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Biomedical subjects

R M Ferguson

Publications and source records attributed to R M Ferguson.

At least 73 records · Page 4Linked to original sources
PubMed1994

Differential effects of gallium nitrate on T lymphocyte and endothelial cell activation.

The immunosuppressive agents used clinically to prevent allograft rejection exert their effects by interfering with antigen-dependent T cell activation, endothelial cell function, or both. Gallium nitrate (GN) is immunosuppressive both in vitro and in vivo, and has potential for clinical use in transplant recipients. Therefore, we analyzed the influence of GN on gonadal vein endothelial cell (GVEC) and T cell activation. GVEC were stimulated with IFN gamma or TNF alpha in the presence or absence of GN, and tested for changes in levels of MHC class I, MHC class II, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 expression. GN did not interfere with the baseline or cytokine-enhanced expression of these molecules. Rather, it increased the expression of intercellular adhesion molecule-1 on GVEC, and this effect was further augmented in the presence of IFN gamma. In contrast, GN inhibited T cell proliferation stimulated by allogeneic GVEC or allogeneic monocytes in a dose-dependent manner. In transwell experiments, GN blocked the induction of MHC class II expression on isolated GVEC caused by alloactivated T cells, but not by recombinant IFN gamma. This suggests that GN can interfere indirectly with inflammatory responses of endothelial cells by interfering with local T cell activation and lymphokine production. Once lymphokines are produced, GN does not interfere with their effects on endothelial cells. GN is thought to act through transferrin receptors, but GVEC, unlike T cells, do not increase their expression of transferrin receptors, after stimulation with cytokines. This may explain their relative lack of sensitivity to GN. In general, GN appears to stimulate endothelial cells but suppress T cells. This paradoxic effect suggests that therapy with GN may enhance T cell-independent inflammatory responses, such as cellular infiltration and repair of tissue damage, while suppressing T cell-dependent responses, such as T cell-mediated tissue destruction and allograft rejection.

Antineoplastic Agents↗
PubMed1994

The frequency of rejection episodes after combined kidney-pancreas transplant--the impact on graft survival.

The recipients of combined kidney-pancreas transplants (SPK) are unique because they routinely receive two allografts from the same donor. In a previous study, we found that the long-term graft survival of the two allografts was different, with better graft survival seen in the pancreas allograft. In an attempt to understand the reason for the different graft survival in the recipients of organs from the same donor, we have reviewed the incidence and timing of rejection episodes in 160 consecutive technically successful whole-organ bladder-drained SPK performed at a single institution using a uniform immunosuppressive regimen. Rejection episodes were common. A total of 53% of the recipients had at least one episode of rejection in one of the organs. Multiple rejection episodes requiring hospitalization occurred in 23% of the recipients. The kidney allograft had more frequent rejection episodes than the pancreas allograft: 78 patients had 130 renal rejection episodes while only 50 patients had 65 episodes of pancreas rejection. No rejection episodes occurred in 111 pancreas and 82 kidney grafts (P = 0.0014). Multiple rejection episodes were three times as common in the kidney grafts (20%) than in the pancreas grafts (6%; P = 0.0001). The timing of the first rejection episode was also different. The median time to the first kidney rejection episode was 29 days compared with 39 days to the first pancreas rejection episode (P = 0.0191). Graft survival in the organs was equal when stratified by the number of rejection episodes (none, one, > one) per organ (P = 0.9378). These data suggest that the worse long-term kidney graft survival seen in SPK recipients is due to the greater risk of rejection (relative risk: 2.04; [95% conf. interval: 1.29-3.23]) and a greater frequency of rejection episodes of rejection episodes in the kidney (0.81/patient) compared with the pancreas (0.41/patient). The implications for patient management and the possible reasons for the different rates of rejection are discussed.

Adult↗
PubMed1994

Transmission of hepatitis C by kidney transplantation--the risks.

The use of cadaveric organ donors with positive serologic tests for hepatitis C (HCV) has caused considerable debate. We have reviewed the clinical course of 43 EIA1 HCV-negative recipients who received kidney transplants from EIA1 HCV-positive donors (Study). We have attempted to define the rate of HCV-RNA transmission and to determine the frequency of HCV disease transmission as determined by abnormalities in liver function tests. Viral transmission was assessed using serologic assays for HCV antibody formation (EIA1, EIA2, and Matrix--an automated multiple antigen immunoblot assay) and with PCR testing for the presence of HCV-RNA on recipient sera. Liver function was followed longitudinally in the Study patients and compared with a group of 103 kidney recipients of organs from EIA1 HCV-negative donors (Control). Of the Study patients, 56% became PCR-positive for HCV-RNA, suggesting the transmission of HCV-RNA from the HCV-positive donor. Interpretation of serologic tests for HCV was complex. Currently available first (EIA1) and second (EIA2) generation serologic assays were always negative. The multiple antigen immunoblots assay (Matrix) had a high positive predictive value (93%) for the presence of HCV-RNA transmission, but one-third of Matrix-negative Study patients were PCR-positive (sensitivity = 66%). Currently, only 38% of recipients have HCV-RNA, suggesting that the virus may have been cleared by one-third of Study recipients who had circulating virus. Traditional tests of liver function (ALT, AST, AP, and GGT) were of limited use in predicting HCV-RNA transmission. Average AST, AP, and GGT were similar in the two groups. Average ALT was increased (93 I/U and 47 I/U) in Study and Control patients, respectively, but this difference was not significant. Episodes of abnormal liver function (ALT 60-99 IU for > or = 14 days) occurred in 22% of Study and 10% of Control patients (P = NS) and lasted longer in Study compared with Control patients (301 vs. 138 days; P < 0.02). Hepatitis (ALT > or = 100 IU for > 14 days) occurred with an equal frequency (6.5%) in both groups. The presence of HCV-RNA did not predict episodes of abnormal liver function. Fulminant hepatitis or rapidly progressive cirrhosis did not occur in the recipients of organs from HCV-positive donors. These data demonstrate a high efficiency of transfer of HCV-RNA by kidney transplantation from an HCV-positive donor to an HCV-negative recipient. A majority of the patients have asymptomatic HCV infection.(ABSTRACT TRUNCATED AT 400 WORDS)

Cadaver↗
PubMed1994

Alloantigenicity of human endothelial cells. IV. Derivation, characterization, and utilization of gonadal vein endothelia to control endothelial alloantigenicity during lymphocyte-endothelial interactions.

Most previous studies to evaluate endothelial cell-T lymphocyte interactions have used human peripheral blood as a source of T lymphocytes and human umbilical vein endothelial cells as a source of endothelia. Implicit in this experimental system are allogeneic lymphocyte-endothelial interactions, which are largely ignored. To overcome this problem, we isolated gonadal vein endothelial cells (GVEC) along with matched splenic macrophages and T lymphocytes from cadaveric donors, thus providing a completely autologous series of cells for experimentation. First, GVEC were analyzed for morphology, surface phenotype, and cytokine mRNA expression, and found to be indistinguishable from human umbilical vein endothelial cells. Using this system, we observed that irradiated GVEC were able to promote a 2- to 3-fold increase in the proliferation of matched autologous splenic T cells after PHA stimulation. This indicates that the costimulator activity of endothelial cells reported by others is an intrinsic property of endothelial cells, and is not a consequence of endothelial alloantigens. We also used this system to assess the relative abilities of GVEC and macrophages obtained from the same donor to stimulate the proliferation of purified allogeneic CD3+ PBL. We found the following hierarchy of alloantigenicity in this experimental system: splenic macrophages > IFN-gamma-treated GVEC >> untreated GVEC = TNF alpha-treated GVEC. These studies demonstrate that allogeneic macrophages are intrinsically more antigenic than endothelial cells derived from the same donor. Furthermore, they illustrate the utility of this experimental system to obtain data regarding lymphocyte-endothelial interactions that are otherwise unobtainable.

Base Sequence↗
PubMed1994

Renal transplantation in older people.

Renal transplantation in people 60 years old or more is controversial due to the morbidity associated with immunosuppression and the scarcity of renal allografts. We have reviewed the outcome of 1222 consecutive renal transplants done at a single institution with a uniform immunosuppressive protocol over 10 years. 5-year graft survival was the same in the under sixties as in the sixties and over. Patient survival was worse in the older group (p = 0.0001), but there were significantly fewer immunological graft losses: 11% vs 31% (p = 0.0009; relative risk [RR] = 0.36 [95% confidence interval 0.19-0.66]). A majority of the deaths in both groups were secondary to cardiovascular disease, not due to complications of immunosuppression. We conclude that renal transplantation in people 60 and over has results equivalent to a younger population. Age 60 and over should not be a major factor in considering if a patient is eligible for renal transplantation.

Adult↗
PubMed1994

Pancreas transplantation and dysuria.

Bladder drainage of the pancreatic graft remains the most common technique in pancreatic transplantation. Graft and patient survival is superior to duct injection and bowel drainage techniques. However, several urological complications develop as a result of bladder drainage. We report 6 cases of the dysuria syndrome after combined kidney/pancreas transplantation. Retrograde urethrography or cystoscopy showed extravasation from the bulbous urethra in all cases, which was most likely caused by activated proteolytic exocrine enzymes from the transplanted pancreas. Minor urethral trauma due to Foley catheterization or cystoscopy may predispose patients to this syndrome. Short-term urethral catheterization or suprapubic catheter drainage led to resolution in all cases. A high index of suspicion coupled with early intervention is recommended for patients with the dysuria syndrome.

Adult↗
PubMed1994

Xanthogranulomatous pyelonephritis in renal allografts: report of 2 cases.

We report 2 cases of xanthogranulomatous pyelonephritis that occurred in renal transplant recipients. Both cases were successfully treated with antibiotics. The traditional treatment of choice has been nephrectomy. No graft was lost as a result of xanthogranulomatous pyelonephritis and no nephrectomy was required in either patient. The course of these 2 patients is discussed and literature on this disease is reviewed.

Female↗
PubMed1994

Alloantigenicity of human endothelial cells. II. Analysis of interleukin 2 production and proliferation by T cells after contact with allogeneic endothelia.

In organ allograft recipients, the first point of contact between the host immune system and the graft alloantigens is the graft vascular endothelia. Our previous experiments have established that there are multiple pathways by which T cells can be activated in vitro by endothelial alloantigens. In this report, we focus on the first of these pathways: the direct activation of T cells by endothelial MHC class I molecules. Using conventional mixed cell cultures and limiting dilution analyses, we demonstrate that "resting" allogeneic human umbilical vein endothelial cells (HUVEC) stimulate IL-2 production, but not proliferation of purified CD3+ PBMC. Transwell experiments demonstrate that soluble suppressive factors are not responsible for the lack of proliferation. Instead, they suggest that the production of growth factors, such as IL-2, is suboptimal in this system. Indeed, submitogenic concentrations of IL-2 synergize with HUVEC to induce strong T cell proliferative responses. This proliferation is associated with a detectable increase in T cell IL-2R expression, which is not apparent after stimulation with HUVEC or IL-2 alone. In conjunction with previous data, these observations characterize the first direct pathway of endothelia-induced T cell activation. Via this pathway, a small number of CD8+ T cells can be activated by the allogeneic MHC class I molecules displayed by resting allogeneic endothelial cells. This activation results in the elaboration of IL-2, among other things, in concentrations that are too small to promote IL-2R up-regulation, and thus T cell proliferation. Proliferation readily occurs if sufficient IL-2 is available in the environment to overcome this cytokine deficit. These studies suggest that endothelial MHC class I alloantigens are mildly antigenic to a small subset of T cells. However, in an inflammatory environment that is rich in cytokines and growth factors, these endothelial alloantigens may become potent direct stimulators of T cell activation and clonal expansion.

CD3 Complex↗
PubMed1994

Pulsatile kidney perfusion for evaluation of high-risk kidney donors safely expands the donor pool.

Pulsatile preservation of cadaveric kidney allografts allows effective organ preservation and the opportunity to obtain information about the quality of the organ during storage. The use of information obtained by measuring FLOW (ml/min) and renal resistance (mean perfusion pressure/FLOW (ml/min)) while kidneys are undergoing pulsatile perfusion offers quantitative data to determine suitability of an organ for transplant. This may be more accurate than the combination of demographic variables with past and current medical information that has been traditionally used to evaluate donor suitability. We have evaluated 82 kidneys that received a period of pulsatile preservation at our institution. Kidneys were from consecutive donors age > or = 42 years and were stratified into three high risk groups: donor age > or = 60 (48%), the presence of hypertension (52%), and IMPORT kidney (48%). All IMPORT kidneys were obtained through UNOS after the local center considered them unacceptable for transplant and none were 6-antigen match organs. Kidneys were discarded if they failed to have a FLOW > or = 70 ml/min or RR < or = 0.4. Twelve kidneys (15%) failed to meet these criteria and were discarded. All 12 kidneys were from donors age > or = 60 (p = 0.002). The average FLOW and RR of transplanted kidneys was 103 ml/min and 0.3283 respectively. Six of 69 (8.6%) transplanted organs required dialysis (ATN). No pump parameters predicted the development of ATN although 5 of 6 kidneys were IMPORTs. Recipient outcome data, including 72-hour urine output and day 10 serum Cr, were affected by organ risk group, but these did not impact on patient care.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1994

Antibody depletion prolongs xenograft survival.

BACKGROUND: The lack of human organ donors has prompted a renewed interest in xenotransplantation. Xenoantibody is believed to be an initiator of a complex cascade of events ultimately ending in rapid xenograft destruction. METHODS: Cell-free plasma was obtained via plasmapheresis of the recipient canine. This plasma was then perfused in an ex vivo fashion through either the donor (pig) spleen or liver, allowing for specific antidonor antibody deposition in the "screening" organ, and is then returned to the animal. A porcine kidney is then transplanted to the dog, and the outcome is observed. RESULTS: We have used specific antibody depletion to prolong xenotransplant survival. In the untreated pig-to-dog combination, the transplanted pig kidney is destroyed by the dog in 13 minutes (mean). Adsorption using either the donor spleen or liver resulted in an increase of 3.4 hours and 7.8 hours of graft survival, respectively. The histologic picture of rejected kidneys after adsorption shows a modified form of rejection. CONCLUSIONS: In this pig-to-dog xenograft combination, xenoantibody adsorption allows for prolonged graft survival as compared with control animals. Subsequent xenograft destruction occurs but in a modified manner.

Adsorption↗