Posttransplant nonfunction of canine islets in PVG rats deficient in complement component C6

BACKGROUND: Discordant islet xenografts are immediately nonfunctional in nonimmunosuppressed recipients other than the mouse, a process called primary nonfunction. Although at present it is unknown whether complement is involved, complement might participate in the induction of primary nonfunction through a number of mechanisms. We investigated the potential role of the membrane attack complex of complement in primary nonfunction of transplanted xenoislets. METHODS: Canine islets were transplanted into both nonimmunosuppressed and immunosuppressed normocomplementemic and C6-deficient (C6D) PVG rats. Cyclosporine, rapamycin, deoxyspergualin, and mycophenolate mofetil were used for immunosuppression from day -3 to cessation of islet cell function. Serum glucose was measured at 6 hr after transplant and daily thereafter. Xenograft tissue sections were obtained at various times after transplant and stained for inflammatory cells and insulin. RESULTS: Canine islets grafted in nonimmunosuppressed C6D rats and normocomplementemic rats underwent primary nonfunction in all animals. The incidence of primary nonfunction in animals receiving a four-drug immunosuppressive regimen was 33% in the normocomplementemic rats but only 10% in the C6D rats. The mean functional islet survival time was 1.57+/-0.33 days in the normocomplementemic group and 2.70+/-0.67 days in the C6D group (P=0.38). The islet xenografts showed little difference in degree and composition of cell infiltration between normocomplementemic and C6D rats. CONCLUSION: The membrane attack complex does not appear to play a major role in primary nonfunction of canine islet xenografts in nonimmunosuppressed PVG rats. However, there was a lower incidence of primary nonfunction and a longer posttransplant survival time in immunosuppressed C6D rats, suggesting the membrane attack complex may play a minor role in recipients that are heavily immunosuppressed.     

The role of inducible nitric oxide synthase in cardiac allograft rejection

Rats were exposed to either a footshock stimulus (FS) or emotional stimulus (ES, forced perception of another rat receiving footshocks) during a daily 10-min session for 5 consecutive days. The consequences of FS and ES on their behavioural responsiveness were assessed at different post-stress intervals using a small open-field. FS induced a decrease in ambulation, rearing and sniffing and an increased immobility in the small open field. These effects were present in rats tested immediately after the last session and remained present for at least 15 days. In contrast, ES induced a transient decrease in ambulation and rearing immediately after the last session, but in the period from half an hour until at least 15 days after the stimulus experience, an increase in ambulation, rearing and sniffing was observed. Exposure to one footshock per session for 5 consecutive days or to 10 footshocks in a single session also resulted in a long-lasting reduction in ambulation and sniffing and an increase in immobility. The former regime did not influence the behavioural response of ES rats, but the latter resulted in an increase in ambulation, rearing and sniffing in ES rats. Naloxone (1 mg/kg s.c.) pretreatment antagonized the increased behavioural activity of the ES rats whereas the activity of control and FS animals was not affected, suggesting an involvement of endogenous opioid systems in the behavioural responses observed in ES rats. It is suggested that the behavioural responses of the ES and FS animals are regulated by different mechanisms.     

The effect of dietary polyunsaturated fatty acids (PUFA) on acute rejection and cardiac allograft blood flow in rats

For six weeks, recipient (Lewis RT11) and donor rats (LBNF11/n) were fed three diets that varied only in their lipid content. Diet A (MO) contained 19.5% menhaden oil and 0.5% safflower oil and was rich in omega 3 PUFA; diet B (SO) was 20% safflower oil rich in omega 6 PUFA; and diet C (BT) was 20% beef tallow rich in omega 9 monounsaturated fatty acids and saturated fat. In the first set of graft survival studies a group fed laboratory chow was included (CHOW). Heterotopic cardiac transplantation from donor to recipient animals was performed after the six-week feeding period. The effect of these diets on cardiac allograft survival, mixed lymphocyte response, and blood flow in the rejecting grafts was investigated. The median graft survival in days was significantly prolonged in the rats maintained on either MO (12 days) or SO (14.5 days) compared with the BT (8 days)-or lab chow (7.5 days)-fed animals (P < 0.05). Cyclosporine (CsA) administered at subtherapeutic levels further increased the differences between the PUFA-fed animals and the BT-fed group. The myocardial blood flow of the rejecting allografts was measured using an 85Sr-labeled microsphere technique on the fifth posttransplant day. Flow was greatest in the MO-fed group, and both MO and SO groups had significantly higher myocardial blood flow than BT-fed rats (P < 0.05) or those bearing isografts. The allogenic mixed lymphocyte responses of peripheral blood mononuclear cells (PBMC) and splenic lymphocytes were suppressed in MO- and SO-fed groups compared with BT-fed animals. The immunosuppressive effect of dietary PUFA warrants further investigation, and their use as a possible adjunctive treatment in organ transplantation should be considered.     

Sensitive diagnosis of cardiac allograft rejection by detection of cytokine transcription in situ

BACKGROUND & AIMS: Interleukin 12 (IL-12) is a heterodimeric, macrophage-derived cytokine that is elevated in Crohn's disease (CD). Epstein-Barr virus-induced gene 3 (EBI3) is a recently characterized human glycoprotein that is homologous to the 40-kilodalton chain of IL-12 and forms a heterodimer with the 35-kilodalton chain of IL-12. We investigated the expression of EBI3 in colonic mucosa of normal control subjects, patients with ulcerative colitis (UC), and patients with CD. METHODS: Colonic tissue was analyzed for messenger RNA (mRNA) expression by quantitative polymerase chain reaction and for protein expression by immunohistology and Western blotting. RESULTS: EBI3 mRNA was present in intestinal biopsy specimens from healthy subjects and patients with CD but was elevated only in active UC. EBI3 levels in UC specimens correlated with histological scores of activity and T-cell infiltration. EBI3-positive cells that had a shape consistent with that of macrophages were identified in the lamina propria, and protein was detected by Western blotting. CONCLUSIONS: EBI3 is a novel IL-12-related cytokine that is expressed by macrophage-like cells in normal intestine and CD and has enhanced expression in active UC but not in active CD.     

Long-term results of total lymphoid irradiation in the treatment of cardiac allograft rejection

PURPOSE: To evaluate the short and long-term effects of total lymphoid irradiation (TLI) in the treatment of cardiac transplant rejection. METHODS AND MATERIALS: Between 1986 and 1995, 48 courses of TLI were delivered to 47 cardiac transplant patients. In 37 patients, TLI was administered for intractable allograft rejection despite conventional therapy while 10 patients received TLI prophylactically. The prescribed radiation dose was 8 Gy in 0.8 Gy fractions twice weekly to mantle and inverted-Y plus spleen fields. Postirradiation follow-up ranged from 6 months to 9.1 years, with a mean of 3.1 years. RESULTS: The actual mean dose was 7.3 Gy delivered over a mean of 39 days. Fifty-six percent of patients required treatment delay or abbreviation because of thrombocytopenia, leukopenia, infection, or unrelated problems. In patients treated for intractable rejection, rejection rates dropped from 0.46 to 0.14 and to 0.06 episodes/patient/month before, during, and after TLI (p < 0.0001). Rejection rates continued to drop throughout follow-up. Prednisone requirements decreased from 0.41 mg/kg before treatment to 0.21 mg/kg afterward (p < 0.0001). The ratio of helper to cytotoxic-suppressor T-cells decreased during TLI from 1.33 to 0.89, and remained low at 0.44, 2-4 months after treatment. Infection rates were not increased and two patients developed malignancy. Rejection rates were high during prophylactic treatment and this protocol was abandoned. Three-year actuarial survival after irradiation was 60% for patients with intractable rejection and 70% for the prophylactic cohort. CONCLUSION: TLI is an effective treatment for control of intractable cardiac rejection. Episodes of rejection and steroid dosage requirements are decreased for up to 9.1 years. A possible mechanism of action is long term alteration in T-lymphocyte subsets. Patients experience transient bone marrow suppression but no increase in infection or bleeding. Long-term complications of TLI are not appreciably different than conventional immunosuppression.     

Mechanisms underlying cerebrovascular effects of cigarette smoking in rats in vivo

BACKGROUND AND PURPOSE: The effects of acute smoking on cerebral circulation are controversial. This study was designed (1) to clarify any differences between the effects of cigarette smoking and nicotine infusion and between the effects of single- and multiple-cigarette smoking on cerebral vessels and (2) to probe the mechanism(s) underlying the vascular responses. METHODS: In pentobarbital-anesthetized, mechanically ventilated Sprague-Dawley rats, pial vessel diameters were measured with the use of a cranial window preparation. We studied the effects of (1) 60 puffs per minute of mainstream cigarette smoke from cigarettes having 2 nicotine levels (0.1 and 1 mg per cigarette), (2) administration of nicotine (0.05 mg per body IV), and (3) repeated smoking (four 1 mg nicotine-containing cigarettes at 30-minute intervals) (n=6 each). RESULTS: Inhalation of smoke from a 0.1 or 1 mg nicotine-containing cigarette for 1 minute caused pial arterioles to constrict at 30 seconds (7.2% and 7.3%, respectively) and then to dilate (peak at 5 to 10 minutes; 4.6% and 17.9%, respectively). Nicotine infusion caused pial vasodilation (35.7%) without an initial vasoconstriction. Repeated smoking suppressed the pial vasodilation but not the initial vasoconstriction. The vasodilation induced by a single cigarette was greatly inhibited by pretreatment with mecamylamine or glibenclamide and attenuated by propranolol or Nomega-nitro-L-arginine methyl ester; the initial vasoconstriction was inhibited by seratrodast, a thromboxane A2 receptor antagonist (n=6 in each case). CONCLUSIONS: Single-cigarette smoking had a significant biphasic effect on cerebral arteriolar tone. The vasodilation was attenuated by repeated smoking. The vasodilation is most likely an effect of nicotine, at least in part mediated via sympathetic activation, NO production, and K+ channel activation. The vasoconstriction is partially due to thromboxane A2 induced by cigarette smoke.     

Olfactory basis for the delayed onset of maternal behavior in virgin female rats: Experimental effects.

A previous study showed that intranasal zinc sulfate (ZnSO4) treatment shortens the latencies for the onset of maternal behavior in nonpregnant rats. The present study attempted to determine whether after recovery from the effects of ZnSO4 treatment, the latencies for maternal behavior increased. In Exp I, with 28 Charles River female rats, nonpregnant Ss were intranasally infused with ZnSO4 or air were left untreated and exposed to pups starting 48 hr later. Olfactory discrimination tests using chocolate bits were done simultaneously. The ZnSO4 treatment resulted in short latency maternal behavior (1.1 days) compared with latencies of control Ss (3.8 days), but neither group showed any loss of olfactory discrimination. 3 wks later, ZnSO4-treated Ss showed increased latencies for all but retrieving, while control groups showed decreased latencies for all maternal behaviors. In Exp II, with 13 nulliparous Charles River females, intranasal ZnSO4- and air-treated Ss were given olfactory discrimination tests under food deprivation, using chocolate bits and guinea pig pellets. Choice of guinea pig pellets was more severely affected than choice of chocolate bits, but recovery of the discriminations was complete in 4-5 days. (18 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Expression of interleukin-6 in association with rat lung reimplantation and allograft rejection

Organ transplantation has become a therapeutic option for the replacement of malfunctioning tissues and organs. Since the advent of the first combined heart-lung transplant in 1981, there has been a rapid growth in the popularity of lung transplantation for a number of end-stage pulmonary disorders. Interestingly, these lung transplant patients experience more complications of acute and chronic allograft rejection compared with recipients of other solid organs. These episodes of rejection are related to a complex series of events that depend on the interaction of many cells and soluble mediators leading to cellular and tissue injury. The histopathology of lung allograft rejection has been actively studied and is associated with the sequestration of activated mononuclear phagocytes, T and B lymphocytes. These cells secrete a number of soluble mediators, that is, cytokines, that participate in the evolution of the immune response via autocrine, paracrine, or endocrine mechanisms. The interaction of cytokines with their targets leads to cellular activation, proliferation, and differentiation. In this study, we postulated that interleukin-6 (IL-6) may have a central role in the pathogenesis of acute lung allograft rejection. To test this hypothesis, we employed an unmodified RT1-incompatible rat lung allograft model and assessed the time course and major tissue compartment(s) of IL-6 production during the evolution of lung allograft rejection. The expression and production of IL-6 during the pathogenesis of lung allograft rejection was measured at the whole-animal, organ, cellular, and molecular levels. The expression of IL-6 was found to be bimodal in character, initially related to the reimplantation response and finally to the maximal allograft rejection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Methotrexate or total lymphoid radiation for treatment of persistent or recurrent allograft cellular rejection: a comparative study

Chlorpyrifos, one of the most widely used pesticides, exhibits greater toxicity during development than in adulthood. We administered chlorpyrifos to neonatal rats in doses spanning the threshold for systemic toxicity and examined developing brain regions (brainstem, forebrain, cerebellum) for signs of interference with cell development using markers for cell packing density and cell number (DNA concentration and content) and cell size (protein/DNA ratio). Neonatal rats given 5 mg/kg of chlorpyrifos on postnatal days 1-4 showed significant mortality and the survivors exhibited severe cell loss in the brainstem; brainstem growth was maintained by enlargement of the remaining cells. This effect was not seen at 1 mg/kg, a dose that did not compromise survival or growth, nor was there any adverse effect at either dose in the forebrain, despite the fact that both brainstem and forebrain possess comparable cholinergic projections. When chlorpyrifos was administered later, on days 11-14, the major target for cell loss shifted from the brainstem to the forebrain and in this case, effects were seen at doses that did not compromise survival or growth. The loss of forebrain cell number occurred between 15 and 20 days of age rather than during the chlorpyrifos treatment. The cerebellum differed from the other regions in that it showed short-term elevations of DNA after chlorpyrifos exposure in either early or late postnatal periods; nevertheless, values then regressed to subnormal in parallel with the loss of cells in other regions. Thus, chlorpyrifos likely causes delayed cell death. Although regions rich in cholinergic projections, such as brainstem and forebrain, may be more affected than noncholinergic regions (cerebellum), the maturational timetable of each region (brainstem earliest, forebrain intermediate, cerebellum last) appears to be more important in setting the window of vulnerability. These results indicate that, even when growth or survival are unaffected, chlorpyrifos produces cellular deficits in the developing brain that could contribute to behavioral abnormalities.     

Molecular basis of subtotal complement C6 deficiency. A carboxy-terminally truncated but functionally active C6

Individuals with subtotal complement C6 deficiency possess a C6 molecule that is 14% shorter than normal C6 and present in low but detectable concentrations (1-2% of the normal mean). We now show that this dysmorphic C6 is bactericidally active and lacks an epitope that was mapped to the most carboxy-terminal part of C6 using C6 cDNA fragments expressed as fusion proteins in the pUEX expression system. We thus predicted that the abnormal C6 molecule might be carboxy-terminally truncated and sought a mutation in an area approximately 14% from the carboxy-terminal end of the coding sequence. By sequencing PCR-amplified products from this region, we found, in three individuals from two families, a mutation that might plausibly be responsible for the defect. All three have an abnormal 5' splice donor site of intron 15, which would probably prevent splicing. An in-frame stop codon is found 17 codons downstream from the intron boundary, which would lead to a truncated polypeptide 13.5% smaller than normal C6. This result was unexpected, as earlier studies mapped the C5b binding site, or a putative enzymatic region, to this part of C6. Interestingly, all three subjects were probably heterozygous for both subtotal C6 and complete C6 deficiency.     

Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. CHIB 201 International Study Group

BACKGROUND: Currently available immunosuppressive regimens for cadaver-kidney recipients are far from ideal because acute-rejection episodes occur in about 30% to 50% of these patients. In the phase III study described here we assessed the ability of basiliximab, a chimeric interleukin (IL)-2 receptor monoclonal antibody, to prevent acute-rejection episodes in renal allograft recipients. METHODS: 380 adult recipients of a primary cadaveric kidney transplant were randomly allocated, in this double-blind trial, to receive a 20 mg infusion of basiliximab on day 0 (day of surgery) and on day 4, to provide IL-2-receptor suppression for 4-6 weeks (n=193), or to receive placebo (n=187). Both groups received baseline dual immunosuppressive therapy with cyclosporin and steroids throughout the study. The primary outcome measure was incidence of acute-rejection episodes during the 6 months after transplantation. Safety and tolerability were monitored over the 12 months of the study. FINDINGS: 376 patients were eligible for intention-to-treat analysis (basiliximab, n=190; placebo, n=186). No significant differences in patient characteristics were apparent. The incidence of biopsy-confirmed acute rejection 6 months after transplantation was 51 (29.8%) of 171 in the basiliximab group compared with 73 (44.0%) of 166 in the placebo group (32% reduction; 14.2% difference [95% Kaplan-Meier CIs 3% to 24%], p=0.012). The incidence of steroid-resistant first rejection episodes that required antibody therapy was significantly lower in the basiliximab group (10% vs 23.1%, 13.1% difference [5.4% to 20.8%], p<0.001). At weeks 2 and 4 post-transplantation, the mean daily dose of steroids was significantly higher in the placebo group (p<0.001 with one-way analysis of variance). The incidence of graft loss at 12 months post-transplantation was 23 (12.1%) of 190 in the basiliximab group and 25 (13.4%) of 186 in the placebo group (1.3% difference [-5% to 9%], p=0.591). The incidence of infection and other adverse events was similar in the two treatment groups. The acute tolerability of basiliximab was excellent, with no evidence of cytokine-release syndrome. 14 deaths (basiliximab n=9; placebo n=5; -2.0% difference [-6% to 2%], p=0.293) occurred during the 12-month study and a further three deaths (basiliximab n=1; placebo n=2) occurred within the 380-day cut-off period. One post-transplantation lymphoproliferative disorder was recorded in each group. INTERPRETATION: Prophylaxis with 40 mg basiliximab reduces the incidence of acute rejection episodes significantly, with no clinically relevant safety or tolerability concerns.     

The cellular basis of dilated cardiomyopathy in humans

The present investigation was designed to evaluate whether end-stage cardiac failure in patients affected by dilated cardiomyopathy (DC) was dependent upon extensive myocyte cell death with reduction in muscle mass or was the consequence of collagen accumulation in the myocardium independently from myocyte cell loss. In addition, the mechanisms of ventricular dilation were analysed in order to determine whether the changes in cardiac anatomy were important variables in the development of intractable congestive heart failure. DC is characterized by chamber dilation, myocardial scarring and myocyte hypertrophy in the absence of significant coronary atherosclerosis. However, the relative contribution of each of these factors to the remodeling of the ventricle is currently unknown. Moreover, no information is available concerning the potential etiology of collagen deposition in the myocardium and the changes in number and size of ventricular myocytes with this disease. Morphometric methodologies were applied to the analysis of 10 DC hearts obtained from patients undergoing cardiac transplantation. An identical number of control hearts was collected from individuals who died from causes other than cardiovascular diseases. DC produced a 2.2-fold and 4.2-fold increase in left ventricular weight and chamber volume resulting in a 48% reduction in mass-to-volume ratio. In the right ventricle, tissue weight and chamber size were both nearly doubled. Left ventricular dilation was the result of a 59% lengthening of myocytes and a 20% increase in the transverse circumference due to slippage of myocytes within the wall. Myocardial scarring represented by segmental, replacement and interstitial fibrosis occupied approximately 20% of each ventricle, and was indicative of extensive myocyte cell loss. However, myocyte number was not reduced and average cell volume increased 2-fold in both ventricles. In conclusion, reactive growth processes in myocytes and architectural rearrangement of the muscle compartment of the myocardium appear to be the major determinants of ventricular remodeling and the occurrence of cardiac failure in DC.     

Severe and early alteration of action potential during acute cardiac rejection in rats

INTRODUCTION: Alteration of cardiac action potential and its adaptation to heart rate could contribute to cardiac dysfunction and arrhythmias during acute cardiac rejection. METHODS AND RESULTS: Heterotopic heart transplantation was performed in allogeneic and syngeneic rats in which the action potentials of right and left ventricles were measured at 1, 2.5, 3.3, and 5.7 Hz successively using standard microelectrode techniques and compared with nontransplanted hearts. For each frequency, we measured action potential amplitude, action potential duration, transmembrane resting potential, and Vmax. In the right ventricle, at 1 Hz in the presence of rejection (n = 40), a significant increase was observed in action potential duration at 20%, 50%, and 70% repolarization (82.5%, 75.6%, and 70.8%, respectively) and in action potential amplitude (+17.9 mV), and the resting potential was decreased (-5.3 mV). A lack of adaptation of action potential duration to the driving frequency was observed in the rejecting heart group in contrast to controls (n = 20) and nonrejecting hearts (n = 13). Similar results were observed in the left ventricle and surprisingly in the native hearts (n = 11) of recipients with allografted rejecting hearts in the abdominal position. CONCLUSION: Action potential and its adaptation to the driving frequency is considerably altered during acute rejection. A humoral factor could contribute to cardiac dysfunction.     

Association of parvovirus B19 genome in children with myocarditis and cardiac allograft rejection: diagnosis using the polymerase chain reaction

BACKGROUND: Inflammatory diseases of the heart, including myocarditis and cardiac transplant rejection, are important causes of morbidity and mortality in children. Although viral infection may be suspected in either of these clinical conditions, the definitive etiology is often difficult to ascertain. Furthermore, the histology is identical for both disorders. Coxsackievirus has long been considered the most common cause of viral myocarditis; however, we previously demonstrated by polymerase chain reaction (PCR) analysis that many different, and sometimes unexpected, viruses may be responsible for myocarditis and cardiac rejection. In this study, we describe the association of parvovirus genome identified through PCR analysis of cardiac tissue in the clinical setting of myocarditis and cardiac allograft rejection. METHODS AND RESULTS: Myocardial tissue from endomyocardial biopsy, explant, or autopsy was analyzed for parvovirus B19 using primers designed to amplify a 699-base pair PCR product from the VP1 gene region. Samples tested included those obtained from patients with suspected myocarditis (n=360) or transplant rejection (n=200) or control subjects (n=250). Parvoviral genome was identified through PCR in 9 patients (3 myocarditis; 6 transplant) and no control patients. Of the 3 patients with myocarditis, 1 presented with cardiac arrest leading to death, 1 developed dilated cardiomyopathy, and the other gradually improved. Four of the 6 transplant patients had evidence of significant rejection on the basis of endomyocardial biopsy histology. All transplant patients survived the infection. CONCLUSIONS: Parvovirus is associated with myocarditis in a small percentage of children and may be a potential contributor to cardiac transplant rejection. PCR may provide a rapid and sensitive method of diagnosis.     

Recognition of acute cardiac allograft rejection from serial integrated backscatter analyses in human orthotopic heart transplant recipients. Comparison with conventional echocardiography

The distribution of voltage-sensitive elevations of the level of Ca2+ in untreated SH-SY5Y cells and cells that had been induced to differentiate with staurosporine was investigated by monitoring fura-2 fluorescence in cell suspensions, and by using microfluorometry and quantitative fluorescence imaging on cell bodies and on cellular processes. Cell bodies of both types of cells displayed small Ca2+ elevations, which were composed of transient and sustained components. Elevations were partially sensitive to the L- and N-channel blockers nifedipine (1 microM) and omega-conotoxin GVIA (100 nM) respectively. Up to ten times Ca2+ elevations were observed in varicosities of treated cells than in cell bodies of treated and cells. These elevations were insensitive to compounds known to release Ca2+ from intracellular stores. Elevations of Ca2+ were sustained, and they were insensitive to 5 microM nifedipine, 100 nM omega-agatoxin IVA and 100 nM omega-conotoxin GVIA, and partially sensitive to 2 microM omega-conotoxin GVIA, indicating predominance of non-L-type, non-N-type, non-P-type channel activity. The intracellular localization of neuropeptide Y, a marker of differentiation in these cells, was also investigated by fluorescence immunocytochemistry. Varicosities of treated cells displayed marked fluorescence when viewed in a confocal microscope. These findings show that the varicosities of staurosporine-treated cells exhibit some of the functional properties of nerve terminals. The varicosities resemble boutons en passant nerve endings and they seem to express Ca2+ channels different from those in the cell body.     

Leukotrienes in renal transplant rejection in rats. Distinct roles for leukotriene B4 and peptidoleukotrienes in the pathogenesis of allograft injury

To investigate the role of leukotrienes in renal allograft rejection, we studied the effects of specific leukotriene inhibitors in a rat kidney transplant model. The enhanced renal production of leukotrienes observed in allograft recipients was reduced in a dose-dependent manner by the specific 5-lipoxygenase inhibitor MK886. This suppression of leukotriene production caused a substantial improvement in renal function. Inhibition of 5-lipoxygenase also reduced the severity of vascular inflammation and endothelial injury in allografts, and profoundly inhibited expression of donor MHC class II Ag on kidney cells. Survival of renal allograft recipients was prolonged from 10 +/- 1 days in controls to 16 +/- 1 days in animals that received a 6-day course of MK886 (p < 0.05). To investigate the relative roles of LTB4 compared to peptidoleukotrienes in these processes, we treated a separate group of animals with the specific peptidoleukotriene receptor antagonist SKF106203. This agent inhibits the interaction of peptidoleukotrienes with their receptor(s) but does not affect the biologic actions of LTB4. In these studies, SKF106203 caused a modest improvement in renal allograft function that was of lesser magnitude than that seen with the 5-lipoxygenase inhibitor. SKF106203 also reduced vascular inflammation in allografts, but had no effect on expression of MHC class II Ag. We conclude that leukotrienes play a key role in the pathogenesis of renal allograft rejection. Furthermore, the detrimental effects of leukotrienes in rejection are mediated by distinct actions of LTB4 and peptidoleukotrienes.