Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance.

BACKGROUND: Experimental and epidemiologic investigations suggest that alpha-tocopherol (the most prevalent chemical form of vitamin E found in vegetable oils, seeds, grains, nuts, and other foods) and beta-carotene (a plant pigment and major precursor of vitamin A found in many yellow, orange, and dark-green, leafy vegetables and some fruit) might reduce the risk of cancer, particularly lung cancer. The initial findings of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study) indicated, however, that lung cancer incidence was increased among participants who received beta-carotene as a supplement. Similar results were recently reported by the Beta-Carotene and Retinol Efficacy Trial (CARET), which tested a combination of beta-carotene and vitamin A. PURPOSE: We examined the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of lung cancer across subgroups of participants in the ATBC Study defined by base-line characteristics (e.g., age, number of cigarettes smoked, dietary or serum vitamin status, and alcohol consumption), by study compliance, and in relation to clinical factors, such as disease stage and histologic type. Our primary purpose was to determine whether the pattern of intervention effects across subgroups could facilitate further interpretation of the main ATBC Study results and shed light on potential mechanisms of action and relevance to other populations. METHODS: A total of 29,133 men aged 50-69 years who smoked five or more cigarettes daily were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), alpha-tocopherol and beta-carotene, or a placebo daily for 5-8 years (median, 6.1 years). Data regarding smoking and other risk factors for lung cancer and dietary factors were obtained at study entry, along with measurements of serum levels of alpha-tocopherol and beta-carotene. Incident cases of lung cancer (n = 894) were identified through the Finnish Cancer Registry and death certificates. Each lung cancer diagnosis was independently confirmed, and histology or cytology was available for 94% of the cases. Intervention effects were evaluated by use of survival analysis and proportional hazards models. All P values were derived from two-sided statistical tests. RESULTS: No overall effect was observed for lung cancer from alpha-tocopherol supplementation (relative risk [RR] = 0.99; 95% confidence interval [CI] = 0.87-1.13; P = .86, logrank test). beta-Carotene supplementation was associated with increased lung cancer risk (RR = 1.16; 95% CI = 1.02-1.33; P = .02, logrank test). The beta-carotene effect appeared stronger, but not substantially different, in participants who smoked at least 20 cigarettes daily (RR = 1.25; 95% CI = 1.07-1.46) compared with those who smoked five to 19 cigarettes daily (RR = 0.97; 95% CI = 0.76-1.23) and in those with a higher alcohol intake (> or = 11 g of ethanol/day [just under one drink per day]; RR = 1.35; 95% CI = 1.01-1.81) compared with those with a lower intake (RR = 1.03; 95% CI = 0.85-1.24). CONCLUSIONS: Supplementation with alpha-tocopherol or beta-carotene does not prevent lung cancer in older men who smoke. beta-Carotene supplementation at pharmacologic levels may modestly increase lung cancer incidence in cigarette smokers, and this effect may be associated with heavier smoking and higher alcohol intake. IMPLICATIONS: While the most direct way to reduce lung cancer risk is not to smoke tobacco, smokers should avoid high-dose beta-carotene supplementation.

CSF oligoclonal bands, immunoglobulins, and viral antibodies in progressive myoclonus epilepsy.

We studied CSF and serum samples from 16 patients with progressive myoclonus epilepsy (PME). These patients had juvenile-onset PME with evidence of autosomal recessive inheritance and no Lafora bodies. Twelve of the 16 patients with PME had immunologic abnormalities. Oligoclonal gamma bands were seen in six of the eight patients from whom sufficient CSF was available. The CSF albumin and serum/CSF albumin ratios were normal in all 16 patients, indicating the presence of intact blood-brain barriers. Six of the 16 patients showed increased CSF IgG levels and five had an increased CNS IgG synthesis. All patients had normal serum and CSF IgM and IgA levels. Three patients, all with bands, had reduced measles and/or vaccinia serum/CSF antibody ratios. The findings suggest altered immune response of the CNS of some patients with PME apparently caused by nonspecific immunostimulation.

Herpes simplex virus encephalitis: new diagnostic and clinical features and results of therapy.

Six patients with herpes simplex virus (HSV) encephalitis underwent diagnostic and clinical evaluation. The HSV or its antigenic material was found in three brain biopsy specimens. In the remaining three cases, the diagnosis was supported by detection of HSV antibodies in the CSF. Cell count and total protein concentration in the CSF reached a maximum level at three weeks and two months, respectively. The IgG index and HSV antibody level in the CSF often remained constant after reaching maximal values. In three patients, a transient low serum sodium level was observed. Characteristic EEG changes were present five to 11 days after the onset of symptoms. Computerized tomographic scanning revealed a temporal low-density lesion. Three patients became deeply comatose and had respiratory failure. The patient without vidarabine therapy and one of the five patients treated with vidarabine died.

Relationship of serum selenium and antioxidants to plasma lipoproteins, platelet aggregability and prevalent ischaemic heart disease in Eastern Finnish men.

In a cross-sectional population study of 1132 unselected Eastern Finnish men aged 54 years, serum selenium concentration had a weak positive association with plasma HDL cholesterol (standardised partial regression coefficient, beta = 0.061, P = 0.019) and a fairly strong inverse relationship (beta = -0.223, P less than 0.001) with the extent of ADP-induced platelet aggregation. Neither plasma ascorbate concentration nor alpha-tocopherol to total cholesterol ratio had any association with plasma lipoproteins, platelet aggregability or prevalent ischaemic heart disease (IHD). When a covariance-correction was applied, men with ischaemic ECG findings at exercise had a lower mean serum selenium than others (81.5 micrograms/l vs. 85.9 micrograms/l, P less than 0.01 for difference). This difference was equally large for men with neither symptoms nor previous diagnosis of IHD.

Bronchoalveolar lavage fluid findings following radiotherapy for non-small cell lung cancer.

PURPOSE: To evaluate the diagnostic potential of bronchoalveolar lavage fluid analysis in radiation-induced lung injury. METHODS AND MATERIALS: Thirty patients with inoperable non-small cell lung cancer received either high-dose hyperfractionated radiotherapy or radiotherapy and interferon, a potential radiosensitizer, or radiotherapy and N-acetylcysteine, a potential radioprotector. Bronchoalveolar lavages were performed before and immediately after radiotherapy, and thereafter 6-8 weeks and 3 months after radiotherapy. Total and differential cell counts were measured from the bronchoalveolar lavage fluid samples. Urea measured in serum and in bronchoalveolar lavage fluid was used to calculate epithelial lining fluid. The concentrations of protein and phosphatidylcholine, the major surfactant phospholipid, in epithelial lining fluid were measured. The extent of radiation-induced lung injury was assessed from computed tomographies performed before radiotherapy, and 6-8 weeks and 3 months after radiotherapy. RESULTS: More patients in the interferon-arm developed radiation pneumonitis than did patients in the other groups, but no significant differences in alveolar fluid indices were noted between the groups. When all the patients were studied together, radiation was shown to have induced a significant relative increase of lymphocytes in bronchoalveolar lavage fluid 6-8 weeks and 3 months after the end of radiotherapy. The concentration of phosphatidylcholine in epithelial lining fluid decreased significantly 6-8 weeks and 3 months after treatment. The increase in protein concentration in epithelial lining fluid reached a statistically significant level 6-8 weeks after radiotherapy. CONCLUSION: Analysis of bronchoalveolar lavage fluid predicts the degree of radiation pneumonitis; however, radiology remains to be "the gold standard."

Inhaled recombinant interferon gamma in patients with lung cancer: pharmacokinetics and effects on chemiluminescence responses of alveolar macrophages and peripheral blood neutrophils and monocytes.

PURPOSE: A Phase I trial was conducted to investigate clinical toxicity, pharmacokinetics, and chemiluminescence (CL) responses of alveolar macrophages (AM) and peripheral blood neutrophils and monocytes after inhalation of recombinant interferon (r IFN)-gamma. METHODS AND MATERIALS: Eight patients with lung cancer inhaled r IFN-gamma as single doses of 0.1, 0.2, 0.6, 1.8, or 5.4 mg. Bronchoalveolar lavage was performed three times, 21 h before as well as 3 and 27 h after inhalation. RESULTS: Interferon-gamma was detectable in bronchoalveolar lavage fluid (BALF) samples taken 3 h after inhalation in doses of > or = 0.6 mg. Before inhalation, AM in four out of seven patients studied showed vigorous lucigenin-enhanced CL responses to N-formyl-methionyl-leucyl-phenylalanine and opsonized zymosan particles. Furthermore, the responses were markedly increased 3 h after inhalation. In three out of seven patients, AM in the pretreatment BALF samples showed low or no CL responses, and the responses did not increase after inhalation of IFN-gamma, suggesting that the patients were anergic. Postinhalation CL responses did not correlate with the dose of IFN-gamma inhaled. Circulating IFN-gamma was detected in one patient receiving the highest dose. No changes referable to IFN-gamma inhalation were found in the CL responses of blood neutrophils and monocytes. During the 24 h follow-up, two patients developed transient fever-reactions. CONCLUSIONS: The findings suggest that inhalation may provide a way to increase alveolar concentrations of IFN-gamma and to augment respiratory burst capacity of AM without any major side effects. This approach may have clinical implications for the treatment of tumors and infections of the respiratory tract.

Histological chronic allograft damage index accurately predicts chronic renal allograft rejection.

Chronic rejection has emerged as a major problem in renal transplantation, and clinical trials for prophylaxis and therapy are underway. Use of graft and patient survival as endpoints in prophylactic studies requires long follow-ups to read the endpoint. There is also an obvious need for a starting point for intervention studies. Previously, we formed a histological chronic allograft damage index (CADI), based on numerical scoring of histological alterations compatible with chronic rejection. Using protocol core needle biopsies of 89 functioning grafts 2 years after transplantation and a follow-up of 6 years, we demonstrate now that (a) the CADI at 2 years correlates significantly (r = 0.717, P = 0.0001) with transplant function at 6 years, and (b) that the CADI at 2 years reliably (P = 0.001) predicts the patients who will proceed to clinical chronic rejection later. As protocol core biopsy is an early predictive parameter for chronic rejection, our results suggest that a protocol core biopsy (at 2 years or possibly even earlier) should be included in all clinical investigative protocols dealing with chronic renal allograft rejection.

Elevated cerebrospinal fluid CD4+/CD8+ T cell ratio in myasthenia gravis.

The proportions of CD2+, CD4+ and CD8+ lymphocytes were determined with the 3-layer indirect immunoperoxidase technique in the cerebrospinal fluid (CSF) of 31 patients with myasthenia gravis (MG) and 21 control subjects without autoimmune or central nervous system (CNS) diseases. None of the MG patients were using immunosuppressive drugs and all were thymectomized shortly after CSF sampling. Analysis of the reference population showed that the percentage of CD4+ lymphocytes and accordingly the CD4+/CD8+ T cell ratio is normally higher in CSF than in peripheral blood (PB). Compared to the controls, the mean percentage of CD4+ lymphocytes and the mean CD4+/CD8+ ratio in CSF were significantly higher in MG patients. In addition, the CD4+/CD8+ ratio was elevated in the CSF of 15 MG patients (48%) as a result of an elevation in the proportion of CD4+ and/or a decrease in CD8+ T cells. Among MG subjects the mean proportion of CD4+ lymphocytes was higher in the CSF of patients with also an elevated number of enlarged stimulated lymphoid cells in their CSF, which implies that these lymphocytes are often of the CD4+ phenotype. The percentage of CD4+ T cells in CSF was significantly higher in MG patients with a hyperplastic thymus or a thymoma than in those with an involuted thymus. Neither in MG patients nor in the reference population could an association be observed between CSF and PB lymphocyte subsets. In the controls this suggests that immunologic events of the CNS are normally not directly reflected in PB.(ABSTRACT TRUNCATED AT 250 WORDS)

Histological alterations in implant and one-year protocol biopsy specimens of renal allografts.

BACKGROUND: The natural course of histological changes and their correlations with clinical parameters have not been studied in large numbers in renal allograft specimens. The aim of this study was to determine whether any histological alterations developed during the first posttransplantation year. Immunological and nonimmunological factors possibly associated with subsequent histopathological changes and development of chronic rejection were also assessed. METHODS: We studied 102 cadaveric kidney allografts for which both implant and 1-year protocol biopsy specimens were available. The chronic allograft damage index (CADI) was used to quantify the extent of histological changes that developed during the first year. RESULTS: Overall, an increase in histological alterations were seen during the first posttransplantation year, and the CADI increased significantly. The mean CADI was 0.7 in relation to implant biopsy samples and 2.9 in relation to 1-year biopsy samples (P<0.05). Although the degree of changes increased during the first posttransplantation year, they were seldom severe. Significant increases in incidences of interstitial inflammation and fibrosis, tubular atrophy, and basement-membrane thickening were seen. Vascular intimal proliferation and glomerular mesangial matrix increase and glomerular sclerosis were also noted. In contrast, anisometric vacuolization in the tubular epithelium decreased significantly in incidence during the first year. CADI values 1 year after transplantation were significantly affected by donor age, occurrence of acute rejection episodes, and prevalence of HLA-DR mismatches. CADIs were also significantly higher in grafts with decreased function. CONCLUSIONS: Histopathological alterations increased in almost every graft, even well-functioning grafts, during the first year. The CADIs relating to alterations seen in cases of chronic rejection increased significantly and were strongly affected by both immunological and nonimmunological factors.

Monitoring of bone marrow transplant recipient liver by fine-needle aspiration biopsy.

Acute graft-versus-host disease (aGVHD) of the liver was studied with fine-needle aspiration biopsies of thirty-four bone marrow transplant recipients. White cell differentials of liver FNABs and simultaneously taken blood samples were performed, and the increment and corrected increment methods were used to quantitate the inflammatory reaction in the liver. Biopsies taken before transplantation were used as the baseline. During aGVHD, the percentage of lymphoid cells and monocytes increased in the liver. The appearance of immunological blasts, together with a high proportion of activated lymphocytes in the FNABs, were typical findings during aGVHD. In patients with apparent prolonged liver graft-versus-host disease small lymphocytes were the predominating cell type. After initiating corticosteroid treatment, the number of blasts and the proportion of activated lymphocytes decreased. There was no significant difference in the proportions of CD4- and CD8-positive lymphoid cells in FNABs during or after aGVHD.

Fine-needle aspiration biopsy in the monitoring of liver allografts. I. Correlation between aspiration biopsy and core biopsy in experimental pig liver allografts.

We have used allogeneic pig liver transplants to investigate the structure of inflammation in acute liver allograft rejection. An inflammatory episode of acute cellular rejection was observed in 9/10 allografts in nonimmunosuppressed recipients, when monitored with simultaneous fine-needle aspiration biopsies (FNAB) and core needle biopsies (NB). The intensity of inflammation in FNAB was quantitated using the corrected increment method and correlated with NB findings. In FNAB, all inflammatory episodes were detected on the 4th day after transplantation with lymphoid blast and lymphocyte infiltration, later accompanied by monocytes and macrophages. Maximal intensity of inflammation was recorded in FNAB on day 14. In NB, histology demonstrated distinct inflammation in the portal area on day 4. The predominantly lymphocytic infiltration, also containing varying numbers of plasma cells, eosinophils, neutrophils and macrophages, reached its maximum 7-14 days after transplantation. With the indirect immunoperoxidase technique, lymphoid cell subpopulation analysis of FNAB demonstrated an increase of both T4 and T8 cells during rejection. The T4/T8 ratio was first low, and increased at the beginning of the episode, on day 4, but decreased again on days 7 and 14. The number of B cells in the graft was also elevated during rejection. The cellular changes in the corresponding blood specimens followed approximately the same lines, although the changes were less prominent. NB immunohistology, using immunoperoxidase and frozen sections, correlated well with FNAB results, and demonstrated a T4 predominance in the portal area on day 4 but a T8 predominance on days 7 and 14. In addition to lymphoid cells, macrophages/granulocytes were also frequent in the portal area and scattered in the parenchyma on days 7 and 14. An additional inflammatory cell component in liver allograft rejection, detectable only in the NB, was eosinophils in the portal area, recorded in maximum on day 14. Taken together, the inflammatory changes in the FNAB and NB were similar, and time-related changes of cellular infiltrate in FNAB and NB correlated closely.

Induction of HLA class II antigen and interleukin 2 receptor expression in acute vascular rejection of human kidney allografts.

The induction of HLA class II antigens on graft tubular cells and IL-2 receptor expression on the infiltrating lymphoid cells was studied in 245 prospective aspiration biopsies taken during the first posttransplant month from 20 human renal allografts with histologically verified acute vascular rejection (AVR). Based on the histological findings, the specimens were categorized into two main groups: biopsies from grafts with features of AVR only, and biopsies with a combination of AVR and acute cellular rejection (ACR). Also in the second group the AVR findings were predominant. Biopsies were further divided into two subgroups, depending on whether the rejection was reversible or irreversible. Evaluation of class II and IL-2R expression was done by indirect immunoperoxidase staining using monoclonal antibodies. The initial posttransplant tubular cell class II expression was low in all 20 grafts, with 5-15% positive tubular cells, and IL-2R expression was negative. All 13 grafts with a combination of AVR and ACR displayed class II induction, closely correlating to the blast response, with 50% positive tubular cells on days 2-7 after the onset of rejection, and declining thereafter back to prerejection level in grafts with reversible rejection. In grafts with irreversible rejection, tubular cell class II expression remained elevated. A similar pattern was observed with regard to IL-2R expression: the IL-2R positive cells disappeared from the grafts with reversible rejection, but they persisted in the irreversible rejections. The same pattern of class II and IL-2R expression was observed in grafts with pure AVR and reversible rejection. Instead, completely different findings were seen in grafts with pure AVR and irreversible rejection: there was neither class II induction on tubular cells nor IL-2R expression on lymphoid cells. The persistant inflammation was dominated by mononuclear phagocytes, and no blast response could be detected during the entire follow-up. These findings demonstrate a close relationship between IL-2R expression and tubular cell class II induction also in AVR, in the majority of cases. On the other hand, the findings in grafts with pure AVR in histology and irreversible rejection suggest that AVR is a heterogenous group of rejections, where different cellular and molecular mechanisms are operating.

Single lung allotransplantation in pigs. A morphologic study of tissue preservation with modified Euro-Collins and fluorocarbon solutions.

In the present study the functional and morphologic effects of two pulmoplegic solutions are evaluated. Single left-lung allotransplantation with ligation of the right pulmonary artery was performed in 15 piglets (13-20 kg). The lungs were preserved after donor prostaglandin E-1 treatment with single pulmonary artery flush with either modified Euro-Collins solution (mECS) (9 pigs) or oxygenated fluorocarbon emulsion (FC-43) (6 pigs) and transplanted after 6-hr storage in cold Physiosol solution. Tidal volumes of 15 ml/kg x fr (18) with 40% inspired oxygen were used for ventilation during reperfusion. Function of the transplanted lung was monitored for 4 hr postoperatively by determining pa CO2 and pa O2 levels from arterial samples and by noninvasive monitoring of end-tidal CO2 values and arterial oxygen saturations. Sequential morphologic changes in pulmonary artery flow surface and lung tissue were studied after 6-hr storage and 4-hr reperfusion, using light, scanning, and transmission electron microscopy (LM, SEM, TEM). There was no mortality. After transplantation the mECS group experienced significant hypoxia and hypercarbia and had low end-tidal CO2 values as signs of defective oxygenation and gas exchange, whereas the FC-43 group was normoxic and normoventilated without disturbed elimination of carbon dioxide. After storage and reperfusion, LM showed signs of increased vascular permeability and reperfusion damage--more evident in the mECS group compared with the FC-43 group--while the lymphoid cell population was more intensely activated in the latter group. Electron microscopy after storage showed good overall preservation of structures in both groups. After reperfusion preservation of pulmonary artery flow surface and lung tissue was estimated to be moderate in the mECS group, whereas it was good-to-moderate in the FC-43 group by SEM (NS). TEM of lung tissue, however, showed significantly better-preserved alveolar epithelial lining in the FC-43 group compared with the mECS group. In conclusion, oxygenated fluorocarbon (FC-43) pulmoplegia gave better functional and morphologic preservation of lung grafts compared with modified Euro-Collins solution.

Fine-needle aspiration biopsy allows early detection of acute rejection in children after renal transplantation.

UNLABELLED: analysis detected rejections often before clinical signs. Half of the patients had increased serum creatinine concentration and 38% had fever at the time of rejection diagnosis. Both signs were present in only 19% of the episodes. A decrease in urine output (>20%) was seen in a third of the episodes. The rejections responded well to oral methylprednisolone (3 mg/kg/day), and lymphoglobulins were needed in only 12% of the episodes. More than 90% of the rejections were completely reversible and no transplant was lost because of acute rejection. CONCLUSION: The results indicate that FNAB is a safe and sensitive method for the diagnosis and follow-up of acute cellular rejection in pediatric recipients of different ages.

Obliterative lesions in a heterotopic bronchial xenograft model--a preliminary study.

BACKGROUND: We further developed our heterotopic pig model of obliterative bronchiolitis to study airway obliteration in xenografts. METHODS: Four domestic piglets each received 40 bronchial xenografts s.c. from a donor lamb. Piglet X was not immunosuppressed. The other animals received daily oral cyclosporine, 15 mg/kg (XC), or SDZ RAD, 1.5 mg/kg (XR), or both (XCR). Five implants at a time were serially removed from each animal during 17 days for histological assessment. RESULTS: In contrast to the grafts of the others, the xenografts of XCR recovered after initial ischemic damage. No epithelial damage (P<0.01) or mural necrosis occurred on day 7. Airway obliteration developed in all, but was significantly delayed in XCR. CONCLUSIONS: Invariably developing airway obliteration in nontreated xenografts was delayed by immunosuppression, making the model useful, especially in testing the efficacy of immunosuppressive drugs in a xenogeneic system.

Immune cells and immunosuppression in a porcine bronchial model of obliterative bronchiolitis.

BACKGROUND: To study obliterative bronchiolitis (OB), we have developed a porcine heterotopic bronchial model. Allografts obliterate within 3 weeks, the immunosuppression cyclosporine (CsA)-azathioprine (AZA)-methylprednisolone (MP) delays OB, but OB is prevented when AZA is switched to 40-0-(2-hydroxyethyl)-rapamycin (RAD). To characterize our model, we studied immune cells under various immunosuppressive conditions. METHODS: The groups studied were autografts (U), allografts (A), and allografts given either CsA-RAD-MP (R), or CsA-AZA-MP (C). The implants were harvested at 3, 7, 10, 14, 21, 30, 60, and 90 days after transplantation. Epithelial damage and obliteration were graded histologically, and the number of CD4, CD8, MHC class II expressing cells, macrophages, and B lymphocytes were counted (mean+SEM)/high-power visual field. RESULTS: In group U, normal epithelium was regained with no obliteration and only few immune cells. In group A, consistent with initially acute ejection, an influx of CD4 (105+23), CD8 (166+23), and class II (92+20) cells was seen up to day 21, when total obliteration preceded by epithelial destruction had already developed. Some macrophages were seen and B cells were scarce. In group R, epithelial damage and obliteration were insignificant, but moderate numbers of CD4, CD8, and class II cells were seen. In group C, epithelial damage and obliteration were only delayed, but the immune cell response was clearly blunted. CONCLUSIONS: In our model, rejection with significant immune cell influx was still active when obliteration was total in nontreated allografts. In immunosuppressed allografts, decrease in the number of immune cells alone did prevent OB. These results support OB being T-cell mediated. RAD may have additional important effects on growth factors and proliferation in prevention of OB.

Is uremia immunosuppressive in renal transplantation?

We have quantitated the impact of post-transplantation uremia on the antiallograft immune response by transplant aspiration cytology. Sixty-four consecutive renal transplants, treated with a similar immunosuppresive regimen, were aspiration biopsied at 2-day intervals during the first 15 days postoperatively. The patients were allocated into three groups on the basis of their serum creatinine level on the 3rd postoperative day: transplants with a delayed onset of function (highly uremic group, serum creatinine level greater than or equal to 600 mumol/liter; 24 cases), transplants with a partially delayed onset of function (partially uremic group, 200 to 600 mumol/liter; 21 cases), and transplants with an immediate onset of function (nonuremic group, less than or equal to 200 mumol/liter; 14 cases). These three groups were comparable in respect to the mean age, sex ratio, number of HLA-ABC mismatches (DR was not typed), number of pretransplant blood transfusions, and underlying diseases. Seventy percent of the transplants in the high uremic group, 60% in the moderately uremic group, and 60% in the nonuremic group underwent an early inflammatory episode during days 0 to 15 post-transplantation. The date of onset of inflammation was not significantly different in the three groups. However, the size and type of inflammation were significantly different: compared with the transplants in nonuremic patients, the total inflammatory response was slightly (P = 0.272) depressed in the transplants of moderately uremic patients and significantly (P = 0.007) depressed in the transplants of highly uremic patients. This depression was attributable to the depression of the blastogenic response: compared with nonuremic patients the blastogenic response was distinctly (P = 0.059) depressed in the moderately uremic group and significantly (P = 0.003) depressed in the highly uremic group. Instead, the frequency of in situ macrophages was the same in the three groups, or moderately elevated in the highly uremic group (P = 0.079). However, the graft survival was only 40% in the highly uremic group compared with 79% in the nonuremic controls and 81% in the moderately uremic patients (P = 0.016). We conclude that post-transplantation uremia partially impairs the antiallograft immune response, but this impairment is so small that other factors, whose nature cannot be explained on the basis of the present results, overrule the effects of uremia on graft survival.

Fine-needle aspiration cytology of liver allografts in the pig.

We have analyzed the inflammatory changes in pig liver allografts and autografts by fine needle aspiration biopsy (FNAB) and correlated the cytological findings with transplant histology and changes in recipient blood. In nonimmunosuppressed piglets (n = 9) the inflammatory episode of rejection occurred promptly, peaked on days 4-7, and thereafter subsided in cases in which the graft was accepted (n = 6). The early inflammatory infiltrate consisted of all major types of inflammatory leukocytes, including T lymphoblasts, B plasmablasts, and plasma cells, lymphocytes and monocytes; macrophages dominated the late inflammatory lesion of irreversible rejection. In piglets that died of rejection (n = 3), the inflammation peaked earlier and the total amount of inflammation, including the frequency of blast cells and mononuclear phagocytes, was higher. These differences were, however, statistically insignificant and not predictive for irreversible rejection. In sham-operated autograft recipients (n = 5) no inflammation was recorded in the graft. Application of cyclosporine (n = 5), significantly suppressed the total inflammation (P = 0.02 and 0.06 on days 4 and 7, respectively) and delayed the peak; in addition, both the blastogenic component (P = 0.08 on day 4) and the mononuclear phagocyte component (P = 0.03 on day 7) were clearly suppressed. These inflammatory changes, recorded by the FNAB, had a close correlation with biopsy histology. On the other hand, determinations of S-ASAT, S-ALAT, and S-AFOS was not correlated with the episodes of rejection, and no characteristic changes were seen in blood cytology during the rejection episodes either.

Long-term graft outcome is not necessarily affected by delayed onset of graft function and early acute rejection.

BACKGROUND: Both acute rejection episodes and delayed graft function (DGF) have been shown to be associated with decreased 1-year renal allograft survival. In our center, the incidence and the intensity of acute rejection episodes have been reduced by cyclosporine-based triple-drug therapy. We have also shown that DGF alone is not a risk factor for long-term graft survival. METHODS: We have now investigated whether an acute rejection episode together with DGF significantly effects long-term graft outcome. This study involved 862 first cadaveric renal allografts and 182 regrafts. RESULTS: The incidence of DGF was 33% after first transplants and 44% after retransplants. The overall incidence of acute rejection episodes was 23% in first grafts and 28% in regrafts. After first grafts, there were no statistically significant differences in graft survival rates and half-lives between the early graft function (EGF) and DGF groups with or without acute rejection. In regrafts, graft survival was significantly higher in the EGF group without acute rejection than in the DGF group with acute rejection. However, if all other causes except chronic rejection were censored, the half-life in the EGF group without acute rejection was 17.3 years in first grafts, and in the DGF group with acute rejection, that number was 11.5 years in first grafts; for regrafts, the half-life was 12.3 years and 6.1 years, respectively. CONCLUSIONS: Acute rejection together with DGF could contribute to initial damage to the graft, and this might lead to later chronic allograft failure. In our study, this effect was evident only in the case of retransplants.

Alloimmune injury preceding airway obliteration in porcine heterotopic lung implants: a histologic and immunohistologic study.

BACKGROUND: Obliterative bronchiolitis (OB), the major long-term complication of lung transplantation, has thus far lacked a good large-animal model. Our goal was to develop such a model on the basis of previous rodent models with tracheal implants. METHODS: Fragments of pulmonary tissue with structures of terminal bronchi were subcutaneously transplanted to four random-bred domestic piglets. Each animal received 10 autograft and 10 allograft implants. The histologic findings were graded from 0 to 3 for implants harvested repeatedly over 2 months. RESULTS: In autografts, partial destruction of the respiratory epithelium and gradual luminal obliteration as well as mild damage to the cartilage and the bronchial wall underwent rapid reversal after initial ischemic injury. In the allografts, epithelial destruction and gradual obliteration were total within 14 days, the difference being statistically significant (P<0.05) in both. The histologic features of the obliterative plug were similar to those of human OB. In the allografts, cartilaginous destruction and pericartilaginous inflammation increased gradually to severe levels, significantly worse than in the autografts (P<0.05). Necrosis and inflammation of the bronchial wall were also more severe in the allografts (P<0.05). CONCLUSIONS: At the end of follow-up, all autografts were vital, whereas the allografts were almost totally rejected and were without native structures. All bronchi in the allografts exhibited accelerated obliteration with histologic features characteristic of human OB, thus providing a model for research into OB and its prevention.