Rapamycin suppression of host-versus-graft and graft-versus-host disease in MHC-mismatched rats.
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Animals↗
Biomedical subjects
R R Bollinger
Publications and source records attributed to R R Bollinger.
Transport of free fatty acid and triglyceride in anhepatic rats.
Without a liver the fractional plasma removal of free fatty acid is one third and chylomicron triglyceride one half of that in the intact rat. The intestine of the anhepatic rat converted enteral fatty acid to plasma triglyceride but was unable to do the same for plasma free fatty acid. This decrease in plasma free fatty acid removal and the inability to recycle the acid as triglyceride were, in part, responsible for the conversion of large fractions of plasma triglyceride flux to the plasma free acid in hepatectomized rats. Increased intravascular triglyceride lipolysis resulting from high circulating lipoprotein lipase concentrations and reduced plasma triglyceride removal were other factors shifting the partition of anhepatic plasma fatty-acid transport from the ester to the free. After the anhepatic plasma clearance of either free fatty acid or triglyceride, relatively more of both compounds was recovered in the lipid of actively metabolizing (heart and muscle) as opposed to storage (adipose) tissue when compared with controls. Sequential evaluations of the recovery of plasma free fatty acid and triglyceride in tissues of anhepatic rats demonstrated accumulation or storage solely in adipose tissue and only when the plasma fatty acid was in triglyceride. This observation and the large conversion of anhepatic circulating triglyceride to the free acid may, in part, explain the lack of an increase in adipose lipid with reduced hepatic mass. The data help explain the preferential use of a lipid fuel in liver disease and the difficulties in obtaining carbon storage in this condition.
Animals↗
The effect of soluble complement receptor type 1 on hyperacute allograft rejection.
A major obstacle to successful organ transplantation in sensitized recipients is antibody-mediated hyperacute rejection. We hypothesized that human recombinant soluble complement receptor type 1 (sCR1), which inhibits activation of the complement cascade at multiple stages, would delay this process. Using a well-established model of hyperacute rejection, 21 Lewis rats each received three successive ACI rat skin grafts which resulted in high serum titers of ACI-specific antibodies. These hypersensitized Lewis rats then received heterotopic ACI cardiac allografts. Immediately prior to allograft reperfusion, sCR1 at 3 mg/kg (n = 11) or an equivalent volume of phosphate-buffered saline (PBS) (n = 10) was administered intravenously. Five minutes following allograft reperfusion, hemolytic complement activity was reduced by 63 +/- 2% (SEM) in the sCR1 group vs 25 +/- 3% in the PBS group (P less than 0.0001, Wilcoxon rank sum test (WRST)). Graft survival in the sCR1 group was prolonged to 32.0 +/- 4.47 hr vs 3.25 +/- 0.81 hr in the PBS group (P less than 0.0001, WRST). Serial histologic examination of allografts showed that sCR1 therapy prevented the early development of luminal platelet thrombi in the allograft coronary vessels. This study demonstrates that a single 3 mg/kg dose of sCR1 significantly prolongs ACI cardiac allograft survival in the hypersensitized Lewis rat recipient. Complement inactivation, mediated by sCR1, may prove useful for transplantation in sensitized recipients.
Acute Disease↗
Evaluation of solutions for small intestinal preservation. Biochemical changes as a function of storage time.
A number of organ preservation solutions have been formulated to slow the inevitable progression of ischemic injury, thus prolonging the storage time between removal and implantation. As adenine nucleotide content has been shown to correlate with the functional recovery of transplanted livers and hearts, this study investigated the effects of 24 hr of storage in three preservation solutions, saline (SA), Euro-Collins (CO), and University of Wisconsin (UW) on adenine and nicotinamide adenine nucleotides and inosine content of the rat small intestine. Significant biochemical differences were found between segments as early as after the initial perfusion when the inosine content was higher in UW-perfused than CO- or SA-perfused segments. After 2 hr of storage in CO solution and after 6 and 24 hr in both CO and UW solutions, the ATP content was higher than in SA-stored segments. In addition to inosine, which was significantly higher at all time points for UW-stored segments, the AMP and total adenine nucleotide content of UW-stored segments at 24 hr was significantly higher than SA- or CO-stored segments. After 24 hr of storage, those segments stored in UW were able to utilize significantly more oxygen than SA-stored. These data provide biochemical evidence supporting the advantages of CO and UW storage solutions over SA for preservation of small intestine segments.
Adenine Nucleotides↗
The effect of soluble complement receptor type 1 on hyperacute xenograft rejection.
In the guinea pig-to-rat model of hyperacute xenograft (Xg) rejection, the effect of complement inhibition using systemically administered soluble complement receptor type 1 (sCR1) on discordant cardiac Xg survival was investigated. In PBS-treated control Xg recipients (n = 13), hyperacute rejection was rapid, with a mean Xg survival of 17 +/- 4 min. Therapy with sCR1 prolonged survival of cardiac Xgs in a dose-dependent manner. A 3 mg/kg bolus of sCR1 (n = 4) prolonged Xg survival to 64 +/- 29 min (not significant). Increasing the sCR1 dose to 5.9 mg/kg (n = 4) significantly delayed Xg rejection to 71 +/- 17 min (P-0.026, log-rank test vs. control). In 10 recipients treated with 15 mg/kg sCR1, mean Xg survival was further prolonged to 189 +/- 36 min (P-0.0004) with no adverse effects. While 2 of 8 recipients receiving 60 mg/kg sCR1 died with functioning Xgs at 30 and 300 min due to anastomotic bleeding, Xg survival averaged over 12 hr (747 +/- 100 min, P-0.0004) in the remaining 6 recipients. sCR1 administration significantly inhibited serum complement activity in a parallel dose-dependent fashion, with the 60 mg/kg dose reducing complement activity by 95 +/- 1 and 96 +/- 1% five and 30 min following Xg reperfusion, respectively. Immunofluorescence microscopy revealed rat IgM bound to all cardiac Xgs in control as well as sCR1-treated recipients. In addition, serial histologic examination of cardiac Xgs harvested within 21 min of graft reperfusion revealed occlusive platelet aggregates within the coronary vessels as well as interstitial hemorrhage and myocardial necrosis in Xgs from control recipients, all of which were only minimally present in Xgs from recipients treated with sCR1. These studies show that complement inhibition with sCR1 significantly delays hyperacute cardiac Xg rejection in this discordant model and may be an important component in a therapeutic protocol for xenotransplantation.
Animals↗
Total lymphoid irradiation for cardiac xenotransplantation in nonhuman primates.
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Animals↗
The effect of 15-deoxyspergualin on hamster-to-rat cardiac xenograft survival.
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Animals↗
Irradiation for xenogeneic transplantation.
Xenogeneic transplantation (XT) is the transplantation of organs or tissues from a member of one species to a member of another. Mammalian species frequently have circulating antibody which is directed against the foreign organ irrespective of known prior antigen exposure. This antibody may lead to hyperacute rejection. There is no reliable means to avert hyperacute rejection once it ensues so efforts must be directed towards eliminating the pre-existing antibody. In those species in which hyperacute rejection of xenografts does not occur, cell-mediated rejection, similar to allograft rejection, may occur. It is in the prevention of this latter form of rejection that radiation is most likely to be beneficial in XT. Both total lymphoid irradiation (TLI) and selective lymphoid irradiation (SLI) have been investigated for use in conjunction with XT. TLI has contributed to the prolongation of pancreatic islet-cell xenografts from hamsters to rats. TLI has also markedly prolonged the survival of cardiac transplants from hamsters to rats. A more modest prolongation of graft survival has been seen with the use of TLI in rabbit-to-rat exchanges. Therapy with TLI, cyclosporine, and splenectomy has markedly prolonged the survival of liver transplants from hamsters to rats, and preliminary data suggest that TLI may contribute to the prolongation of graft survival in the transplantation of hearts from monkeys to baboons. SLI appears to have prolonged graft survival, when used in conjunction with anti-lymphocyte globulin, in hamster-to-rat cardiac graft exchanges. The current state of knowledge of the use of irradiation in experimental XT is reviewed.
Animals↗
Significant prolongation of hamster liver transplant survival in Lewis rats by total-lymphoid irradiation, cyclosporine, and splenectomy.
The effects of total lymphoid irradiation, cyclosporine and splenectomy alone and in combination have been studied in liver transplants from the LVG hamster to the LEW rat. Neither CsA alone, splenectomy alone, nor TLI alone prolonged graft survival. CsA/splenectomy and TLI/CsA produced significant prolongation of graft survival. TLI/CsA/splenectomy prolonged graft survival by over sixfold compared with controls. While CsA alone was ineffective in reducing lymphocytotoxic antidonor antibody, splenectomy alone or CsA/splenectomy did significantly suppress production of antibody. Only very low levels of antibody could be detected in animals treated with TLI/CsA/splenectomy. TLI/CsA/splenectomy has an immunosuppressive effect sufficient to significantly prolong liver graft survival in the LVG hamster to LEW rat combination and may represent a promising treatment protocol in experimental cross-species transplantation.
Animals↗
The effect of TLI and cyclosporine on xenograft survival.
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Animals↗
Suppression of hepatic allograft rejection in the rat by mitomycin C-treated donor splenocytes: analysis of the immune status.
A single intraperitoneal injection of 3 x 10(6) donor splenocytes treated with mitomycin c (MMC) seven days before hepatic transplantation prolongs survival of hepatic allografts in the ACI (RT1a) to LEW (RT1l) rat combination. This effect is donor specific. An intravenous injection of the same dose of splenocytes treated with MMC seven days before transplantation also tends to prolong hepatic allograft survival. Furthermore, lymphocytotoxic antibody can be detected in rats 30 days after transplantation. Adoptive transfer of 5 x 10(7) splenocytes taken from long-term surviving hepatic allograft recipients pretreated with MMC-treated donor ACI splenocytes into irradiated (750 rads) LEW rats prolongs the survival of donor-type skin grafts, whereas third-party strain (BN) grafts are rejected. Similarly, prolonged survival of ACI cardiac allografts in irradiated (450 rads) LEW recipients is achieved following the transfer of spleen cells taken from longterm surviving hepatic allograft recipients pretreated with MMC-treated donor ACI splenocytes, whereas third-party (BN) cardiac allografts show rejection. These findings suggest the presence of donor-specific suppressor cells and indicate that a single injection of donor splenocytes treated with MMC to the recipient seven days before transplantation can induce specific suppression of rejection in a rat hepatic allograft model.
Animals↗
Percutaneous transhepatic ultrasonic cholelithotripsy.
In a patient with acute cholecystitis whose body habitus precluded cholecystectomy, we used percutaneous transhepatic ultrasonic cholelithotripsy. We compare it with other modalities applicable in such cases. Although not commonly used, these alternatives may be the most appropriate therapy in certain unusual circumstances.
Aged↗
A simplified single stage total hepatectomy in the rat with maintenance of gastrointestinal absorptive function.
A technique is described to remove the entire liver in a single stage with preservation of intestinal absorptive function. An inverted V-shape polyethylene cannula, either heparin bonded or silicon coated, was inserted into the portal vein and inferior vena cava to maintain venous return from the splanchnic and lower caval regions of the anhepatic rat. Blood glucose fell at a rate of 7 to 11 mg per hr per total plasma volume (4% body weight), usually resulting in hypoglycemia within the initial 2 hr. Euglycemia could be maintained in the first 3 hr after hepatectomy with hourly intravenous infusions of 2.5 to 5 mg per 100 gm body weight of glucose. Larger infusions of glucose (10 to 12.5 mg per hr per 100 gm body weight) were necessary for normal levels at later times. A 0.5 gm per 100 gm rat weight intestinal glucose bolus restored euglycemia for at least a 2-hr interval. Intestinal absorption of cholesterol and oleic acid was demonstrated in the anhepatic rat, although the latter was not so efficiently absorbed as in the control. The plasma cholesterol decreased with time in the anhepatic rat. Prompt increases were observed in plasma free fatty acid and glycerol concentrations after hepatectomy. Progressive increases in both direct and indirect plasma bilirubin levels were noted after hepatectomy. With appropriate maintenance of blood sugar, survival of 36 hr was observed. This procedure for single stage total hepatectomy in the rat can be performed in less than 30 min. The model is particularly useful for studies of the influence of the liver on postabsorptive metabolism.
Animals↗
Prevention of hemodialysis fistula thrombosis. Early detection of venous stenoses.
Venous dialysis pressures were measured consecutively in 168 chronic hemodialysis patients for 265 patient-years of monitored dialysis. Venous dialysis pressure greater than 150 mm Hg measured by the protocol were considered elevated. Seventy-three patients had elevated venous dialysis pressures and 58 agreed to undergo elective venography (fistulogram). Fifty of 58 patients studied (86%) had significant venous stenoses. A combination of percutaneous transluminal angioplasty (PTA) and surgical revision were used to electively treat these stenoses. Early detection and treatment of these stenoses decreased fistula thrombosis and fistula replacement threefold compared with our earlier experiences. Patients with elevated venous dialysis pressure who were venogramed and treated had an occurrence of fistula thrombosis similar to patients with normal dialysis pressure (0.15 and 0.13 episodes per patient year of dialysis respectively, P = NS). In contrast patients with elevated venous dialysis pressure who refused elective fistulogram and treatment averaged 1.4 episodes of thrombosis per patient year of dialysis (P less than 0.001) compared to both other groups). We conclude that elevated venous dialysis pressure is a reliable method of detecting fistula stenoses and that the elective treatment of these stenoses significantly decreases fistula thrombosis and fistula loss.
Angioplasty, Balloon↗
The role of class I major histocompatibility complex antigens in prolonging the survival of hepatic allografts in the rat.
In an attempt to study the role of class I major histocompatibility complex antigens in inducing immunological unresponsiveness, the survival rates of hepatic allografts were compared in rats pretreated with blood taken from various rat strains. A single intravenous injection of 1 ml fresh heparinized whole blood seven days before transplantation significantly prolonged the survival of subsequent donor-specific hepatic allografts in the fully allogeneic ACI(RT1a)-to-LEW(RT1l) rat combination. However, pretreatment with blood taken from the third-party strain BN(RT1n) did not produce suppression of rejection, attesting to the specificity of the pretransplant transfusion effect. Interestingly, pretransplant transfusion of PVG.r1 blood, sharing only the RT1.A MHC region with ACI, significantly prolonged the survival of ACI-to-LEW hepatic allografts. In addition, no lymphocytotoxic antibodies could be detected at 30 or 100 days after transplantation in animals with long-surviving hepatic allografts pretreated with either PVG.r1 or ACI whole blood. On the other hand, pretreatment with PVG(RT1c) blood increased the survival of ACI-to-LEW hepatic allografts only moderately compared with controls. This finding may be consistent with a partial effect of some third-party blood transfusion. The experimental data suggest that the class I MHC antigens can be immunosuppressive in rat hepatic allografts. Adoptive transfer of 5 x 10(7) splenocytes taken from long-term-surviving hepatic allografts pretreated with donor ACI whole blood or PVG.r1 blood into irradiated (750 rads) LEW rats prolonged the survival of donor-type skin grafts, whereas third-party strain (BN) grafts were rejected. This finding suggests the presence of donor-specific suppressor cells.
Animals↗
Variable allograft responses to pretreatment with donor splenocytes treated with mitomycin C in the rat.
In an attempt to investigate the nonspecificity of the effect of administration of donor splenocytes treated with mitomycin C (MMC) 7 days before transplantation in inducing immunological unresponsiveness, the survival rates of liver, heart, small bowel, and skin allografts were compared in the RT1-incompatible ACI(RT1a) to LEW(RT1l) rat combination. ACI donor splenocytes (3 x 10(6)) treated with MMC were administered i.p. or i.v. via the penile vein 7 days before transplantation. Both routes of administration prolonged the survival of hepatic allografts (greater than 87.2 +/- 22.2 days and greater than 78.9 +/- 28.2 days, respectively), compared with controls (10.6 +/- 0.5 days). Cardiac allograft survival in untreated controls was 6.0 +/- 0.4 days. A single i.v. injection of 3 x 10(6) donor splenocytes resulted in significantly prolonged survival (10.0 +/- 4.3 days), whereas i.p. injection showed rejection at a mean of 6.0 +/- 1.2 days. A single i.p. injection of 3 x 10(6) splenocytes did not increase survival of small bowel allografts (10.3 +/- 4.8 days), compared with controls (8.8 +/- 1.8 days). On the other hand, a single i.v. injection of donor splenocytes prior to transplantation significantly prolonged survival of small bowel allografts (13.4 +/- 3.5 days). No signs of graft-versus-host reaction (GVHR) were observed during these experiments. Neither a single i.p. nor a single i.v. injection of donor splenocytes resulted in prolonged survival of ACI-to-LEW skin allografts (6.3 +/- 0.8 days and 6.6 +/- 0.9 days, respectively), compared with controls (5.7 +/- 0.5 days). Interestingly, we confirmed the relative ease with which survival of hepatic allografts can be prolonged in the rat by donor antigen treatment alone, even in a strongly rejecting RT1-incompatible rat strain combination, in contrast to other organ allografts such as heart, small intestine, and skin. The discrepancy in survival of different organ allografts following pretreatment with donor splenocytes treated with MMC may be explained by a difference in the immunogenicity of the organs transplanted or other factors.
Animals↗
Intravenous digital subtraction renal angiography: use in screening for renovascular hypertension.
Intravenous digital subtraction renal angiography (DSRA) has been compared with conventional angiography only in small, selected series of hypertensive patients. The authors prospectively examined with intravenous DSRA 94 patients at increased risk for renovascular hypertension and compared these studies with conventional angiography. A stenosis of at least one main renal artery was identified with intravenous DSRA in 22 patients and confirmed in 20 patients. No significant stenoses were seen with conventional angiography in any of the 64 patients in whom lesions were not seen with intravenous DSRA. Since inadequate DSRA studies were considered positive for renal artery stenosis, the sensitivity of intravenous DSRA was 100% (25 of 25); specificity, 93% (64 of 69); positive predictive value, 83% (25 of 30); and negative predictive value, 100% (64 of 64). The authors conclude that intravenous DSRA is a sensitive test for identifying stenosis of the main renal arteries and is appropriate to use as a screening test among patients at increased risk for renovascular hypertension.
Adult↗
Prospective analysis of strategies for diagnosing renovascular hypertension.
Renovascular hypertension is a potentially curable form of high blood pressure. However, it is unclear how best to select patients who are likely to have renovascular hypertension, what diagnostic strategy to use in these selected patients, and how to predict the hemodynamic significance of a renal artery stenosis. We determined the prevalence of renovascular hypertension in adults who exhibited suggestive clinical features. In these clinically selected patients, we then determined the test characteristics of various diagnostic and potential screening tests. Renovascular hypertension was diagnosed if correction of renal artery stenosis resulted in decreased blood pressure. Of the 66 hypertensive adults evaluated, 11 (16.7%) had renovascular hypertension. Captopril-stimulated peripheral renin activity detected renovascular hypertension with 73% sensitivity, 72% specificity, 38% positive predictive value, and 92% negative predictive value. Less optimal combinations of sensitivity and specificity were found for differential glomerular filtration rate renography, differential effective renal plasma flow renography, and selective renal vein renin ratios, each performed after a single dose of captopril. Intravenous digital subtraction renal angiography detected all patients with renovascular hypertension and was normal in 71% of patients with essential hypertension. To evaluate potential screening tests for renovascular hypertension, we calculated predictive values applied to a low prevalence population. If the observed sensitivities and specificities apply to a population with 5% prevalence of renovascular hypertension, captopril-stimulated peripheral renin would have a positive predictive value of 12% and a negative predictive value of 98%. In 16 patients with known renal artery stenosis, neither the captopril-stimulated renal vein renin ratio nor captopril-stimulated differential renography accurately predicted blood pressure response to correction of the stenosis. We conclude that clinical criteria can identify a subgroup with 16.7% prevalence of renovascular hypertension. In this high prevalence group, intravenous digital subtraction renal angiography will identify virtually all patients with renovascular hypertension, and a normal study will be sufficient to exclude renovascular hypertension. In unselected hypertensive patients, screening with captopril-stimulated peripheral renin activity may be the most useful and efficient procedure for identification of patients with renovascular hypertension. Functional tests do not accurately predict the hemodynamic significance of a renal artery stenosis.
Adult↗