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Biomedical subjects

W C Waltzer

Publications and source records attributed to W C Waltzer.

At least 37 records · Page 2Linked to original sources
PubMed1992

Homing of CD8CD57 T lymphocytes into acutely rejected renal allografts.

This study compares the cellular events in excised rejected renal allografts (RKT), with concurrent data in the peripheral blood (PB) in the same patients. The kidney transplants were obtained from recipients after rejections crises that were refractory to treatment. Two-color flow cytometry data was used for quantitation of cell subset profiles and quantitation of the density of individual lymphocyte surface antigen(s). The level of CD3DR-positive T cells in RKT was significantly higher than in PB. This difference ranged from 3 to 19-fold increases. There was an even more pronounced increase in CD8CD57 cell subset levels in RKT versus PB. In parallel with these findings, there was a 15-fold greater mean density of the CD8CD57 markers on T cells in RKT, when compared with the same cells in PB. The density of CD8 and of DR markers on CD3+ cells was also significantly higher (4-fold in each instance) in RKT. These data point to a homing of CD8CD57 cells with corresponding increases in the density of these markers in acutely rejected renal allografts, with only a relative decrease of this cell subset in peripheral blood. The appearance of a high preponderance of CD8CD57 cells in the renal allograft at the time of a rejection crisis may constitute a particularly severe prognostic sign regarding the reversibility of the response after treatment with steroids and/or monoclonal antibodies.

Acute Disease↗
PubMed1991

Quantitative analysis of surface marker densities after exposure of T-cells to concanavalin A (Con A): a sensitive early index of cellular activation.

The kinetics of expression of activation-linked T-cell surface markers were analyzed in T-cells obtained from normal donors. The cells were cocultured in triplicate for 0, 1, 24, 48, and 72 hr in the presence of Con A in RPMI 1640. The density of HLA-DR, interleukin 2, and transferrin receptors (IL-2-R and TR, respectively) on the surface of CD3- and CD8-positive cells was computed by a mathematical model based on fluorescence intensity vector analysis, adjusted for cell size, utilizing two-color flow cytometry. The results were compared with controls obtained at the same time with control cells cultured in RPMI 1640 alone. There was a significant increase in the mean density of HLA-DR on the surface of CD3- and CD8-positive cells as early as 1 hr after exposure to Con A when compared with controls (250 and 300%, respectively; P less than 0.0001). The mean density of IL-2-R and TR on CD3+ cells increased by 265 and 208%, respectively; P less than 0.06 and P = n.s., respectively, when compared with control cells. The mean density of Class II MHC products on CD3+ and CD8+ cells treated with RPMI alone increased by 202 and 468%, 234 and 540%, and 1375 and 2442%, respectively, at 24, 48, and 72 hr of culture. In contrast, the mean cell surface density of these markers in cells treated with Con A increased by 614 and 1962%, 3304 and 7231%, and 8665 and 22,619%, respectively (P less than 0.00001) at the corresponding times following exposure to Con A. The density of IL-2-R and TR on CD3+ cells exposed to Con A also increased significantly at 24, 48, and 72 hr (P less than 0.0001). At the same times, the relative percentage of cell subsets bearing these particular markers increased by 78, 138, and 175% at 24, 48, and 72 hr, respectively. The data suggest that objective quantitative evidence of lymphocyte activation after exposure to Con A may be obtained as early as 1 hr after antigen stimulation, and before significant changes in cell numbers occur. Measurement of cell surface marker densities may provide a useful index for the detection and quantitation of cell activation in the early phase of antigenic stimulation.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1991

Paradoxical effects of cyclosporine on concanavalin A-induced blastogenesis.

The effects of increasing in vitro cyclosporine concentrations (0, 50 100 or 200 ng./ml.) on lymphocyte blastogenesis, measured by incorporation of tritiated thymidine and induced by varying levels of concanavalin A (0, 0.25, 1.0 or 5.0 ng./ml.), were studied in regard to mean serum level of cyclosporine in 26 renal allograft recipients. Results were compared to similar data obtained in healthy controls. Patients were divided into group 1 (13 patients, mean serum cyclosporine trough level less than 150 ng./ml.) and group 2 (13 patients, cyclosporine level greater than 150 ng./ml.). With no cyclosporine added to the assay proliferation of lymphocytes obtained from all patients inversely correlated to the mean serum trough cyclosporine level at all stimulatory levels of concanavalin A (0.25 ng./ml., p less than 0.01; 1.0 ng./ml., p less than 0.001 and 5.0 ng./ml., p less than 0.001) and was significantly lower than in controls (p less than 0.0002). Whereas increasing in vitro cyclosporine concentrations has produced the expected increase in suppression of blastogenesis in controls and group 1, a paradoxical effect became evident in group 2. Under stronger stimulatory conditions (concanavalin A 1.0 or 5.0 ng./ml.) increasing in vitro cyclosporine concentrations were associated with significantly decreased suppression of blastogenesis (p less than 0.01) compared to group 1. These results confirm previous reports and suggest that the duality of effect of cyclosporine in this in vitro model may be related to its functional relationship to the calcium ion (Ca++)/calmodulin complex and to its cellular concentration/solubility curve. These considerations may be of importance in adjusting cyclosporine dosage based on serum trough levels of cyclosporine.

Cells, Cultured↗
PubMed1991

Prognostic significance of T cell associated surface antigen density changes during OKT3 therapy of renal allograft rejection.

We describe 12 acute rejection episodes in 11 cadaver donor renal allograft recipients who required OKT3* rescue treatment for steroid-resistant acute rejection (9) or for severe vascular (antibody-mediated) rejection (3). There were 3 treatment failures with subsequent graft loss. Using 2-color flow cytometry the total T (CD3), B (DR+), activated T (CD3DR), T helper/inducer (CD4), T cytotoxic/suppressor (CD8) and activated T cytotoxic cell (CD8DR) subsets were analyzed before, in mid course (5 to 7 days) and at the end of 12 to 14 days of therapy with 5 mg. OKT3 intravenously daily. In parallel changes in the density of such T cell associated antigens were analyzed. Significant decreases in the mean levels of the CD3 (p less than 0.001), CD3DR (p less than 0.05), CD4 (p less than 0.05), CD8 (p less than 0.05) and CD8DR (p less than 0.05) subsets were observed at mid course. A significant decrease in the density of CD3 was observed (p less than 0.0001). The surface antigen density of CD3DR, CD4 and CD8 had decreased by 160% (p less than 0.002), 383% (p less than 0.001) and 260% (p less than 0.001), respectively. At the end of treatment CD3 and CD4 subset levels increased by 425% and 240% (p less than 0.001 and p less than 0.005), respectively. In contrast, the CD3DR and CD8DR subset levels continued to decrease (p less than 0.05). A higher pre-treatment level of CD3DR and a less sharp decrease in CD3, CD4 and CD8 subsets were associated with a higher risk of treatment failure (p less than 0.05, p less than 0.01, p less than 0.05 and p less than 0.05, respectively). The mean decrease in the density of the CD3 marker in the lost grafts was significantly smaller compared to successful outcomes (p less than 0.001). The results of this preliminary study suggest that OKT3 affects T cell associated antigens other than CD3. Such may provide a sensitive prognostic index for the effectiveness of OKT3 therapy, and permit the identification of those patients who might require higher doses and/or duration of OKT3 therapy to enhance renal allograft salvage rates.

Antibodies, Monoclonal↗
PubMed1990

Multivariate and Boolean factor analysis of immune complex/complement deposits and their effects on renal blood flow during allograft rejection.

The role of humoral immune factors in graft destruction is not fully understood. With immunofluorescence techniques the possibility of a specific pattern and/or clustering of immune complex or complement deposits was analyzed in 140 percutaneous kidney needle biopsies performed in 73 patients with renal allograft dysfunction. The results were correlated with concomitant alterations in renal blood flow as measured by cortical and global perfusion indexes and graft survival. The deposition of IgG, IgM, C3 and C4 correlated significantly with acute rejection confirmed by biopsy (p less than 0.05, less than 0.001, less than 0.02 and less than 0.001, respectively). Subsequent graft survival was compromised when IgA, IgG, IgM, C3, C4 and properdin were present together in biopsy specimens (p less than 0.05). There was a significant clustering of IgA with C3, of IgG with C3 and C4, and of IgM with C1, C3 and C4 (p less than 0.001). There also was a significant association among alterations in renal blood flow, deposition of IgA (p less than 0.05) and C4 (p less than 0.02), and graft outcome. Higher perfusion indexes, indicative of decreased blood flow, showed significant associations (p less than 0.007 and less than 0.04 for the cortical and global perfusion indexes, respectively) with a greater risk of graft loss. Although it primarily is a cellular event, the data suggest that acute rejection is associated with a deposition of various humoral factors that may mediate alterations in renal blood flow. The latter may affect graft function and structural integrity, and, thus, may show a direct correlation with the outcome of a graft.

Antigen-Antibody Complex↗
PubMed1990

An approach to organ salvage from non-heartbeating cadaver donors under existing legal and ethical requirements for transplantation.

Effective utilization of nonheartbeating cadaver donor organs is limited by the time required to obtain the necessary family consent prior to organ retrieval (a delay of at least 4-6 hr); this exceeds by far the maximum tolerance of kidneys to warm ischemia. Measures that could theoretically permit use of such organs include: (1) rapid in situ flush cooling; (2) continued in situ kidney cooling until permission for donation is secured; and (3) cell-membrane stabilization of vital organs, with only minimal invasion of the donor body. These measures were tested experimentally in dogs. Hemorrhagic shock was produced in mongrel dogs. One hour after cessation of heartbeat, a rapid perfusion tube was placed into the femoral artery; it was advanced, and its balloon was inflated in the aorta above the renal vessels. The kidneys were then flushed in situ with 1000 cc of cold preservation solution containing a calmodulin inhibitor, trifluoperazine. Two other catheters were inserted percutaneously into the peritoneal cavity for continuous intraperitoneal cold perfusion. Core temperatures of 4 degrees C were maintained in situ in the kidneys for 5 hr. Six hours after cardiac arrest, the kidneys were removed and preserved ex vivo at 4 degrees C for 24 hr, and were then transplanted into their respective hosts (n = 11), where they sustained life uneventfully. This method requires a 2-inch incision in the groin of the prospective donor, and two small stab wounds of the abdomen; i.e., semi-invasive procedures which are commonly performed in emergency rooms. The perfused body could then be released to the family if donation is denied. The recently documented increased willingness of the public to donate organs when the termination of life support is not an issue, and court decisions that have authorized the performance of nondeforming diagnostic procedures in cadavers without consent, suggest that the salvage of transplantable semi-invasive procedures described in this study may be useful in helping to alleviate the current shortage of transplantable organs. This technique can provide the time needed for families to consider the option of organ donation from nonheartbeating cadaver donors in an unhurried and unpressured manner, while preserving the viability of vital organs during the decision-making process.

Animal Experimentation↗
PubMed1990

Protective effects of trifluoperazine on the microcirculation of cold-stored livers.

Previous studies have shown a protective effect of trifluoperazine (TFP), a calmodulin inhibitor, upon the microcirculation of cold-stored kidneys. The present study points to similar beneficial effects of TFP on the microcirculation of cold-stored livers; 25 canine livers were preserved for 24 hr with Euro-Collins' solution (EC) (n = 8), University of Wisconsin solution (UW) (n = 7), or UW + TFP (n = 10). The stored livers underwent heterotopic transplantation (HLTX); hepatic-artery and portal-vein pressure and flow were monitored; oxygen consumption and extraction were measured before HLTX and at 15-min intervals after reperfusion, for 1 hr. Mean hepatic-artery and portal-vein flow (HAF & PVF) prior to donor hepatectomy were 172 and 530 cc/min, respectively. Poor HAF and PVF occurred in EC-HLTX (mean 35, 175 cc/min, respectively). The damaged EC-flushed livers could not compensate to the decreased hepatic blood flow by increased oxygen extraction (oxygen consumption and extraction, 8.7 vol.% and 48%, respectively). Light and electron microscopy showed severe liver necrosis and periportal hemorrhages. Improved hepatic-artery and portal-vein flows were seen in UW HLTX (105 and 254 cc/min), and oxygen consumption and extraction were 16.4 vol.% and 66%, respectively. Liver biopsy taken just before reperfusion revealed well-preserved liver architecture. Liver biopsy obtained 1 hr after reperfusion revealed marked edema of the portal triad, sinusoid congestion, and hemorrhage. Electron-microscopy biopsies obtained during reperfusion at 15-min intervals revealed severe vasospasm of the terminal hepatic arterioles and progressive damage to the liver microcirculation. The addition of TFP to the UW-flush solution resulted in excellent protection of the liver microcirculation. Marked increase in hepatic-artery and portal-vein blood flow was noted after reperfusion (mean 167 and 421 cc/min, respectively (P 0.02 vs. UW: P 0.001 vs. EC). The recovery of metabolic activity was evident by the high oxygen consumption and extraction (25.8 vol.% and 80%, respectively). And serial liver biopsies obtained after reperfusion have shown excellent protection of liver architecture and the absence of hepatic arteriolar vasospasm. Taken together, these data suggest that the addition of TFP to the UW solution protects the liver microcirculation by rendering the hepatic microcirculation insensitive to vasospastic stimuli during reperfusion, thus permitting better metabolic recovery after transplantation.

Adenosine↗