strain rat. Median survival times in days for the groups were as follows: control without amino acids, 19.0; 2% arginine, 68.0; 4% arginine, 35.5; 2% glutamine, 28.5; 4% glutamine, 53.5; 4% glycine, 31.5; 2% arginine with 2% glutamine, 39.5; 2% arginine with 4% glutamine, 42.5 and 1% arginine with 2% glutamine, 35.5. Each experimental diet except 2% glutamine and 4% glycine significantly enhanced allograft survival (P < 0.05) with the 2% arginine diet being the best (91.6 +/- 32.3 d [mean +/- SEM] versus 20.1 +/- 3.2 d for control). It is concluded that both arginine and glutamine enhance the immunosuppressive effects of donor-specific transfusion and cyclosporine.

The effect of sennosides on bacterial translocation and survival in a model of acute hemorrhagic pancreatitis.

Bacterial translocation leading to subsequent infectious complications is a significant determinant of outcome in acute hemorrhagic pancreatitis (AHP). The colonic ileus and impaired intestinal barrier function that often accompany AHP may predispose to translocation. Sennoside is a naturally occurring cathartic and choleretic agent that stimulates intestinal mucous secretion and has potent promotility effects. The impact of sennoside-induced intestinal motility and secretory function on bacterial translocation and survival was studied in a rat model of AHP. Severe acute pancreatitis was induced in rats by the intraductal infusion of 2% sodium deoxycholate (DCA, 0.4 ml/kg). A group of sham-operated rats (group A) received intraductal saline, whereas experimental animals were subsequently administered distilled water (group B) or sennoside solution (group C) by gavage every 8 h. After 48 h, intestinal transit of fluorescein isothiocyanate-labeled dextran, serum endotoxin, and amylase levels, and bacterial translocation to mesenteric lymph nodes (MLNs) and pancreatic tissue were determined. The pancreas and intestine were sampled for histologic study. All group A animals survived and did not develop pancreatitis or endotoxemia, whereas groups B and C all demonstrated severe hemorrhagic pancreatitis with evidence of necrosis. Mortality at 48 h was 55% in group B versus 12.5% in group C. Inhibition of intestinal motility was noted in 40% versus 20%, and endotoxin levels were 61.36+/-28.26 pg/L versus 5.41+/-3.58 pg/L in group B versus group C rats, respectively (p<0.001). Pancreatic tissue and MLN cultures were positive in 100% of group B survivors versus 14% of group C survivors (p<0.05). Histologic examination of the intestine in group C animals showed increased mucous secretion, proliferation of goblet cells, and evidence of rapid turnover/renewal of enterocytes. Treatment with the cathartic agent, sennoside, reduced translocation of endotoxin and bacteria, restored intestinal motility, increased mucous secretion, and reduced mortality in a model of acute hemorrhagic pancreatitis in the rat. Other cathartics may have similar properties and may be useful in preventing infectious complications in acute pancreatitis.

Dietary omega-3 and omega-9 fatty acids uniquely enhance allograft survival in cyclosporine-treated and donor-specific transfusion-treated rats.

BACKGROUND: Both laboratory and clinical studies have shown that dietary lipids may affect immunologic responses. This study was conducted to compare different classes of long-chain unsaturated fatty acids for their effect on allograft survival in animals receiving a donor-specific transfusion and a short course of low-dose cyclosporine (CsA). METHODS: Heterotopic ACI strain cardiac allografts were transplanted to Lewis strain rat recipients given diets with different lipid composition. In experiment 1, animals received CsA for 14 days and different diets were enriched with lipids with high concentrations of omega-3, omega-6, or omega-9 fatty acids. In experiment 2, animals received CsA for only 8 days and different diets were enriched with corn oil (omega-6), canola oil (omega-3 and omega-9), fish oil (omega-3) or a mixture of sunflower oil and fish oil (omega-3 and omega-9). RESULTS: In experiment 1, animals receiving the diet with 30% sunflower oil had the best allograft survival (200+/-42 days vs. 53+/-8 days for regular chow plus donor-specific transfusion and CsA, P<0.05). In experiment 2, diets containing canola oil (a mixture of omega-3 and omega-9 fatty acids) were associated with the best survival (P=0.0011 vs. regular chow). CONCLUSION: Dietary omega-3 and omega-9 fatty acids both enhanced cardiac allograft survival in a stringent rat strain combination. Canola oil is a convenient oil for administering both alpha-linoleic acid (omega-3) and oleic acid (omega-9) in a palatable form for human consumption. Further investigation of the potential usefulness of lipids in transplant therapy is warranted.

Arginine, fish oil, and donor-specific transfusions independently improve cardiac allograft survival in rats given subtherapeutic doses of cyclosporin.

BACKGROUND: Dietary supplementation with a fish oil and arginine-enriched immunoenhancing diet (Impact; Sandoz Nutrition, Minneapolis, MN) in a rat cardiac allograft model using donor-specific transfusion (DST) and cyclosporin (CsA) resulted in significant prolongation of cardiac allograft survival with many animals developing long-term tolerance. This study was done to determine whether arginine or fish oil was the active ingredient. METHODS: A standard AIN-76A diet was modified to include either 10% fish oil, 2% arginine, or 5% arginine with or without fish oil. Diets were fed to Lewis strain rats that received Ax C9935 Irish (ACI) heterotopic cardiac allografts beginning on day 1 and continuing indefinitely. A DST (1.0 mL ACI whole blood) was given with 10 mg/kg CsA on day 1 relative to transplant and 2.5 mg/kg/d on days 0 to 6. Groups of animals receiving AIN-76A diet fortified with 2% glycine and animals receiving a DST or DST/CsA and regular laboratory chow served as controls. RESULTS: Mean survival times +/- SEM in days were as follows: untreated, 7.1 +/- 0.4; CsA/2% glycine, 8.5 +/- 0.6; DST only, 9.6 +/- 1.1; DST/CsA, 26.6 +/- 6.4; CsA/2% arginine, 25.5 +/- 3.9; DST/CsA/2% arginine, 68.7 +/- 8.9; DST/CsA/5% arginine, 90.1 +/- 31.1; CsA/fish oil, 73.6 +/- 26.1; and DST/CsA/fish oil/5% arginine, 90.1 +/- 31.1. The effect of arginine was slightly dose dependent and was seen best in combination with DST, but the effect of fish oil was not enhanced by DST. CONCLUSIONS: Both fish oil and arginine dietary supplementation significantly improved allograft survival but through different mechanisms (DST vs non-DST dependent).

Ischemic stricture and perforation. An unusual complication after successful barium reduction of an intussusception.

Intussusception is a common cause of intestinal obstruction in infants. Use of a barium enema affords both diagnostic confirmation and a chance for nonsurgical reduction of the intussusception. While failed hydrostatic reduction is an indication for surgical intervention, delayed complications of hydrostatic reduction have not been described. We present a case of ischemic stricture and perforation developing after the successful reduction of an intussusception.