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Biomedical subjects

F Sanfilippo

Publications and source records attributed to F Sanfilippo.

At least 109 records · Page 6Linked to original sources
PubMed1989

Association of chronic thromboxane inhibition with reduced in situ cytotoxic T cell activity in rejecting rat renal allografts.

The development of allospecific cellular immunity during acute rat renal allograft rejection parallels alterations occurring in arachidonic acid metabolism, including increased production of the vasoconstrictor eicosanoid thromboxane A2 (TxA2). We have previously demonstrated that chronic inhibition of thromboxane synthetase is associated with improved renal allograft function as well as significant reductions in renal production and urinary excretion of Tx metabolites. In this study, we evaluated the effects of chronic administration of the specific Tx synthetase inhibitor OKY-046 on in situ and systemic alloimmune effector cell function. PVG (RT1c) strain rats were transplanted with fully allogeneic ACI(RT1a) kidneys, and intrarenal artery infusion of OKY-046 (50 micrograms/mg/min) or its saline vehicle was begun at the time of surgery utilizing an osmotic pump. Four days following transplantation, spleen cells and inflammatory cells eluted from the graft were tested. The frequency of antidonor precursor cytotoxic T cells (pCTL), as measured by limiting dilution assay, was consistently lower in allografts from OKY-046-treated animals (1/3146-1/5160) compared with vehicle treatment (1/661-1/1878), while no difference in pCTL ranges were seen in splenocytes from both groups. However, following short-term culture (10-15 days, lymphocytes from treated and control allografts were equally proficient in specifically lysing donor targets. Proliferative response to donor stimulators measured by mixed lymphocyte reaction assays were consistently greater in spleen cells than allograft eluate cells for both groups, but there were no significant differences between OKY and vehicle groups in terms of either splenocyte or allograft eluate proliferative responses. Immunohistologic labeling and flow cytometric analysis of renal allograft infiltrates showed similar percentages and distributions of immune cell populations in treated and control groups. These results suggest that Tx inhibition is capable of temporarily reducing cytotoxic T cell function in the local environment, which may partially account for the improved graft function seen.

Animals↗
PubMed1988

Human suppressor T cells induced in vitro with an autologous renal allograft-derived T cell line. I. Suppressor cell induction, function, and specificity.

The functional characteristics of T suppressor (Ts) cells generated from the peripheral blood lymphocytes (PBL) of a kidney transplant recipient who had excellent graft function for 1 year were examined. Ts cells were induced by co-culture of PBL with an autologous alloreactive cytotoxic T lymphocyte (CTL) line (EE-1) previously grown from a routine renal allograft biopsy of this patient performed 10 days posttransplant. The EE-1 line included CD3+ T cells of CD8+ and CD4+ phenotypes with cytotoxic specificity for disparate class 1 (HLA-B8) and class II (HLA-DR1 and 3) antigens of the kidney donor (JC). The EE-1 induced Ts cell lines (designated TsEE) were found to significantly suppress (50%-95%) autologous fresh responder EE-PBL stimulation by donor EBV-transformed cells (JC-EBV) in mixed lymphocyte reaction (MLR) assay. TsEE cells were CD3+ (98%) and predominantly CD8+ (68-80%), showed no cytotoxic activity, and were suppressive only at the early phase of MLR stimulation. In three-party cell test MLR assays, TsEE-mediated suppression appeared restricted to responder cells sharing HLA-B7 with the suppressor line, and was not abrogated by the addition of exogenous interleukin-2 (IL-2). TsEE cells also showed restricted suppression of CTL generation but not mature CTL activity. The restricted suppressor activity of TsEE lines was dependent upon their induction and restimulation with the autologous EE-1 line.

Adult↗
PubMed1988

Evidence that pretransplant donor blood transfusion prevents rat renal allograft dysfunction but not the in situ cellular alloimmune or morphologic manifestations of rejection.

The effects of preoperative donor-specific blood transfusion (DSBT) on the physiologic, morphologic, and immunologic aspects of allograft responsiveness were evaluated in a rat renal transplant model, using the ACI (RT1a) into PVG (RT1c) high-responder strain combination. Indefinite graft survival (mean greater than 63 days) could be induced by DSBT administration alone. In comparison, animals receiving autologous blood transfusion (ABT) all died within 7 days posttransplantation. As assessed by clearance of inulin and paraaminohippurate, renal allograft function in DSBT-pretreated recipients at 6 days was equivalent to that of isograft recipients, and in contrast to the significant reduction seen in ABT treated rats. Likewise, thromboxane B2 (TXB2) production by ex-vivo-perfused allografts from DSBT-treated recipients was comparable to that of isografts, and significantly lower than that of allografts from ABT-treated rats. A significant inverse correlation was found between renal TXB2 production and inulin clearance. Despite these substantial differences in renal function and eicosanoid metabolism, morphologic evaluation of renal allografts from DSBT-enhanced and ABT-rejecting recipients at comparable time points showed equivalent histologic manifestations of rejection. In addition, immunohistologic labeling of renal allograft sections and fluorescence-activated cell sorter analysis of cells eluted from allografts showed the same phenotype and pattern of infiltrating T cell subsets in both groups. Specific antidonor cytotoxic T lymphocyte precursor (pCTL) frequencies of cells eluted from kidney grafts were equivalent in DSBT and ABT-pretreated animals, and both groups expressed significantly higher (but equivalent) pCTL frequencies in the kidneys than spleens. Comparisons of the lysis of PVG.R1 (RT1.Aa on a PVG background) and ACI targets indicated that cytotoxic responses from effector cells freshly eluted from DSBT and ABT kidneys were primarily directed against allogeneic class I major histocompatibility complex (MHC) specificities, whereas several long term T cell lines generated from 6-day kidney transplants of both groups expressed a predominant W3/25+ (T helper) phenotype and cytotoxic activity against donor specificities other than RT1.Aa class I MHC. Specific antidonor proliferative T lymphocyte (pPTL) precursor frequencies of cells eluted from renal allografts were also equivalent for both DSBT- and ABT-treated recipients, and the range of pPTL frequencies for allograft cell eluates was similar to that in spleens, regardless of the source of the transfusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Associations between cyclosporine therapy and interstitial fibrosis in renal allograft biopsies.

A retrospective masked study of 120 consecutive renal transplant biopsies was performed to evaluate the potential associations of cyclosporine (CsA) therapy and other factors on the degree and progression of interstitial fibrosis (IF). Allograft biopsies were obtained from patients receiving CsA (CsA+; n = 59) and not receiving CsA (CsA-; n = 46); pretransplant donor biopsies were used as controls (n = 15). IF was evaluated by histologic grading (0-3+) as well as by quantitative morphometric measurements of Masson's trichrome stain positive material. Other biopsy measurements included the pattern of IF (focal, diffuse; graded 0-3+), and tubular epithelial cell reactivity, necrosis, and vacuolization (each graded 0-3+). Potential confounding variables were also considered, including time interval between transplant and biopsy; creatinine levels at the time of biopsy, 2 weeks and 10 weeks postbiopsy, and the last stable (baseline) creatinine prior to biopsy; recipient age, clinical evidence of rejection, and duration of rejection reactions; transplant number; and postbiopsy graft outcome. No significant difference in any measure of IF was found between all CsA+ vs. CsA- patients, although both groups showed a highly significant increase in IF compared with control pretransplant donor biopsies. Similarly, no differences in tubular changes or the patterns of fibrosis were identified between CsA groups. However, since the mean interval between transplant and biopsy was significantly (P less than 0.04) greater for the CsA- group, measures of creatinine and IF were normalized by the time interval between transplant and biopsy, and were stratified into biopsies obtained before or after 6 months posttransplant. By this stratification and normalization, both the baseline creatinine (P less than 0.01) and the degree of IF as measured by morphometry (P less than 0.04) were significantly higher in the CsA+ group, but only for biopsies obtained greater than 6 months posttransplant. Evaluation of biopsies less than 6 months posttransplant normalized by interval showed no suggested differences between the CsA+ and CsA- groups in terms of creatinine levels or any measure of IF. Tubular epithelial changes were not different in the CsA+ and CsA- groups within either period. These results suggest that CsA therapy is not associated with increased interstitial fibrosis in renal allografts prior to 6 months posttransplant, after which there is a significant increase in fibrosis relative to patients not receiving CsA.

Biopsy↗
PubMed1988

Organ sharing for good HLA-A,B, and DR matching improves cadaver renal graft survival in SEOPF: retrospective and prospective studies considering delayed graft function, race, center effects, cyclosporine, and other factors.

1. HLA matching is associated significantly with factors including CsA use, ALS use, recipient race, prior graft loss, presensitization, preservation time and most strongly, with organ sharing. However, HLA match is not directly associated with delayed graft function. 2. By univariate and multivariate analyses, good HLA matching provides significant benefits in graft survival regardless of CsA use, organ source or other potentially confounding factors. 3. HLA-A,B, and DR matching have independent and essentially equivalent benefits on graft survival in CsA-treated patients, whereas HLA-A,B matching has a greater benefit in non-CsA-treated patients. 4. Organ sharing, per se, provides no direct detrimental effect on graft survival by univariate or multivariate analysis. 5. By multivariate and univariate analyses, shared/well-matched kidneys provide significantly better graft survival than local/poorly matched kidneys. 6. Delayed graft function is associated in a complex relationship with organ sharing, prior graft failure, presensitization, and CsA use. 7. The increased rate of delayed graft function associated with organ sharing is overcome by the benefit of good HLA matching. 8. Since April 1986, purposeful organ sharing at SEOPF centers for good HLA matching has been associated with improved graft survival, especially in patients at high risk due to presensitization or prior graft failure.

Actuarial Analysis↗
PubMed1987

Hepatic transplantation into sensitized recipients. Demonstration of hyperacute rejection.

Hepatic transplantation into humorally presensitized patients has occasionally been performed without reported accelerated rejection. To study survival of orthotopic hepatic transplants in sensitized recipients a series of studies in rats were performed. Lewis rats sensitized by three successive skin grafts from fully allogeneic ACI strain donors then underwent orthotopic hepatic transplantation from ACI donors. Nine of ten recipients died within 4 hr with bleeding from the liver surface. By comparison, nine unsensitized recipients survived a mean of 10.7 +/- 0.5 days before succumbing with cellular rejection. Death of the sensitized recipients was not due to coagulopathy or technical failure. Histological studies of hyperacutely rejected livers demonstrated marked hemorrhage, edema, congestion, and necrosis within the hepatic parenchyma. There was a relative lack of cellular infiltrate compared with livers rejected by unsensitized recipients. Immunofluorescent staining showed IgG bound to perivascular tissues and sinusoids, and complement bound to perivascular tissue. Serum from presensitized, but not control, recipients showed a high titer of donor-specific, complement-dependent cytotoxic activity. It is concluded that hyperacute rejection of hepatic transplants can occur in sensitized rats and is mediated by a humoral mechanism. The immunohistopathology of this process is described.

Animals↗
PubMed1987

Infiltrating cell phenotypes and patterns associated with hepatic allograft rejection or acceptance.

The association of inflammatory cell infiltration with orthotopic rat liver transplant rejection was studied by immunopathologic evaluation of allografts at different time points using high- and low-responder strain combinations. PVG(RT-1c) recipients of ACI (RT-1a) liver transplants had prolonged survival (greater than 100 days) without immunosuppression. In contrast, Lewis (RT-1l) recipients of ACI liver transplants had severe acute rejection with mean survival of 10.7 +/- 0.5 days (n = 9). Graft recipients of both strain combinations, as well as control syngeneic PVG-to-PVG and Lewis-to-Lewis graft recipients were sacrificed at various time points posttransplant. Sections of livers were evaluated in a masked fashion for histologic changes as well as the extent and phenotype of cellular infiltrates, as determined by immunoperoxidase labeling using monoclonal antibodies OX1 (pan leukocyte), W3/13 (pan T cell), W3/25 (T helper cell:Th), and OX8 (T cytotoxic-suppressor:Tc-s). The results suggest that: the intensity and relative distribution of rat hepatic allograft T cell infiltrates at a given time point do not necessarily correlate with eventual outcome; the intensities of W3/25 (Th) and OX1 (pan-leukocyte) cell infiltrates parallel each other in both high- and low-responder strain combinations; the relative ratio of T cells (W3/13) to non-T cells increases over time in low-responder strains but remains relatively constant in high-responder strains during active rejection; and the relative ratio of W3/25:OX8 (Th:Tc-s) decreases in high-responder strains but increases in low-responder strains.

Animals↗
PubMed1987

Immunopathologic patterns of cyclosporine deposition associated with nephrotoxicity in renal allograft biopsies.

Using antibody directed against cyclosporine (CsA-Ab) in an avidin-biotin-complex immunoperoxidase technique on routine formalin-fixed tissue specimens, 46 renal biopsies from CsA-treated renal allograft recipients and 23 biopsies from non-CsA-treated patients were examined to identify staining patterns potentially associated with CsA nephrotoxicity (CsA-NT). All specimens were examined independently in a masked fashion by two pathologists for the intensity of (CsA-Ab) specific staining for each of the four distinct patterns identified: diffuse interstitial staining (DIS, 0-3+); fine granular staining of tubular epithelium (FGS, 0-3+); coarse granular staining of tubular epithelium (CGS, 0-3+); and dark cellular staining of mononuclear inflammatory cells (DCS, 0-3+). Based on standard clinical criteria all CsA-treated patients were categorized according to the degree of CsA nephrotoxicity (grades 1-4). Significant differences in the intensity of CsA-Ab labeling were found for three of the four immunohistologic grading patterns (DIS, FGS, DCS). For the DIS and FGS patterns, cases with clinical evidence of moderate-severe CsA-NT (grades 3 and 4) had significantly higher average staining than either the slight-mild CsA-NT cases (grade 1 and 2) or the control cases (grade 0). The DCS pattern demonstrated significantly more staining in the moderate-severe CsA-NT cases than in the controls. The sum of individual scores for the DIS, FGS, and DCS immunohistologic pattern (CsA index) was also significantly higher in the moderate-severe CsA-NT cases (3.57 +/- 0.44) than in either the controls (1.73 +/- 0.23, P less than 0.05) or the slight-mild CsA-NT cases (1.98 +/- 0.27, P less than 0.05), demonstrating a specificity of 78% for identifying moderate-severe CsA nephrotoxicity. The extent of infiltration by Leu 2 (CD8; T cytotoxic-suppressor phenotype) positive cells was not significantly different between the moderate-severe versus the slight-mild CsA-NT outcome groups. However, when CsA index values were used in combination with the intensity of Leu-2-positive cell infiltrates to predict CsA-NT (CsA-treated patients with high CsA-Ab staining as well as low levels of Leu-2-positive infiltrate) the specificity for identifying moderate-severe CsA-NT was 96%. These results suggest that CsA labeling of renal allograft biopsies may be useful for identifying CsA-NT, especially when considered with the nature of inflammatory cell infiltration.

Biopsy↗
PubMed1987

The effect of first cadaver renal transplant HLA-A, B match on sensitization levels and retransplant rates following graft failure.

Data were collected retrospectively on all 449 first-transplant cadaver renal allograft recipients transplanted at four centers between 1/1/78 an 12/31/82 who had graft failure by 1/1/85. A total of 383 of these patients had information available regarding subsequent disposition. Of these, 182 (47.5%) were placed on an active waiting list for retransplantation. There were no associations found between placement on a waiting list and the following variables: panel reactive antibody (PRA) prior to first transplant or subsequent to graft failure, recipient age at first transplant or at the time of graft failure, recipient race, PRA after first graft loss, or HLA-A, B match of the first transplant. When stratified by level of HLA-A, B match as poor (0-1 antigen, n = 150) or good (2-4 antigens, n = 233) the poorly matched recipients as a group had a significantly lower mean PRA prior to first transplant (9.4 +/- 1.6 vs. 15.5 +/- 1.7, P less than 0.01), but a significantly higher PRA within the first year following graft failure (48.1 +/- 4.8 vs. 36.2 +/- 3.2, P less than 0.04). In addition, the poorly matched (vs. well-matched) group had a significantly higher mean increase in PRA following graft failure (45.1 +/- 4.4 vs. 33.7 +/- 3.5), and a significantly higher percentage of patients with PRA level greater than or equal to 60% within a year after graft failure (40% vs. 25%). Of the 182 patients who were placed on a waiting list, 113 (62.1%) were regrafted. As a group, regrafted patients had a significantly lower PRA within the first year following graft failure compared with the group not regrafted (33.6 +/- 3.9 vs. 54.0 +/- 5.0, P less than 0.002). Patients with a good first transplant HLA match had a higher overall regraft rate compared with those with a poor match (70.0% vs. 50.0%, P less than 0.01). Likewise, the percentage of well-matched patients regrafted within two years of first graft failure was significantly higher (55.5% vs. 32.5%, P less than 0.02). By multivariate analysis using the Cox proportional hazard model with 13 separate variables and considering all patients, the relative risk (RR) of not being regrafted was significantly (P less than 0.012) associated with poor HLA-A, B matching of the first transplant (RR = 1.7).(ABSTRACT TRUNCATED AT 400 WORDS)

Follow-Up Studies↗
PubMed1987

Identification of donor factors predisposing to high discard rates of cadaver kidneys and increased graft loss within one year posttransplantation--SEOPF 1977-1982. South-Eastern Organ Procurement Foundation.

From 1977 to 1982, the South-Eastern Organ Procurement Foundation (SEOPF) conducted a prospective study to determine the fate of all cadaver kidneys retrieved by member institutions. During the study period, 6152 kidneys were retrieved, 1264 being discarded. Donor factors predisposing to wastage included AB and A blood groups, donor age greater than 30, hospitalization greater than 3 days, serum creatinine greater than 2.0 mg%, average systolic blood pressure less than 80, last-hour urine output less than 100 ml, proteinuria, heart not beating at time of nephrectomy, and kidneys not removed en bloc. Donor factors affecting graft survival rate at one year include age, length of hospitalization, last-hour urine output, and changing serum creatinine. The data suggest that certain donor kidneys are less likely than others to be transplanted depending on donor characteristics and retrieval practices. Furthermore, some of these factors have a negative impact on long-term success when kidneys are transplanted.

Adolescent↗